Fatty Acid and Fatty Acid Synthesis Short term allosteric regulation:

Triacylglycerol Metabolism (Primarily Liver)

Rate limiting enzyme
for fatty acid synthesis + Citrate: Active Polymer
Fatty Acids - Palmitoyl CoA (Long-Chain Fatty Acid): Inactive dimer
Occurs in well-fed state
Pyruvate Ketone Bodies Acetyl CoA
- Liver major site
CO2 Short term hormonal regulation
- also lactating mammary gland
Amino Acids + ATP + Insulin (dephosphorylation)
- minor - adipose tissue and kidney
- Occurs in cytoplasm Biotin Acetyl CoA - Glucagon and Epinephrine -> AMPK (phosphorylation)
carboxylase
OAA Acetyl-CoA Long-term regulation (up/down regulation)
High ATP + High carb fat-free diet
Citrate Synthase Malonyl CoA - High-fat diets, fasting, glucagon
Key between
fat and carb
- +
CoA
metabolism (2NADPH + ATP) X n
Isocitrate
Citrate Mitochondria
Dehydrogenase

Cytosol Fatty acid synthase +

- Seven reactions Insulin
CoA Citrate ATP (active dimer)
- CYS residue and ACP
(inactive monomer)
ATP-citrate
Malate Lyase ADP + Pi Overall requires
Dehydrogenase 14 NADPH and 7 ATPs
Malate OAA Acetyle CoA

Malic NAD+ NADH

enzyme H+ Palmitate (16:0) Electron transport
system in the ER involving:
NADPH Fatty acid 1. cytochrome b5
synthesis Modification: 2. (fatty acyl CoA) desaturase
Pyruvate 3. NADPH-cytochrome b5 reductase
x (malonyl CoA) Dietary and Endogenous FAs
Cholesterol
Synthesis Elongation
membranes of ER Desaturation
(Mitochondria - minor pathway Double bonds at positions
- occurs via reversal beta oxid) 5,6 or 9
(Linoleate and linolenate have
TAG synthesis unsat beyond 9, thus
essential fatty acids)
Longer FA
Liver and Adipose tissue Intestinal mucosal cells
(Mammary)
2-Monoacyl glycerol Fat soluble
ATP
DHAP (Glycolysis) ADP Vitamin Unsaturated FA Structure of FA
Glycerol - amphipathic
Glycerol Phosphate
Glycerol (liver) ->90% FA in plasma as fatty acid esters
Kinase TAG (TAGs, cholesteryl esters, phospholipids) in lipoproteins
Lysophosphatidic acid (1Acyl)
Essential fatty acids
Phosphaticid acid (DAG phosphate) - linoleic acid (important precursor to arachadonic)
- if not supplied, arachidonic acid becomes essential in diet
Chylomicron
DAG

TAG
 Adipose Tissue
B-oxidation + Primarily reg by serum free fa levels Odd Chain FA
Mitochondrial Matrix
Insulin (Phosphatase) TAG Free Fatty Acids Propionyl CoA

- Dephosphorylation Binding
16C fatty acid
- TCA Propionyl CoA
Biotin
Oxidation Cycle carboxylase
Hormone Sensitive Albumin FADH2 -> 2 ATP
Acyl CoA dehydrogenase
Lipase MCAD 4 Methylmalonyl CoA
+ Phosphorylation Transport
Methylmalonyl CoA Vitamin B12
Epinephrine (Active protein Addition of Enoyl CoA hydratase Oxaloacetate mutase
kinase) Free fatty acids water
NADH
Succinyl CoA
Glycerol 1 Liver
Skeletal and
Cardiac Muscle Oxidation NADH+H2 -> 3ATP + NAD+
3-hydroxy acyl CoA dehydrogenase
Malate
1 Glycerol cannot be reused -oxidation -oxidation TCA Cycle
- adipose lacks glycerokinase 4 Cleavage Thiolase
-oxidation
- Enters glycolysis, gluconeogensis
or triacylglycerol synthesis Acetyl CoA Gluconeogensis
dicarboxylic Acetyl CoA 14C fatty acid + Acetyl CoA Ketogensis
ketogensis Ketogensis (liver Mitochondria)
Minor pathway for oxidation (in ER) acids
4
-MCAD Deficincy
-> decarb acids found in circulation and urine
ketone
bodies
CO2+H2O + Kreb’s cycle
2 Acetyl CoA
Pyruvate Thiolase CoA
Carboxylase
Acetoacetyl CoA
Fatty acyl CoA synthetase 2 4 MCAD deficiency
(thiokinase) - Most common autosomal recessive enzyme def HMG CoA synthase
Fatty acid + CoASH Fatty acyl CoA - Decreased ability to oxidize 6-10C FA
HMG CoA
- Hypoglycemia during fasting (liver and muscle not utilize FA)
due to high glycolysis HMG CoA lyase

ATP AMP + PPi B-oxidation - Medium chain (8-10C) acyl carnitines excreted in urine
Acetoacetate
NADH
-Dicarboxylic acids found in urine (high omega oxid) spontanous
3-hydroxybutyrate
3 - CK-MM and myglobin CO2 dehydrogenase
Fatty NAD+
Fatty Acyl CoA JAMAICAN VOMITING SICKNESS - unripe ackee fruit Acetone
Acyl CoA - hypoglycin A inhibits MCAD (beta oxidation) 3-hydroxy butyrate
Acyl CoA ( -hydroxy butyrate)
Carnatine 1 - vomiting after ingest, drowsiness (hypoglyc), coma and death Peripheral tissues:
3
- Carnitine - Skeletal and cardiac muscle
CPT-II - Brain
CPT-I 2 2 CPT-I deficiency Ketoacidosis in uncontrolled diabetes
- hypoglycemia and hypoketonemia Utilization of Ketone Bodies
mellitus (Cardiac and Skeletal muscle and Brain)
- Systemic form: Predominantly affects liver
Acyl Carnatine Acyl Carnitine - Very low insulin
Malonyl CoA isoform 3-hydroxy butyrate
- Super active lipoysis in adipose
- serum carnitine levels usually elevated NAD+
- Ketone bodies = weak acids
Translocase 3 hydroxybutyrate
- HCO3- buffer thus acidosis
3 CPT-II Deficiency
- Ketone bodies in urine
dehydrogenase NADH
Fatty Acid Synthesis - cardiomyopathy and myopathic Acetoacetate
Carnitine Carnitine - Resipiration increased (resp comp) Succionyl CoA
- Lipid deposits in skeletal muscle Succinyl CoA:acetoacetate
- prolonged exercise -> myoglobinuria CoA transferase (Thiophorase) Succinate
Outer Mit Inner Mit
and CK-MM levels in serum Acetoacetyl CoA
Thiophorase not present CoA
Present in outer mitochondrial membrane 1 Primary Carnitine deficiency in liver
2 (cytosol side) Increased Ketogensis during Starvation Thiolase
- carnitine uptake into tissues impared
Fatty acid chains shorter than shorter than - transport of long chain FA into Mit impaired 2 Acetyl CoA
3 - B oxidation decreased
1) decreased insulin glucagon ratio,
12 C atoms can cross without carnitine activation of hormone sensitive lipase
or CPT - Hypoglycemia and hypoketonemia 2) Inc FFA = Inc B-oxid due to absence
-> impaired gluconeogensis (pyruvate carboxy) inhibit CPT-I by malonyl CoA
- Systemic car def - ketogensis decreased if liver 3) Inc B-ox = inc NADH/nAD+ and inc ATP Krebs cycle
carnitine deficient. Presents at early age 4) Acetyl CoA stimulates Pyruvate Carbox and pyruvate
- Reduced serum carnitine shunted to glyconeogensis and Inc NADH/NAD+ = malate
*Secondary-> liver disease/chronic renal failure 5) Acetyl Coa shunted towards ketogensis rather than TCA
 Synthesis of Cholesterol
- Requires Acetyl CoA, NADPH and ATP
- occurs in cytoplasm with enzymes in cytosol and ER
- Cholesterol levels carefully regulated Cholesterol
Liver plays central role in cholesterol homeostasis
-Atherosclerosis -> too much plasma cholesterol - Most abundant sterol in body
Sources of liver cholesterol
- gall stones -> too much cholesterol secretion - Synthesis most important in liver,
1) De novo synthesis in liver
- Pyrophosphate helps with solubility intestine, adrenal cortex,
2) Cholesterol synthesized in extrahepatic itssues (HDL)
3) Dietary cholesterol (Chylomicron remnants) reproductive organs
(AH! AH! Her Man Penis Is Disgusting! Go Find Scissors! Let’s Chop!)
Major routes cholesterol leaves liver Functions:
2 Acetyl CoA
1) Secretion of HDL and VLDL 1) component of all cell membranes
Insulin Phosphoprotein Thiolase
2) Free Cholesterol secreted in bile 2) precursor of bile acids
Phosphatase 3) precursor of all steroid hormones
Acetoacetyl CoA 3) Conversion to bile acids/salts
and Vitamin D
HMG-CoA

De
ph
Synthase

os
ph
HMG CoA (6C)

or
Activator (+) Inhibitors (-)

yl
Statins leading to rhabdomyolysis

at
- Statin cause long-term regulation 3-hydroxy-5-methyl glutaryl CoA - glucagon

io
n
through upregulation - cholesterol - interferes with synthesis of IPP and FPP
HMG-CoA 2NADPH HMG-CoA - Statin drugs: e.g. Zocor, Lipitor (competitive inhibition)
- reduced protein (iso)prenylation, dolichol
reductase 2NADP+ reductase - High cholesterol -> downregulation
and ubiquinone
Ph

Increased transcription: upregulation

+ mevalonate (6C)
- os
ph
or
yla
t ion

5-pyrophosphomevalonate (6C) AMP Kinase

Ra
pid
dolichol

de
Nucleus

gre
isopentenyl pyrophosphate (IPP) (5C)

da
Sterol Regulating Element ubiquinone High intracellular

tio
AMP

n
(SRE) on HMG CoA reductase gene

Cholelithiasis - bile salt deficiency

SREBP Binds to

3,3-dimethylallyl pyrophosphate (DPP) (5C)

- deficiency of lecithin and/or bile salts cause cholesterol
to precipitate in gall bladder
Catalysis
Potential causes:
Protein prenylation Ubiquitin Cytosolic domain - malabsorption of bile acids from intestine
-protein modifiction for system - obstruction of biliary tract
membrane integration via geranyl pyrophosphate (GPP) (10C) Sense level of derivatives of
hydrocarbon tail cholesterol and mevalonate - interruption of enterohepatic circulation
- decreased bile production (hepatic dysfunction)
Membrane domain
- accelerated rate of bile recycling
dolichol:
n-linked glycoprotein farnesyl pyrophosphate (FPP) (15c) Proteosome
- Intestinal bacteria can remove taurine or glycine from bile salts
ubiquinone: - Other intestinal bacteria convert primary bile salts into secondary by removing
coenzyme Q synthesis (ETC)
hydroxyl groups
squalene (30C) Intestine - deoxycholic acid and lithocholic acid from cholic acid and chenodeoxycholic acid
Release of
SREBP
ER Glycocholic acid Taurocholic acid
+ +
lanosterol (30C) glycochenodeoxycholic acid Taurochenodeoxycholic acid
Upregulation of LDL
receptor
Low
intracellular Cholesterol (27C) High
More cell surface LDL receptors
(statin treatment) Glycine lts
+ of B
ile s
a
3 % excretion
7- -hydroxylase at i on -major pathway for
Form cholesterol elimination
Increase uptake of LDL from serum
Therefore low serum cholesterol -
Smith-Lemli-Opitz Syndrome (SLOS) Taurine
- 7-dehydrocholesterol reductase partially deficient
Cholic acid + Chenodeoxycholic acid Clinical Significance of Bile acid synthesis
- Autosomal recessive - only significant mechanism for cholesterol elimination
- Needed for correct double bond formation in ring B - solubilize cholesterol thus preventing cholesteral precipitation
- Leads to microencephaly and other embryonic malformation Major primary bile acids
in gall bladder
- Children have IQ of 20-40 - facilitate TAG digestion
- facilitate intestinal absoprtion of fat-soluble vitamins
 Cholesterol and Steroid Metabolism: 1) 3- -hydroxysteroid dehydrogenase deficiency 3) 21- -Hydroxylase Deficiency
- Cholesterol is precursor of five classes of steroids, - Virtually no glucocorticoids, mineralocorticoids, - Most common form of CAH
glucocorticoids, mineralocorticoids, androgens Steroid hormones active androgens, or estrogens - Mineralocorticoids and glucocorticoids are virtually
and progestins - use carrier proteins in blood - Marked salt excretion in urine absent (classic form) or deficient (non-classic)
- Synthesis and secretion in: 1) transcortin for cortisol - Patients have female-like genitalia - Overproduction of androgens leads to masculinization
2) sex hormone binding protein for
1) Adrenal cortex (cortisol, aldosterone) of external genitalia in females and early virilization in men
sex hormones
2) Ovaries and ovarian corpus luteum (estrogens 3) can non-specifically bind albumin 2) 17- -Hydroxylase Deficiency
and progestins) - Virtually no sex hormones or cortisol are produced 4) 11- -Hydroxylase Deficiency
3) Testes (testosterone) - Increased production of mineralocorticoids cause - Decrease in serum cortisol, aldosterone, and corticosterone
sodium and fluid retention -> hypertension - Increased prod of deoxycorticosterone causes fluid retention
Cholesterol used for steroid hormone synthesis suppressing renin/angiotensin system thus causing low-renin
- taken up via LDL, HDL or synthesized - Patients have female-like genitalia
hypertension
- stored as cholesterol ester
- PKA activates cholesterol esterase
- Masculinization and virilization as with 21- -Hydroxylase Deficiency
- transport of cholesterol into mitochondria important regulatory step of cortisol synth
- Performed by StAR (steroidogenic acute regulatory protein)

Cholesterol
NADPH + O2

CYP 11A1 Mitochondrial

Rate-limiting enzyme: (Desmolase)
Desmolase 2 Testosterone
Cholesterol side chain cleavage enzyme - Produced in Leydig cells when LH receptor
CYP 11A1 Pregnenolone CYP 17A1 17-hydroxypregnenolone 17, 20 lyase DHEA increases c-AMP and PKA
- DHT (more potent than Testosterone)
3 -hydroxysteroid 3 -hydroxysteroid 3 -hydroxysteroid produced by Sertoli cells
1 dehydrogenase 1 1
dehydrogenase dehydrogenase - Stimulate spermatogensis
2 - Promotes development of male and
Progesterone:
- Secretory phase of uterus and mammary glands LH
+ Progesterone CYP 17A1 17-hydroxyprogesterone 17, 20 lyase Androstenedione
secondary sex characteristics
- Promotes anabolism
- implantation and maturation of fertilized ovum
Masculinization of fetus
3 CYP 21A2 3 CYP 21A2 17, 20 lyase 17 -reductase Aromatase

Deoxycorticosterone 11-deoxycortisol LH
+ Testosterone Estrone

4 CYP 11B 4 CYP 11B 5 -reductase Aromatase 17 -reductase

Aldosterone:
- Principal mineralcorticoid Mitochondrial Corticosterone
+ Estrogens:
- Control menstrual cycle
ACTH Cortisol Dihydrotestosterone Estradiol
- Raises blood pressure and fluid volume - Promote development of female
- Increases Na+ uptake and K+ excretion CYP 11B2 + P45c11as secondary characteristics
+
Angiotensin II/III
+ FSH
Aldosterone Mitochondrial

Cushing’s Syndrome: Hypercortisolism Z. Glomerulosa Z. Fasiculata Z. Reticularis

- Hyperfuctin of adrenal cortex, usually due to Extra-Adrenal Androgen Prod
adrenocortical tumor DHEA Androstenedione
- High cortisol and low ACTH concetration in plasma Cortisol:
(high cortisol in urine) - Dominant glucocorticoid in humans
- Glucocorticoid excess leads to protein loss and - Involved in stress Androgens: Adipose
- Produced in Z. reticularis and fasiculata Testes
characteristic fat distribution - Needed in adition to glucagon in liver for gluconeogensis Tissue
- Protein breakdown in muscle (counteract insulin) - Mainly DHEA and androstenedione,
- Anti-inflammatory action but some testosterone
- Bound to transcortin (75%) and albumin (15%) Estrogen Testosterone
Addison’s disease: Primary adrenal cortical - Only unbound can enter cells
insufficiency -areas of inflammation, binding to transcortin is reduced
- Adrenal cortex atrophy due to disease- Mostly by - Inhibits PLA2 and COX2 - lower eicosanoids
autoimmune destruction
-Aldosterone and cortisol levels are low, and ACTH is
high, which does not leadto hyperplasia due to
cortex atrophy
 HDL HDL Function
LPL - Extracellular enzyme - Anti atherogenic properties - Rever cholesterol transport
Apo B-48 HDL - bound to capillary walls of - reverse cholesterol using - mobilization of free cholesterol
- synthesized in intestional mucosal cells
Lymph Blood heart, skeletal muscle and 1) apo A-1 from plasma membranes or arterial
- needed for release of chylomicrons into lymph Donates adipose tissue 2) LCAT walls
- structure is 48% of apo B-100 (mRNA editing) CM + apo B-48 - Anchored by heparan sulfate 3) free cholesterol ABC-transporter- delivery as cholesteryl esters to liver
Thoracid apo C-II 4) CETP or steroidogenic tissues
+ Heart LPL Fat tissue LPL - Reduces LDL oxidation
Duct
Intestinal mucosal cell apo E - smaller Km for TAGs - Large Km (high lipopro 1) Paraoxonase
- needs FA even when concentrations) HDL and apolipoproteins
2) PAF acetylhydrolase
apo B-48 plasma lipoprotein - activated by insulin - plaque stabilization properties - 70% apo A-1
CM + Apo B-48 conc. low - Insulin enhances LPL - 30% apo C-II + E
- Dietary TAGs (90% highest of required - reduces plaque lipid content
lipoproteins) LPL - FA mpt stpred but used synthesis and placement - reduce plaque macrophage
- Cleave dietary TAGs for life-long E demand in capillary endothelial - increase plaque smooth muscle Nascent Discoidal HDL
- Cholesterol and cholesteryl
- needs apo C-11 for of heart surface - prevent rupture apo A-1
esters (5%)
activation - released by liver
- Lipid soluble vitamins
- or a transfer of phospholipids
in blood
Type I:
Heart Hyperchylomicronemia
FAs
HDL apoprotein donation to chylomicrons or VLD
Adipose Membrane cholesterol
apo C-II apo E - vascular tissue or other
- activates LPL - Lipoprotein receptor - cholesterol from inner leaflet
recognition LCAT - Esterifies Cholesterol
moved to outside by ABC1
(ATP-binding casette protein-1) - cholesterol - chol ester

HDL Smaller CM Remnants apo A-1 HDL3

Returns
VLDL - mainly dietary cholesteryl esters (activates LCAT) - trapped
apo C-II LDL IDL
- 60% TAGS - some TAGs with dietary FA CE cholesteryl
- 20% cholesterol + CEs - lipid-soluble vitamins Requries CE esters (CE)
CE TAG
- VLDLs + CMs lead to Apo E 70%
high TAGs in blood Donates Specific hepatic 50%
Returns
remnant receptors CE CETP
LDLs
- 50% Chol and CEs apo C-II Liver
- 8% TAGs LPL + - Central organ to handle cholesterol CE
IDL + apo E - Cleaves TAGs apo E - bile acid synthesis and cholesterol CM remnants TAG
HDLs - VLDL remnants - require apo C-II elimination (feces) + apo B-48
- 40% proteins VLDL + - Provide cholesteryl esters to other
+ apo E VLDL
- 25% CEs + Chol Apo B-100 cells via VLDL/LDL
- 30% Phospholipids
Apo B-100
- Synthesized in liver
Apo B-100 needed
for VLDL release
VLDL + Apo B-100 - needed for release of
Also Delivered to
VLDLs in blood steroidogenic tissue
- largest single polypeptide via SRB1
Release of VLDLs from liver allows chain
1) to rid of hepatic TAGs
2) to provide cholesteryl esters for Apo E
other cells inside of LDLs - Different isoforms HDL2
- apo E-3 most common SR-B1
Return via: - binds SR-B1
1) remnant receptor
(75%)
50%
(recognize apo E) Cholesterol ester - Apo E-2 (10%) binds
2) LDL receptor-related poorly to IDL remnant Hepatic
reservoir
Hepatic lipase (HTGL) protein LRP receptor lipase
+
- cleaves TAGs and phospholipids 3) LDL-receptor
(apo B-100/apo E)
in IDLs ACAT
- boundto hepatic capillaries - (fatty) acyl CoA
Taken up by cells which contain LDL + cholesterol transferase
via heparin sulfate
receptors in plasma membrane
- Cells need cholesterol HDL Type IIa: Familia
Opens HDL2 allowing
- once cells fill up, LDL receptor synthesis Hypercholesterolemia High free
apo C-II Cholesteryl esters to enter
stops cholesterol
Returns + the liver
- After cholesterol-rich meal, chylomicron
remnants in liver lead to high free cholesterol SCAP-SREBP complex retained
in ER (SREBP cannot enter nucleus)
levels which reduce LDL-receptor synthesis 70% LDL receptor
leading to high serum LDL LDL + Uptake via endocytosis

- when dietary cholesterols reduced, LDL- apo B-100 - recognize apo B-100 - LDL receptor recycled -
receptor synthesis returns and LDL blood HMG CoA reductase
levels decrease -SREBP (from ER) binds to SRE (nucleus)
- synthesis of LDL receptors
 Lipoprotein (a) or Lp(a) Hyperlipidemias
- similar to LDL but with additional apo(a) Risk factors for Coronary Heart Disease (CHD)
- structure of “kringles” Total cholesterol : HDL ratio >5 - High levels of lipoproteins in serum
- apo(a) - glycoprotein covalently linked to apo B-100 - high LDL : HDL ratio - Hereditary or acquired
via disulfide bond and structural analog to plasminogen - TAG : HDL ratio > 4
- Frederickson Classification (Type 1-5)
- Apo(a) may compete with plasminogen binding to
oxLDL
fibrin thus decreased removal (increase of blood clots
- formed from LDL by oxidation of phospholipids Hypertriacylglycerolemia Hypercholesterolemia
or apoB-100 - Lipoproteins with high TAGS - HIgh lipoproteins with high cholesterol
- (+) Superoxide, nitric oxide, H2O2
- (-) Vit E, Ascorbic acid, B-carotine
(chylomicrons and VLDLs) and cholesteryl esters
- attach macrophage via SR-A (back door) - related to reduced LPL (LDL and lipoprotein remnants)
- converts to foam cell - defective apo C-II - Defective LDL receptors
- fibrofatty atheroma and fatty streaks
- oxLDL accumulate in blood b/c not recognized by
- increase release of VLDL - apo E deficiency
LDL receptor, thus plaque formation Acquired onset associations: Acquired onset associations
- Hypertension - Hypothyroidism
LDL -A and B (bad)
- A large and less dense - Untreated diabetes mellitus - Nephrotic syndrome
- B (bad) small and dense, penetrate endothelium easily - Alcohol abuse - Obstructive liver disease
- B retained by ECM and proteoglycans - Usage of oral contraceptives - Treatment with specific medical drugs
B- can be oxidzed to ox-LDL
-B risk factor for CHD - Hyperuricemia

Type I: Hyperchylomicronemia Type IIa: Familial Hypercholesterolemia

- high chylomicrons in blood after 12-14 hr fast - High LDL with normal VLDL
- genetic deficiency of LPL or apo C-II - Defective LDL receptor (autosomal dom)
- childhood onset - hetero 1:500 Adult, risk of coron disease
- eruptive xanthomas on trunk butt or extremmities - Homo 1:mil, child onset, child MI and death
- creamy layer on top of blood vial - xanthoma over tendon and xanthelasmas
- lipemia retinalis, hepatosplenomegaly, irritability
recurent epigastric pain, increased risk of pancreatitis
Type III: Dysbetalipoproteinemia (rare)
Hyperlipidemia Type IIb: - high remnants: IDL and chylomicron
- Familial combined hyperlipidemia - apo E deficiency
- onset puberty, 1:10 - homozygous for apo E-2
Hypolipidemias
- high LDL and VLDL - complex but similar blood choles to
- uncommon
- very complex (several genes) Type IIa or IIb
- TAG serum level can be elevated
Hypoalphalipoproteinemia
- palmar xanthomas over elbows and knees
- Low serum HDL
- adult onset with accelerated athersclerosis
- related to obesity, smoking, some Hyperlipidemia Type IV (common 1:100)
medical drugs and cholesterol - hyperprebetalipoproteinemia
reducing drugs - High serum VLDL Hyperlipidemia Type V:
- Caused by LPL deficiency or over- - Mixed hypertriacylglycerolemia
Tangier disease production of VLDL - High serum VLDL and high chylomicrons
- hereditary disease - High TAG can lead to pancreatitis - Creamy layer of top on serum
- low serum HDL and coronary
heart disease in childhood
- orange tonsils, corneal opacities
Treatments:
hepatosplenomegaly
1) Statins
- defective cholesterol ABC transporter
- Competitive inhibitor drugs
- leads to less substrate for LCAT and
- Inhibition of HMG CoA reductase
early degen of lipid poor apo A-1
2) Plant stanols and sterols
- displace cholesterol from micelles
Abetalipoproteinemia
during absorption into intestine
- rare
3) Ezetimibe
- low serum VLDL, LDL and chylomicrons
- reduces cholesterol absorption
- defect in microsomal TAG transfer protein
- blocks transporter protein
(MTP)
4) Bile acid sequestering drugs
- MTP needed for formation of VLDL or CM
- bind bile acids/salts in intestine
with interaction with apo B
- less dietary lipid digest
- fat malabsorption
- bile acid/salt excretion in feces
- TAG accumulation in liver and intestine
- low free cholesterol in liver leads
- retinitis pigmentosa
more hepatic LDL-receptor synth
- peripheral neuropathy
- Thus lower serum LDL
 Alanine Metabolism
- Amino group of alanine transferred Glutamate Metabolism
- glutamate and glutamine imp for sources of ammonia Aspartate metabolism Leucine**
- Pyruvate contains keto group Alanine**
- Transamination is reversible for urea cycle - Transamination, aspartate to OAA glucose Lysine**
- Glut DH does Oxidative deamination (need NAD+) - Aspartate used for Asparagine synth Isoleucine Phenylalanine
- Alanine is major transport for amino acid
from muscle (especially during starve) (also reductive amination) - ASN amide deriv of ASP Leucine Tryptophan
-Alanine (pyruvate) major precursor of - Glutamine Synthetase imp for scavenging NH3 from circulation
(imp in brain and endothelial cells of Hepatic vein) Pyruvate Tyrosine
gluconeogensis during starve
- Glucose-alanine cycle involves muscle and liver -Glutamine is non-toxic transport form of NH3
(where alanine is gen to where gluconeogenesis occurs - Renal tissue rich in Glutaminase - acid/base homeostasis Used to treat leukemia Acetyl CoA
Acetoacetyl CoA
by reducin asparagine
(Renal tubule, (peripheral tissues:
level inhibiting tumor
Alanine and liver) Glutamine
very important in brain)
growth Asparagine** OAA
Aspartate**
-Ketogluterate Alanine amino transferase/ Glutaminase Glutamine Asparagine alpha keto
alanine transaminase (ALT) synthetase Glutamate**
Glutamate Asparaginase Asparagine gluterate
Ammonia Ammonia Glutamine**
Pyridoxal phosphate Synthetase
(PLP or B6) Glutamate Ammonia
Fumarate
Pyruvate Glutamine phenylalanine*
Aspartate Tyrosine* succinyl CoA
Glutamate (Liver) imp for most -Ketogluterate
Dehydrogenase transaminase Aspartate
Ammonia
reactions Transaminase (AST)
-Ketogluterate isoleucine
Glutamate PLP Valine
Oxaloacetate
Nitrogen Metabolism
- needed for:
1) growth (protein synthesis)
2) amino acid derivatives
(Creatine, Purines, heme neurotrasmitters
pyrimidines, many others)

Proteosome Deg
Pathway (intracellular) Diff Proteins have Dif T1/2
Tissue protein catabolism
Protein in need Dietary protein
Aged,
of degred damaged (amino acids) Synthesis of non-
oxidative damage Amino acid Amino group comes
protein essential amino acids Transamination
of protein off, or given to another
Poly ubiquitinated or deamination
alpha keto acid
ATP dependant Hydrophobic core -Keto Acid
Tissue Proteins Amino acid pool
denaturation of proteins gets exposed, (Carbon skeleton)
destroy old protein Catabolism/Synthesis (nitrogen pool)
(danger of agglutination) synth new (turnover 400g/day) - no storage form of nitrogen
Proteosome (lysosome and proteosome)
recognize UB UB-chain added to
Pyruvate/TCA Acetyl CoA/
- protein degraded ubiquitination protein, tagging for cycle intermediate Ketone body
to peptide destruction by proteosome Amino acid catabolism Ketogenic amino acid

reabsorption
- ATP dependant
Gluconeogensis
Synthesis of nitrogen - Yields acetoacetate, acetyl CoA
PEST sequence Proteins rich in Pro, Glu, Ser & Thr or acetoacetyl CoA
have shorter t1/2. preferentia UB Carbon skeleton containing compounds: (not gluconeogensis substrate)
UB not recognized Ammonia (toxic) Heme, creatine, Glucose
and destruction
thus recycled neurotransmitters,
Purines, Pyrimidines, Glucogenic amino acid
Glucose/lipid synthesis many others
- catabolism yields pyruvate or TCA intermediate
Urea cycle (gluconeogensis substrate)
Lysosomal protein degredation
- normal degredation of some cell componants
- Digest from phagocytosisLi
- Digest receptor mediated endocytosis (LDL receptor)
- Autophagy
- Extracellular (sperm to fertilize egg, inappropriate
white blood cell lysosome component release and
Liver Hartnup’s disease
- Site where most aa release amino groups as ammonia
joint tissue damage - BAD) Cystinuria (COAL - dibasic) - Defect in transport of neutral amino acid (Tryptophan)
- lysosomal enzymes stain dark red (work in low pH) - Tubuluar reabsorption of Cystine decreased - Decreased tryptophan dietary absorption
Amino acid NH3 (Toxic) (along with ornithin, arginine, lysine) - increased tryptophan excretion
carbon skeletons - inherited deficiency of cystine transporter - Most patients normal
detoxify
- cystine excreted in urine - May lead to NAD+ deficiency (pellagra) - niacin
- cystein precipitates in renal tubules not synthesized from tryptophan
Urea (major end product - renal stones in children (typically with low protein diet lacking niacin - rare)
Gluconeogensis TCA
of N metabolism) 4 D’s (diarrhea, dermititis, dementia, death)

Kidney
- excrete ammonia as ammonium ions NH4+
(regulation of acid base balance)
(Ammonia source -> glutamine, Brush border absprbs AA via secondary
glutaminase enzyme) active transport (kidney)
-Other non-protein nitrogen secreted: -Na+/K+ ATPase
1) uric acid (purine deg) (electrochemical gradient)
2) creatinine - Na+ gradient harnessed by some
3) other amino acid transport systems
(Mostly Urea - 86%)
 PKU Decreased melanin Alkaptonuria
- Autosomal Recessive and relatively common synthesis; tyrosine - relatively benign inborn error
- Developmental delay, seizures, spasticity, autistic behaviors PKU I becomes an - Deficiency in enzyme
hypopigmentation, skin rashes (Classic PKU) essential amino acid - Manifestations:
- Dietary treatment - low protein, no eggs, milk, meat, aspartame 1) Darkening of urine on standing
- tested by tandem mass spec (high Phenylalanine levels) Phenylalanine 2) Discoloration of cartilage and CT
- test infants twice (first may be false negative) Phenylalanine hydroxylase (Ochronotic pigments (ochronosis)
Tyrosine 3) Leads to severe arthritis
(PAH)
PKU I (Classic PKU) (due to oxidation of excess homogentisic acid)
- CNS: low IQ, seizures if blood Phe high (most severe Tetrahydrobiopterin Discoloration: Bluish-black ear, Sclera darkens
Dihydrobiopterin
development seen early in development) (BH4) (BH2)
- Phe to phenylacetate and phenyllactate (mousey urine) Sapropterin
- Phe levels elevated PKU I
Phenylalanine Tyrosine
- Decreased Pig. Blonder Blue eyes Pale skin Dihydrobiopterin reductase
- Treatment: diet or Sapropterin (synthetic form of BH4 Phenylpyruvic acid Dihydrobiopterin
PKU II Synthesis Homogentisic acid
(mild form of disease, may have low affinitity mutant enzyme) Homogentisic acid
(malignant PKU) deposits in cartilage &
Phenylpyruvic acid
connective tissue Homogentisic
Maternal PKU syndrome excreted in urine Alkaptonuria
(ochronosis) acid oxidase
- High maternal blood Phe leads to fetal defects (mousey odor of urine)
(microcephaly, mental retard, congen heart def )
- High Phe leads to teratogenic properties Maleylacetoacetate
- Mom’s fault, typically child is heterozygous Homogentisic acid is several
Sulfer of homocysteine may be transferred excreted in urine (brown steps
to serine to form Cysteine (B6; PLP), and carbon discoloratino of urine)
PKU II (malgnant PKU) skeleton eventually forms Succinyl-CoA (B-12)
- deficiant of one of two enzymes for BH2/BH4 for entry into TCA cycle Fumaryl acetoacetate Tyrosinemia
- more severe CNS (decreased neurotransmitters: seratonin, hydrolase Type I
dopamine, catecholamines) Methionine
- Treatment is diet restriction, biopterin diet and neurotransmitter Homocystein may be recycled Fumerate +
precursors (difficult because BBB) High levels of back to methionine Acetoacetate
(THF & B12)
homocysteine
in plasma & Homocysteine Tyrosinemia Type I
urine
Cystathionine - Buildup of fumaryl acetoacetate
PLP Homocystinuria - INborn error of enzyme deficiency
Disrupts beta-synthase
- Manifestations severe and fatal
connective
tissue 1) Liver Failure
Cystathionine 2) Renal Failure
3) Cabbage like odor of urine
- Dietary restriction of Phe and Tyr may be tried
Branched chain Cystine (Difficult because 2 essential aa must be avoided)
Branched chain
amino acids keto acids - Tyrosine required for NT synthesis (epi, norepi)
MSUD Homocystinuria
Branched chain alpha-keto
- Defect in homocystein metabolism thus
TPP high in plasmaand urine
acid dehydrogenase
Neurological - Deficiency of cystathionine beta-synthase
manifestations Ketosis &
(transulfuration pathway)
maple syrup Coresponding - Homocysteine binds to CT and disrupts structure
odor of urine acyl CoA - Characterized by
1) Dislocatino of lens
(ectopia lentis)
2) Skeletal abnormalties
Maple Syrup Urine disease (MSUD) 3) Mental retardation
- Relatively rare inborn error of metabolism Valine and Isoleucine
4) premature arterial disease (Also Methionine, Threonine,
- Symptoms develop 4-7 days - Some patients respond to oral Vitamin B6 and Odd chain fatty acids)
-detected by neonatal screening
-Presents with poor feeding, vomiting, poor weight gain Homocystinuria interferes with collagen and:
and increased lethargy 1) Lens dislocation after age 3
- Neuro signs develop rapidly: (other ocular abnormalities Propionyl CoA
1) Alternating muscular hypotonia and hypertonia 2) Osteoporosis develops during childhood Methylmalonic aciduria
2) seizures Propionyl CoA - Deficient enzyme resulting in elevated levels of
3) Lipid deposits form atheromas Biotin
carboxylase methylmalonic acid in circ
3) encephalopathy 4) Other effects (lipid oxidation
- Ketosis and characteristic odor present when first and platelet aggregation -> - Metabolic acidosis
symptoms develop leading to fibrosis and Methylmalonyl CoA - Neuro manifestations
- Coma and death of child in early infancy if not recog and treat calcification of Methylmalonic 1) seizures
Methylmalonyl
Treatment by restricting branched chain aa. atherosclerotic plaques acidemia / CoA mutase
Vit B12 2) encephalopathy
(difficult and all 3 BCAA essential and 25% aa are VIL) aciduria - In some children, milder form may manifest
- Dietary Supplementation with TPP (B1) maybe - treatment with B12 (cobalamin)
useful when enzyme has low coenzyme affinity Succinyl CoA (this form has mutant enzyme with
-Tissue catabolism mobilize aa to metabolism reduced affinity for B12 coenzyme)
-Similar to Enzyme similar to Alpha ketoglutarate DH and TCA Cycle
PDH
 Urea Cycle Disorders (UCD) Pyruvate Glutamate
- Urea formation decreased (hyperammonemia) Amino Acids
- symptoms appear during first few days of life
1) Lethargy Gluconeogenesis Glucose
2) Irritability Alanine Alpha-Ketogluterate NH3
NH3 Formation in liver Pyruvate Glutamate
3) Feeding difficulties - From alanine and other amino acids
- Results in Neurological manifestations, seizures and - requires PLP Muscle Tissue
mental retardation Alpha-Ketogluterate NH3
Alanine
Management of Hyperammonemia
1) Dialysis Systemic Circ
2) Benzoic acid (conbines with glycine to form (15%)
Hippuric acid - excreted in urine) Mitochondria
3) Phenylbutyrate - Converted to phenylacetate Activated
- condenses with glutamine Portal circ. by arginine Oxaloacetate
HCO3- + NH4+ + 2 ATP Glutamate
- form phenylacetylglutamine 85%
- excreted in urine Acetyl AST
Rate-
- Removes 2 N per molec. CoA
limiting CPS I NAG
3) Low protein high carb diet L-Aspartate
4) Prevention of stresses inducing catabolic state
Step + Citrulline
5) Long term: Liver transplant Carbamoyl
Colon
Phosphate OTC Orotic acid ATP
CPS 1 Deficiency (Type I Hyperammoniemia)**
excreted in
- Sometimes responds to Arginine intervention urine
(Arg stimulates formation of NAG) NH4+ NH3 AMP
- High levels of NAG might stimulate ASS
Cytoplasm
deficient CPS1
NH3 from gut L-Ornithine
Ureases or Argininosuccinate
OTC deficiency (X-linked) - (Type II Hyperammoniemia)** - Bacterial ureases in colon
Proteases
- Most common UCD - Then goes to gut
- more common and severe in males - With liver disease, ammonia
ASL
- Mitochondrial ornithine transcarbamoylase not detoxified
- Diagnosed by: (Ammonia Toxicity)
1) Elevated serum ammonia UREA
ARG
2) Elevated serum & urine orotic acid Argnine
(orotic aciduria - b/c high carbamoyl phosphate) Fumerate

CPS I +
ASS - Argininosuccinate synthetase deficiency Renal Excretion Urea Cycle
(Feed Forward)
(Classic Citrullinemia) (75%) -Urea contains 2 nitrogen atoms
- Hyperammonemia with very high levels of serum - In liver
citrulline, and citrulline in urine - Partly mitochondrial (2) and Cytosolic (3) TCA or oxidized
Blood Urea Nitrogen - Kidney Failure back to OAA
- Treatment may include arginine - All disorders of UC result hyperammonemia
Elevated Blood Ammonia - Urea Cycle Disorder
(Enhances urinary Citrulline excretion)
(Activate urea cycle b/c excess substrate)
- Also other listed treatments

ASL - Argininosuccinate lyase deficiency Transport of Nitrogen from peripheral tissues

(Argininosuccinic aciduria) - Ammonia neurotoxic
- Differential diagnosis of hyperammonemia Hyperammonemia,
- Transported as Glutamine or Alanine CPS
- Argininosuccinate elevated in plasma & CSF Neurological
- Ammonia not directly excreted in urine manifestations
- moderately high levels of citrulline Acquired Hyperammonemia (direction excretion resulting in
- Arginosuccinate detected in urine - Liver disease due to viral or drug induced large obligate water loss)
hepatitis, alcoholic cirrhosis OTC Hyperammonemia,
- Sometimes treated with surplus of arginine
(x-linked) Increased orotic acid
(urinary excretio not argininosuccinate) - Cirrhosis - porto-systemic shunting of blood (most common) excretion in urine
(May affect Km) - Ammonia produced in intestine directly enters Two hypotheses for mechanism of ammonia
- Treatments listed previously - Results in Neurotoxicity neurotoxicity (unknown) Hyperammonemia,
Treatment: 1) Energy and osmotic effect ASS Increased citrulline
1) Low protein/high carb diet - alpha-ketogluterate to glutamate excretion in urine
ARG - Arginase deficiency (Hyperargininemia) -taking TCA intermediates
- Diff diagnosis: elevated serum ammonia and arginine 2) Lactulose (A disaccharide) - reduced TCA cycle activity Hyperammonemia
(Blood NH3 not as high as other UCD) - resistant to digesting in small intestine ASL Increased arginino
- reduced ATP (your brain needs ATP
- Bact in colon digest to lactic acid
- Treat with diet of essential aa excluding arginine - Reduced Na+/K+ ATPase activity succinate levels
- acid neutralized by NH4+
- Other treatments previously listed -osmotic pressure off and neuronal cell death
- More excreted N in feces
- Significantly Adults affected 2) Reduced GABA and glutamate levels in brain ARG Increased arginine
3) Neomycin (or other antibiotic treatment) - Glutamate converted to glutamine
(associated with neurological problems) (reduction in bacterial ureases) levels
- glutamate needed for formation of GABA
4) other previously discussed treatments - GABA is inhibitory NT
** - 1st two enzymes and most severe hyperammonemia - Glutamine is also major excitatory NT
 Tetrahydrobiopterin deficiency
- Deficiency of dihydrobiopterin synthase or dihydrobiopterin reductase Seratonin Synthesis
- hyperphenylalaninemia and decreased neurotransmitter synthesis - Synthesized in gut,
(catecholamines, serotonin) - results in delayed mental devel and seizures platelets and CNS Carcinoid syndrome
- Management includes dietary tetrahydrobiopterin - Tumor of serotonin producing
Tryptophan
cells in GIT (APUD cells)
Tryptophan
- Cutaneous flushing and sweating
Tetrahydrobiopterin - GI hypermobility -> Diarrhea
BH4 Hydroxylase
Tetrahydrobiopterin Phenylalanine - Bronchospasm
- Coenzyme required for - Increased 5-HIAA in urine
Tetrahydrobiopterin
many AA Hydroxylation Phenylalanine 5 Hydroxy tryptophan - B3 Deficiency
reactions Dihydrobiopterin
reductase Hydroxylase
1) Phenyalanine hydroxylase ( Phe to Tyr) Dihydrobiopterin Cu2+ Amino acid
PLP (Vit B6) decarboxylase
2) Tyrosine hydroxylase (Tyr to DOPA)
Tyrosine Tyrosinase Melanin
3) Tryptophan hydroxylase
Dihydrobiopterin
(Trp - 5-hydroxy tryptophan) Synthesis Tetrahydrobiopterin Tyrosine 5-hydroxy tryptamine
BH4 Hydroxylase Albanism (Seratonin) Melatonin Production
- partrial/complete deficiency of MAO - Sleep inducing hormone
Small
DOPA melanin in skin, hair and eyes modifications - Circadian Rhythm
- Severe form affects eyes 5-HIAA - Light/Dark cycle
DOPA - Deficiency of Tyrosinase enzyme
Parkinsons’s Disease PLP (Vit B6)
Decarboxylase Melatonin - Seasonal Affective Disorder
- Neurodegenerative disorder
- loss of dopamine producing cells
Dopamine
in basal ganglia
- Symptoms improved by administering Dopamine -
Vit C hydroxylase
L-DOPA
- L-DOPA converted to Dopamine in brain
Norepinephrine
S-Adenosyl Phenylethanolamine
methionine (SAM) N methyl transferase
Catecholamine degradation
Epinephrine - Urinary VMA levels must be measured
to estimate epi and norepi produced
Norepinephrine
Dopamine Epinephrine
Glutatione Arg + Gly + SAM Creatine
- Intracellular reducing agent - Reservoir of high energy bonds
(antioxidant) Glutamic Monoamine oxidase Monoamine oxidase
- Found in muscle, cardiac brain (MAO) (MAO)
- Imp for Detox H2O2 especially Acid Creatine H2O
- Synth from Arg, Glyc & SAM
in RBCs ATP - Accepts P when muscle resting Catechol O-methyl Catechol O-methyl
- Conjugated to drugs to make Creatine phospho - Donates P when muscle contracting transferase (COMT) transferase (COMT)
them more water soluble
Cysteine Sulfer Creatinine
kinase (CPK, CK - CPK/CK-MB - MI or ischemia
- Cofactor for some enzymes ADP - Also detect renal failure/kidney function
Glycine Homovalnillic acid (HVA) Vanilly Mandelic acid
- Aid in rearrangement of
Creatine - P H2O, Pi
Excreted in - excreted in urine (VMA) excreted in urine
protein disulfide bonds
Createinine
urine
- Production is spontaneous
- end product of creatine metabolism Pheochyromocytoma: Overproduction of
Catecholamines
- High urinary VMA and catecholamines diagnostic
- Adrenal medulla tumor
Arg - Headache, sweating, tachycardia hypertension
Nitric oxide
NO Synthase - Causes local vasodilation Glutamic Acid
- treatment of MI Histamine
Histidine - produced duringn allergic and
- short half-life Glutamate
Citruline NO PLP (Vit B6)
Decarboxylase inflammatory by mast cells
GABA PLP (Vit B6)
Amino acid
Decarboxylase - Vasodilator
- inhibitory
Guanylate cyclase Gamma amino butyric - Antihistamine drugs ability of
neurotransmitter
acid (GABA) histamine to function as signal
GTP in CNS Histamine
cGMP - Receptor antagonist
GMP

Phosphodiesterase
 LIVER
Postprandial (2-3 hrs post meal) Postabsorptive (5-7 hours)
High insulin/glucagon Low insulin/glucagon
Substrate availability Covalent Modivication by insulin (prevent further drop of blood glucose)
- Glycolysis - Activates protein phosphatases Substrate availability Covalent Modivication by Glucagon
- Glycogen synthesis - dephosphorylation - B-oxidation and Epinephrine
- FA Synthesis - Ketone Body Synth - Protein Kinase A (cAMP)
Enzyme induction by insulin
- Cholesterol synthesis
- Glycolysis (glucokinase, PFK-1,
pyruvate kinase) Enzyme induction by Glucagon
- PPP (glucose 6-P dehydrogenase) - PEP carboxykinase
- FA synthesis (acetyl CoA carboxylase) - fructose 1,6 bisphosphatase
- Cholesterol (HMG CoA reductase) - glucose 6-phosphatase

Blood Glucose FA uptake &

Hormone Release
Acetyl CoA
-VLDLs Synth B-Oxidation
GLUT-2 Insulin Stimulation (+) Glucagon Stimulation (+)
- TAG Synth
- Glycolytic key PPP Pyruvate carboxylase - Glucose - Epinephrine
Glycolysis NADH - Amino acids - Amino Acids
Enzyme Synth Glycogen synthesis ETC (Needs acetyl CoA)
FADH2 - Leucine (dietary essential) - Alanine
- Arginine - Arginine
PDH TCA ETC Glycogenolysis Gluconeogensis Insulin inhibition (-) Glucagon Inhibition (-)
- Epinephrine - Glucose
GLUT-2
Citrate Lyase forms acetyl CoA in cytosol
Stress and Cortisol Release
Glucose Released - Stress activiates ACTH release from pituitary gland
FA Synth Cholesterol synth into blood - ACTH stimulates Cortisol from Adrenal Cortex
Acetyl CoA Carboxylase HMG CoA reductase - Cortisol causes methylation of Norepi and epi (PNMT
dephosphorylated dephosphylated Starvation
using SAM) and release from adrenal medulla.
- glucose into blood by only gluconeogensis
- Epinephrine inhibits insulin release but stimulates glucagon
- Glycogen stores decline after 4-6 Hours
Favored at high very high blood glucose - Empty after about 1 day
levels and following extensive glycolysis - Synthesis and release of Ketone Bodies

Muscle Postprandial Exercising Muscle Skeletal muscle Creatine phosphate

- Insulin - Prolonged exercise or starvation - Requires ability for anaerobic contraction - Reservoir of high energy phosphate bonds
- Glucose uptake (GLUT-4) -> low glucose, so high insulin and -> >1min for increased Cardiac output - Resting muscle
- Glycogen synthesis high glucagon - Lactate produced -> High ATP levels drive synthesis of creatine
- Glycolysis -> FA usage favored -> Used by resting skeletal and heart phosphate
-> HSL activated -> Lactate into Cori Cycle - Exercising muscle
- Amino Acid uptake - Contracting muscle - Glycogen use during anaerobic muscle cont -> Low ATP allow creatine-P to drive synthesis
(protein synthesis) -> Elevated AMP signals AMPK -> 3 ATP rather than 2 ATP of ATP from ADP
-> Overides other signals -> IIB fibers have higher levels of glytolytic
-Usage of Branched-chain -> mobilizes GLUT 4 transporters enzymes to compensate
amino acids -> Glycogen used 12x faster than Type I
-> Glyocogen exhausted < 2min anaerobic

Heart muscle
Muscle Postabsorptive - Continuous active
- Glucagon, Epinephrine and Cortisol - Completely aerobic Ca2+ and AMP glycolysis and glycogen degredation
- Protein degredation - negligible glycogen and lipid
Regulation
- AA release (alanine-glucose cycle) - may use any fuel
- AMP
- Usage of ketone bodies (Energy) - Always dependent on vascular’ ‘
-> stimulates PFK-1
- Usage of FA (Energy) supply (interruption = infarc)
-> Stimulates glycogen phosphoylase b (only in muscle)
- Ca2+
Type I slow Type IIA Fast Type II B Fast
-> stimulates glycogen phosphorylase kinase
Property twitch Oxida ve glycoly c -> full activation of glycogen phosphorylase
ATP Hydrolysis Slow Fast Fast - Epinephrine
Contrac on Speed Slow Fast Fast -> stimulates cAMP cascade in muscle
Glycoly c capacity Low Moderate HIgh -> leads to phosphylation and activation of glycogen
Oxida ve capacity High Moderate Low phosphorylation
Glycogen storage + ++ +++
Appearance Red Red White
-> Epinephrine slower than AMP and Ca2+
Capillary supply Good Moderate Poor
Adipocytes Abdominal White Adipose Tissue Brown Adipose tissue
- 83% total energy - antilypolytic effect of insulin is low - Large # mitochondria
- lipolysis vs. Estereification - Very responsive to epinephrine - Multiple fat droplets (increased SA
-> determines level of FA in blood -> releases more FA and regular cytoplasmic dispersion)
- influences metabolism in other tissue - Extra FA released goes to liver - Thermogenin (UCP-1)
-> i.e. liver, skeletal muscle, heart -> leads to increased VLD -> mitochondrial uncoupler
- Have all enzymes for FA Synth -> 2,4 DNP - “Death Diet Drug”
-> Only minor amount in humans White Adipose - High activity of ETC -> heat production
- distributed throughout ody
- Tissue reclaims mobilized FA
Posprandial -> Limited amount of FA in blood
- Insulin mobilize GLUT-4 - Regulated E storage
- Activate lipoprotein lipase
in capillaries
- Lipogenesis (esterification)

VLDLs Chylomicrons
(Liver De novo) (Diet)
Insulin:
CII + Remnants - Stimulates synthesis
LDL lipoprotein lipase and secretion of LPL
(anchored to capillary) by adipocytes
IDL +
Glucose
FA
Glut-4 +
- Increase
Glycolysis postprandial
FA - Facilitated transport

Fatty Acyl Glycerol 3-P

CoAs

TAG Synthesis

To liver for
- TAG synthesis
- Gluconeogensis
- Glycolysis
Postabsoprtive Albumin
- Epinephrine and Cortisol
- Phosphorylation of HSL (active)
FFA Glycerol
- Importantly Low insulin **

TAG mobilization
- Sympathetic nerv sys
- Muscle activity
TAG Degradation
-> leads to increase circulation
(Hydrolysis)
-> increased E demand
- Type I Diabetes
-> Ketone bodies GLUT-4
-> tissues think body starving - Stored in endosomes
- Elevated cAMP
- Activated PKA

Leptin
- Receptors in hypothalamus AMPK
-> aptetite suppression - Response to low E states
Adipose endocrine gland: - Product of Ob gene - many substrates
- excess adipose -> insulin resistance - Satiation + -> regulates lots of stuff
-> altered adipokine leads to insulin -> obesity not b/c low leptin - Catabolic and Anabolic
leads to insulin resistance
-> hyperinsulemia -> pancrease wears down
-> metabolic syndrome
UCP-2
+
- Absence of adipose tissue -> severe insulin
- Sweaty restaurant effect
resistance
- Energy dissipation
-> Loss of hormonal signals
- Futile cycle
-> Dysregulation of TAG and FA levels
 Odd Chain FA Cobalamin (B12)
Resynthesis of methionine requires B12 Clinical correlations of B12:
Degredation of: and THF - Deficiency causes accumulation of fatty
1) Methionine - From meat Methionine acids - > neurological effects (CNS)
2) Valine - Needed by: THF Required for methylation - Pernicious anemia - (autoimmune
3) Isoleucine 1) Methionine synthase (H4Folate) (CH3) reactions: destruction of parietal cells)
4) Throenine 2) Isomerization of methyl
malonyl CoA (mutase)
or S-Adenosylmethionine 1) Norepi -> Epi - Treatment - lifetime B12 injection
go through this same pathways N,N-dimethylglycine 2) PE -> PC - Can produce megaloblastic anemia
- Require B12 (SAM) - Anemia is reversible
Deficiency of B12 Methionine
3) mRNA methylation
(AA that form Succinyl CoA - Results in accumulation of homocysteine (methyl-G-cap) - CNS effects are not
produce propionyl-CoA first) Vitamin B12 Synthase - Causes of B12 deficiency:
and trapping of THF in methyl-THF form
- Decreases formation of other THF derivatives S- Adenosyl homocysteine 1) Pure vegan diet
Propionyl CoA - Impairs DNA, RNA and nucleotide synthesis N5-methyl 2) chronic pancreatitis (can’t cleave off
(SAH)
H4folate R-factor)
or betaine Vitamin defieicncies associated with 3) terminal ileal disease (Chron’s disease)
Propionyl CoA Biotin
carboxylase Homocystinuria
Homocysteine - Folate + Vitamin B12 - required for homocysteine
N10-Formyl-THF Purines N-methyltransferase (methionine synthase)
D-Methylmalonyl-CoA Cystathionine - Vitamin B6 - required for cysthionine synthetase Hyperhomocysteinemia
THF PLP, B6
Folic acid in Nucleotide and Synthase and cysthionine lyase - deficiency of cystathione synthase
- Vitamin Deficiency resulting in Increase plasma
L-Methylmalonyl CoA Thymidine
Amino Acid Metabolism homocysteine, will damage blood vessels and
- lens dislocation after age 3 (other ocular abnormalities
- Requires 2 NADPH - Osteoporosis during childhood
Cysteine poses a risk for thrombosis - Mental retardation
Methylmalonyl CoA THF
Vitamin B12 - lipid deposits form atheromas
mutase - Lipid oxidation and platelet aggregation -> leads to
Methionine fibrosis and calcification of atherosclerotic plaques
-Produce taurine (bile salt)
Succinyl CoA by cysteine dioxygenase
- Produce PAPS (GAG Synthesis
through prod of Sulfate

PLP, B6 Histamine
Amino Acid
Folic Acid: Folate Deficiency Causes: Decarboxylase
- THF is active form 1) Diet lacking fruit and vegetable Histidine
- Synthesized in bacteria and plants 2) Drugs: Methotrexate (chemotherapeutic)
- essential vitamin in humans trimethoprim (kills blast cells and causes Histidinase
- Important in 1C transfer reactions macrocytic anemia) Histidinemia Amino acid
1) DNA and RNA synthesis 3) Alcohol (block reabsorption of Humans and synthesis
Urocanic Degredation of Microorganisms Glutamate
(purines and thymidine) monoglutamate in jejunum microorganisms
2) Some amino acid metabolism 4) Rapidly-growing cancers (malignant cells acid Histidine requires THF
(glycine <-> serine) use more folic acid) - Deficiency in folic acid PABA
3) Met from homocystine 5) Celiac disease results in high FIGIu in urine + Dihydropteroate Dihydrofolate Purine
6) Sulfa drugs N-Formimino- Folic Acid THF
- Used to diagnose low folic acid Pteridine synthetase reductase Synthesis
glutamate (FIGIu) - Histidinemia due to histidinase
precursor
Serine THF THF deficiency - -
Folic acid Deficiency:
Serine - Most common vitamin deficiency in U.S. Glutamate Thymidine
- Common in pregnant women and alcoholics
Sulfonamides Methotrexate
hydroxymethyl- monophosphate
transferase - reduces risk of neural tube defects - Competatively inhibit folic acid - Comp inhibit synthesis
- Results in homocystinuria and megaloblastic in microorganisms - Folic acid analogue
N5,N10-Methylene-
anemia - treat cancer
Glycine tetrahydrofolate

Megaloblastic anemia Cancer cells can become resistant to MTX by amplification

of gene for dihydrofolate reductase
- First sign of Folate deficiencies - MTX and aminopterin affect any rapidly growing cells
- Hemoglobin levels low and bone marrow - Side effects: anemia, scaly skin, GI tract, respiratory tract
shows abnormally high numbers of disturbances, and baldness
megaloblastic cells (large abnormal
immature erythrocytes
Folate and B12 deficiency Summary
Folate: Vitamin B12
- Megaloblastic anemia - Megaloblastic anemia
- Homocystinemia, - Homocystinemia, increased
increased risk for risk for cardiovascular
cardiovascular disease disease
- FlGlu accumulation - Progressive peripheral
- Deficiency is important in neuropathy
pregnancy, can occur in - Methymalonyl aciduria
alcoholics and - Pernicious anemia, gastric
malnourished individuals resection, chronic pancreatitis,
- Develops in 3-4 months vegan, malnutrition
- Develops in years
 Purine Nucleotide synthesis
Rate limiting step
De novo
- Requires 4 ATP
- All enzymes found in cytoplasm
- Constructing purine ring via PRPP AMP, GMP,
IMP Trimethoprim - Inhibits THF synthesis in prokaryotes
1) Aspartate - N
2) CO2 - C
+ - THF
Aminopterin - less commonly used than methotrexate

3) Glycine - N Glutamine: phosphoribosyl 5’-Phopho- 5’-Phosphoribosyl- Formyltransferase 5’-Phosphoribosyl-

PRPP
4) N10-Formyltetrahydrofolate - C Pyrophosphate amidotransferase ribosylamine glycinamide N-formylglycinamide
5) Glutamine - N -
Mg2+
Purine PABA Analogs:
Pi Ribonucleotides Glutamine Glutamate - Block these steps by impairing THF synthesis
+ H2O + PPi
+ - 1) Sulfonamides - Prokaryotes
2) Methotrexate - Humans (used to treat leukemia)
Ribose PRPP
PRPP
5-Phosphate Synthetase
5’-Phosphoribosyl 4-
- 5’-Phosphoribosyl 4-
Mg2+
Cyclohydroxylase carboxamide- Formyltransferase carboxamide-
GDP GTP 5-formamidoimidazole 5-aminoimidazole
ATP AMP
THF
5-phosphoribosyl-1-pyrophosphate (PRPP) Adenylo- Adenylosuccinate IMP Xanthosine
- production necessary before purine synthesis takes place succinate synthetase
IMP Monophosphate
dehydrogenase
- Involved in synthesis of purines, pyrimidines, salvage of - ATP Salvage Pathway for Purines
purines and pyrimidines synthesis of NAD+, histidine - - Salvaged proteins from normal turnover of
Adenylosuccinase GMP synthetase cellular nucleic acids or obtained from diet
biosynthesis, and conversion of guanine to GMP Lesch-Nyan Syndrome
ADP - X-linked
Hypoxanthine HGPRT IMP - Inability to salvage purines hypoxanthine
AMP NMPs convereted to NDP and GMP and guanine
NTP by nucleoside monophosphate - end prod of degredation is uric acid
Purine Degredation kinases (base specific) and nucleoside - Excess uric acid in urine
- Purines/pyrimidines not imp. diet diphposphate kinases, respectively Mycophenolic acid - Orange crystals in baby’s diaper
- in diet, degraded to uric acid, not scavenged
Guanine HGPRT GMP
- reversible uncompetative inhibitor - Severe mental retardation, self-mutilation
- Some pyrimidines absorbed - deprives rapidly proliferating T and and involuntary movements, gout.
B cells of key components of nucleic - Causes increased PRPP levels and de novo
PNP Deficiency acids synthesis
Adenosuccinate - Purine nucleoside phosphorylase deficiency
AMP IMP - used to prevent graft rejection Adenine APRT AMP
Synthase - Impairment of T-cell function
- Decreased uric acid production
- Increased purine nucleosides and nucleotides Ribonucleotides to Deoxyribonucleotides
5’ Nucleotidase 5’ Nucleotidase - Synthesis of deoxyribonucleotides regulated
by enzyme
Pyrimidine Synthesis Degredation of pyrimidine nucleotides - reduction needed for DNA synthesis
Adenosine GMP - Rate-limiting step Carbamoyl phosphate - unlike purines
Adenosine Inosine
deaminase synthetase II (CPSII) - pyrimidine rings can be opened and degraded Hydroxyurea - chemotherapy
5’ Nucleotidase
Purine nucleoside to highly soluble structures SCIDS -> dATP
- Less diverse source of carbons and nitrogens
phosphorylase - Will servbe as precursors for other biomolecules Ribonucleoside
SCIDS - Severe combined immunodeficiency Guanosine 1) Glutamine - N - can be salvaged by pyrimidine phosphoribosyl-
Deoxyribonucleoside
UDP + 2ADP + Pi diphosphate diphosphate
- Adenosine deaminase (ADA) deficiency 2) CO2 - C
- Guanosine and inosine pathway preferred Hypoxanthine 3) Aspartic acid - C
UTP + Glutamate
transferase where PRPP is source of ribose phosphate
-
- DNA not synthesized in T-cells and B-cells
Purine nucleoside
phosphorylase
- Ribonucleotide
Because accumulation of dATP Xanthine reductase
oxidase
Gout Carbamoyl
2ATP + CO2 Phosphate Carbamoyl
Orotate PRPP
Xanthine + Glutamine Synthetase II Phosphate Thioredoxin (2 SH) Thioredoxin (S-S)
Uric Acid Xanthine Guanase Guanine (CPS II)
oxidase CPS II (reduced) (oxidized)
Orotate phosphoribosyl-
- In cytosol of all nucleated cells transferase
Thioredoxin
- inhibited by UDP and UTP
Gout reductase
- not activated by N-acetylglutamate PPi
- Hyperuricemia OMP
Orotidine
(CPS II from urea cycle is) UMP 5’-monophosphate
- Acute arthritic joint inflammation (caused by deposition of uric acid crystals Decarboxylase NADP NADPH
(OMP)
- Primary - Genetic, affects males over 30 years old nucleoside
- Secondary - numer of disorders: Monophosphate Converted to 5-Flouroruracil is uracil analog
-> leukemia, polycythemia (increase RBC mass) HGPRT deficiency, treatment Kinase dFUMP (active form) - used in Cancer treatment
Orotic aciduria - Blocking dTMP inhibits DNA Synthesis
of cancer with antimetabolites, or chronic renal insufficiency - Deficiency in UMP Synthase
Synthesis of - Converted to dFUMP (actual inhibitor
- Diagnosed via monosodium urate crystals UDP - Abnormal growth, megaloblastic anemia 5-Fluorouracil
- Given with thymidine to boost
CTP from UTP
- Glutamine is and excrete lots of orotic acid in urine effectiveness
Treatment of Gout
Nitrogen doner
Nucleoside
Diphosphate
- Rare genetic form missing enzymes
dUMP
- dTMP
- Colchicine (microtubule inhibitor - acquired form appear in patients treated
Kinase Thymidylate
-> improvement but no decrease in serum uric acid for cancer with pyrimidine analog Synthetase
-> inhibits migration of white cells to joints ATP +
- Allopurinol Glutamine UTP
Treatment
THF Dihydrofolate
-> noncompetitive inhibitor of xanthine oxidase CTP - dietary uridine
-> causes excretino of hypoxanthine and xanthine instead of urate Synthase - uridine absorbed enough Dihydrofolate
ADP + reductase Methotrexate
for pyrimidine nucleotide
Glutamate
CTP synthesis Tetrahydrofolate - - indirect
inhibition
 Heme in erythroid cells
Heme Synthesis Heme in liver - Connected to protein synthesis of -globin chains
- Bone marrow (85%) and Liver - tightly regulated (b/c damaging) - stimulated by erythropoietin
- Heme needed for hemoglobin - Drugs increase ALAS1 activity as they - Erythroipoetin released by kidney at low O2
and myoglobin lead to CYP450 which needs heme -> stimulates RBC and hemoglobin synthesis
- Accumulation is important
- Cytochrome p450 enzymes need - Synthesis of ALAS1 stimulated at low
- Heme synthesis controlled by intracellular
heme as prothetic group (liver) intracellular heme iron availability
- other enzymes that need heme -> Low inracellular Iron downregulates ALAS2
-> cytochromes of ETC - ALAS2 - X-chromosome
-> catalase -> Loss of Funct results in X-linked Sideroblastic anemia
-> nitric oxide synthase
- All reactions irreversible
Isoniazid
- used to treat tuberculosis
- depletes PLP
Mitochondria - vitamin B6 given to patients Heme
Porphyrias Zinc
- Chronic or acute
- Can lead to neurologic dysfunction, mental Succinyl CoA and glycine Ferrochelatase ferrous iron
disturbances or photosensitivity - -
- Hepatic or erythropoietic porphyrias Heme ALAS1 - most cells
PLP (Vit B6) Protoporphyrin IX
- accumulation of intermediates of heme Low levels of intracellular iron ALAS2 - RBCs
synthesis in blood, tissues and urine - Lead
- Treatment includes injection of glucose and hemin - Interacts with zinc cofactors
of enzymes
- leads to anemia
2X -aminolevulinic acid (ALA) - High Blood ALA and
protoporphyrin IX in blood
ALA dehydratase porphyria and urine
Acute Intermittent Porphyria (AIP): - Autosomal recessive
AlA dehydratase/ -
Porphobilinogen synthase
- Deficiency of hydroxymethylbilane synthase - high ALA in blood and urine Zinc
- Autosomal dominant
- ALA activity high in liver b/c heme synthesis defective
- High ALA and porphobilinogen in blood and urine
HMB synthase deficiency
4X Porphobilinogen Coproporphyrinogen III
- Change of urine color to dark purple after 24hrs standing
(colorless porphobilinogen spontaneously to porphobilin) - Autosomal dominant
HMB synthase/ Porphyria Cutanea Tarda:
- Ab pain, agitated, tachycardia, respiratory problems confusion - AIP PEG deaminase Uroporphyrinogen decarboxylase Uroporphyrinogen decarboxylase
weakness - High ALA and porphobilinogen deficiency
- NOT PHOTOSENSITIVE in blood and urine Uroporphyrinogen III Porphyrin ring III/
- occurs in patients treated with drugs stimulating Cytochrome - urine changes dark purple Hydroxymethylbilane
(co) synthase uroporphyrinogen III Uroporphyrin III
P450 synthesis, or by infections, ethanol abuse... (HMB)
- Physicians not administer barbituates (asymmetric pyrrole ring D)
(stimulation of CYP450) Congenital Erythropoietic Porphyria
- Treatment: Pain meds, IV glucose, saline or hemin If enzyme is missing, HMB will Urophyrinogen decarboxylase deficiency
spontaneously form faulty ring - Autosomal dominant and acquired
- PCT
Congenital Erythropoietic Porphyria (CEP): - Most common
Uroporphyrinogen I Uroporphyrin I
- Deficiency of RBC uroporphyrinogen III synthase - high red uroporphyrin III in skin and urine
- autosomal recessive trait
- Uroporphyrin I and coproporphyrin I in tissues, blood and Coproporphyrinogen I Coproporhyrin I
urine (RED PISS AND SKIN) (accumulate in skin leading to Porphyria Cutanea Tarda (PCT):
- EXTREMELY PHOTOSENSITIVE extremely severe and painful
- blisters, poor wound healing, infections, werewolf photosensitivity)
- Most common
- Deficiency of uroporphyrinogen III decarboxylase
- Child onset
- Type I - sporadic, 80%
- Hemin infusion would NOT HELP
- Type II - familial, autosomal dominant, 20%
- Treatment: bone marrow transplant
- uroporphyrin III found in tissues, blood and urine (RED)
- Can be caused by
Uroporphyrinogen III synthase deficiency -> hepatitis
- autosomal recessive -> ethanol abuse
- CEP - Cutaneous leasons, erosions and bullous lesions in sun
exposed regions
- Most severe photosensitive
- expression influenced by hepatic iron overload or sunlight
- uropophyrin I and coporphyrin I - Treatment: avoidance of sun-light, alcohol and iron
in tissue and urine
 Jaundice in newborn Inherited hyperbilirubinemia
- Crigler-Najjar syndromes I and II, Gilbert’s syndrome
Dubin-Johnson
- Newborn infnats have low activity of Kidney urobilin Urine
- Deficiency of microsomal bilirubin glucuronyl
Reticuloendothelial syndrome (yellow)
hepatic UDP-glucuronyl transferase System (RES):
- Increased destruction of RBCs as well transferase
- Spleen, Kupfer cells of
- unconjugated hyperbilirubinemia Heme degredation and Urobilinogen
liver, macrophages
- Senile RBCs taken by RES
Crigler-Najjar syndrome type I - in macrophages
Kernicterus - Most severe, complete deficiency of enzyme -> Heme oxygenase
- High serum bilirubin levels in newborns - high serum bilirubin, kernicterus, mental retardation
-> Biliverdin reductase Hemoglobin ABC transporter
- lipid soluble, unconjugated bilirubin passes (MRP2)
- managed by phototherapy, exchange transfusion 3
BBB globin 1
and prevention of kernicterus Conjugated
- Hypoalbuminemia/low pH, weaken albumin Heme Bilirubin
- if not treated, fatal by 2 years NADPH + O2 bilirubin
bond with bilirubin amino acids diglucuronide
Heme oxygenase
- Salicylates and sulfonamides compete for reused NADP+ (conjugated)
10%
Crigler-Najjar syndrome II (Arias syndrome) Fe3+
albumin binding UDP
Bacterial
- lower bilirubin glucuronyl transferase activity (10-20%) CO flora
- Characterized by lethargy, altered muscle Biliverdin UDP glycuronyl Portal
- less severe than type I (green pigment)
tone, high pitched cry, permanent neuro transferase
damage
- Respond to phenobarbital (induces enzyme) Sulfonamides & Salicylates NADPH UDP-glucornoic
Urobilinogen
circulation
- Phototherapy - can displace bilirubin
Biliverdin reductase
acid
(deconjugated
from albumin
- free unconjugated NADP+ UDP colorless)
Gilbert’s syndrome bilirubin cross BBB Bilirubin (orange-yellow) UDP glycuronyl
Phototherapy - mild jaundice following infection, stress or starvation - Cause Kernicterus in children (unconjugated) transferase Bacterial
- 450nm - UDP-glucuronyl transferase activity 50% UDP-glucornoic flora
acid
- converts bilirubin to more polar - mild incrase in unconjugated bilirubin
water soluble isomers Carrier
Bilirubin Bilirubin
albumin Protein Ligandin Stercobilin Feces
Dubin-Johnson syndrome (unconjugated) -> bound to bilirubin (brown)
- Inherited deficiency of ABC transporter from within hepatocyte
hepatocyte into biliary canaliculus Spleen/Blood 2 Liver Large Intestine
- elevated levels of conjugated (direct) bilirubin in
circulation

1) Prehapatic Hemolysis 2) Hepatic Jaundice 3) Posthepatic (obstructive)

“Hepatocellular” Jaundice
Increased breakdown of Breakdown of RBCs
RBCs (Hemolysis) (hemolysis) Breakdown of RBCs
(hemolysis)

Increased formation of bilirubin Forrmation of bilirubin

Forrmation of bilirubin

Increased unconjugated Increased unconjugated

bilirubin in circulation bilirubin in circulation Unconjugated
(albumin-bound) (albumin-bound) bilirubin in
circulation

Jaundice
Normal uptake and Increased conjugated - serum bilirubin >2mg/dL
Decreased uptake and Increased conjugated
Increased uptake and conjugation of bilirubin by liver bilirubin in circulation
conjugation of bilirubin by bilirubin in circulation due to regurgitation
-> Normal <1mg/dL (most unconjugated)
conjugation of bilirubin by liver liver & decreased secretion - Test via Van den Bergh reaction
due to regurgitation
of conjugated bilirubin Obstruction due to -> Diazo reagent (diazotized sulfanilic acid)
gall stones or cancer
-- bilirubin reacts with reagent forming red
Increased excretion of colored complex
conjugated bilirubin into Loss of Decreased/absent excretion of
Decreased excretion of conjugated
bilirubin in
- Total Bilirubin = direct (conjugated) +
bile and intestine bilirubin into bile and intestine conjugated bilirubin into bile and
urine intestine Indirect (unconjugated)
Loss of - Unconjugated bilirubin is water insoluble
(Orange Yellow)
bilirubin in
urine
Increased excretion Increased excretion Decreased formation of Decreased formation of (Dark Orange
of urobilin in urine of stercobilin in feces urobilinogen in intestine Serum Serum Serum
urobilinogen in intestine Urine) Total conjugated unconjugated
Urine Urine
(yellow) bilirubin urobilinogen
Bilirubin bilirubin bilirubin
Absent
Prehepa c
Decreased Decreased Absent Decreased jaundice
Very High N Very High (acholuric High

excretion of excretion of urobilin in excretion of jaundice)

urobilin in urine stercobilin in urine stercobilin in feces Hepa c

Very High High High Present
N or low or
feces (clay colored feces) jaundice high
Post hepa c
Very High Very High N Present Low or Absent
jaundice
 -1 Globulins -2 Globulins globulins

Diseases of -1 antitrypsin 2 macroglobulin Haptoglobin

Emphysema - protease inhibitor - binds to free hemoglobin (form
-1 antitrypsin - one of largest serum protein complex)
- due to low -1 AT. Transferrin Hemopexin
- Synthesized in liver - inhibits plasmin and thrombin -> from RBC hemolysis
- may be genetic - Transports ferric iron between - binds to free heme in blood
- inhibits neutrophil elastase in lungs - Nephrotic syndrome - complex cannot be excreted by
-> M allele normal -> intest, liver, bone mar., spleen - prevents loss of iron by kidneys
- N - glycosylated released into blood -> 10 fold elevated kidneys
-> Z and S allele defective - can bind 2 Fe3+ atoms
and goes to lung -> large so not lost in urine -> prevent loss
- Homo - ZZ, high risk developing - normally 1/3 binding sites filled with Fe3+
pulmonary disease and liver disease -> albumin smaller so excreted - Acute hemolysis
in urine -> Low serum globin - Patients with iron Deficiency
- with defect 15% -1 AT secreted. -> Low serum iron -lipoproteins (LDLs)
fetoprotein (AFP) Ceruloplasmin - used to monitor pts with hemolytic
Rest accumulates in liver (liver -> Low saturation - + charge (have only apo B-100)
- in fetal plasma - Cu2+ containing plasma protein anemia
disease in children - Patients with iron overload
- function similar to albumin in fetal live - ferroxidase activity
- Treatment - iv admin of -1 AT -> High serum iron
- used as marker for cancer of liver ovaries -> Fe2+ -> Fe 3+ then to transferrin
- Heter normal unless smoking -> High saturation
or testes - Wilson’s disease
-> cigarette oxidizes methionine
- Maternal serum AFP -> low levels found
residues - reduces efficacy
-> high - fetal neural tube defects -> due to less attachment of Cu2+
-> low - down syndrome -> Kayser-Fleischer Rings
3) Transcortin --> Cu2+ accum in tissue
- Synth in liver
4) Retinol binding protein (RBP)
- transport for blood cortisol (75%)
- transports retinol (vitamin A) from liver
- unbound hormone enters cells
to peripheral
reducing inflammation
- Retinyl esters stored in liver
- reduced binding near inflam sites

globulins Albumin
IgM: - smalles most abundant serum proteins
- in blood and lymph - anionic at pH 7.4 (negative charge) Kernicterus
- first antibody responder Different causes of hypoalbuminemia
- 70-80% osmotic pressure - infants with displaced bilirubin
IgG: - Decreased albumin synthesis
- synthesized by liver @ 14g/day - because albumin tranportsbilirubin
- in all body fluids -> low protein diet (malnutrition)
- t1/2 20 days and drugs
- smallest but most common -> Chronic liver disease (cirhosis)
- glycosylated in blood - diabetes test?) - thus aspirin will displace bilirubin for
- produced on repeated exposure to same - Increased albumin loss
- single polypetide chain with 585 aa and drugs
antigen (often bacterial and viral infec. -> severe burns (loss from burnt skin)
stabilizerd by internal disulfide bonds -> Loss of albumin in urine (nephrotic
- crosses placenta and confers immunity - indicator of nutritional statis and liver synthetic function Edema syndrome)
to fetus and newborn - low albumin indicates severe liver damage/inflammation - low serum albumin
IgE: - Albumin in urine hypoalbuminemia
- in lung, skin, mucous membranes -> damage to kidney - low colloid osmotic pressure
- secreted in allergic reactions - binds cations in blood (Ca2+) - Congenital analbuminemia appear normal
IgA: PH AND BOUND CA2+ and only show some edema or hypocalcemia
- Found in body secretions - High pH = High bound Ca2+ Albumin
- protects body surfaces - Low pH = Low bound Ca2+ Albumin
IgD:
- role uncertain
Serum proteins
- separated by electrophoresis
- Separation by charge (albumin -)
Acute phase proteins
Multiple myeloma - serum proteins increased (Positive) or decreased (Negative)
- tumor of plasma cells (activated B cells) in response to inflammatory disorders
- increase of monoclonal band - found in response to infection, extreme stress, burns, major
crush injury allergy or other albumin
- specic immunoglobulin produced
by malignant clone Reactants
- typically high amounts of monoclonal - Cytokines
Ig -> stimulate synthesis of positive acute phase reactants
- important in diagnosing and monitoring -> serum proteins serve immun functions
patients with multiple myeloma - Ceruloplasmin and haptoglobin
-> inhibit iron uptake by microbes
- Leads to increase 2 -globin fraction
Liver Cirrhosis - Increase of -1 AT leads to increase in -1 Globulin fraction
- increase in many immunoglobulins - NOT in serum
- of all closses, often includes IgA -> C-reactive protein not found, but released over 30,000 times
-> need specific test and is used to monitor inflammation
+ -
 2) Platelet plug formation: Primary hemostasis
- Greatly limits blood loss by forming plugs Post platelet adheions: B) Platelet aggregation
Step 1: Vascular spasm/
- mediated by Fibrinogen
DRUGS!!
vasoconsytriction - 2 steps: platelet adhesion followed by aggregation
Platelet activation: Shape change -> binds to GPIIb/IIIa on adjacent - Aspirin and COX1 inhibitors
- Trauma to vessel wall results
in contraction Role of Von Willebrand factor A) Platelet adhesion
plates -> prevent formatino of thromboxane
- Thrombasthenia of Glanzman and Naegeli
- factors released from injured - vWf - bridge between specific GPs - Facilitated by endothelial injury -> GpIIb/IIIa defect
in platelets
vessel wall ADP, CA2+ released Synthesis and release
- FAciliatates platelet adhesion and (normally inhibted by negative charges
of thromboxane A2 - Formation of platelet plug/primary hemostasis - Heparin
- Nervous reflexes platelet aggregation of wall and platelets)
- Transient and not long term - complexes with VIII, carries it, stabilizes - mediated by receptors glycoproteins Other platelets activated -> activates antithrombin III
cessation of bleeding it and prevents its degradation (GPlb and Gpla) (Promote aggregation) -> inactivates thrombin
Primary hemostasis - formatin of platelet plug
- Deficiency associated with defect in - Steps:
COX - Formation of platelet plug requries
- Warfarin
formation of platelet plug (primary 1) Platelet GPla binds to collagen
hemostasis) and defect in coagulation and structural changes ADP binding facilitates Ca2+ 1)von Willebrand factor -> blocks epoxide redutase in liver
(due to low VIII) 2) Von Willebrand factor binds to platelet release Aspirin 2) adequate number of platelets -> thus preventing regen of active
3) GpIb platelet receptors
receptor GPlb Phospholipase A2 activated 4) GpIIb/IIIa platelet receptors
form of Vit K
Platelet- 3) binding exposes GPllb/llla for binding (by Ca2+)
of fibrinogen Decreases cAMP - Defects in platelet plug formation -> also inhibits clottin factors (against
Platelet defects: Increased Bleeding time endothelium
(due to defective platelet plug formation) interaction (facilitate aggregation) -> because of missing any of above action of Vit K
No ADP stim = no platelet aggregation -> increased bleeding time
- GpIb defect: Bernard-Soulier syndrome GPlb GPllb GPlIla GPla Platelet-
- Streptokinase
- Normal platelet count and increased endothelium -> thrombolytic agent; plasminogen
bleeding time Platelet-Platelet
interaction activator
- Qualitative platelet defects interaction Control of hemostasis: Anti-coagulant factors
-> converts plasminogen to plasmin
GpIIb/IIIa defect: Thrombasthenia of vWF - Normal endothelia are anti-thrombic - Antithrombin III
enabiling dissoltion of clots
Glanzman and Naegeli
- Normal platelet count and increased BT
- chemical mediators -> inhibits factors Xa and thrombin (IIa)
- Also qualitative platelet defect Subendothelial Collagen ->PGI2 and nitric oxide -> Heparin works by activating this factor
Thrombocytopoenia (low platelet count -> released by healthy endothelium - Protein C and S (also require vit K)
- low platelet count and increased BT -> PGI2 increases cAMP levels, inhibing -> inactivate cofactors Va and VIIIa
- Quantitative platelet defect
platelet activation -> Protein S is cofactor for protein C
Role of vitamin K & -Carboxylation
- Vit K required for hepatic synthesis of -> Protein C activated by binding
3) Blood coagulation (Secondary hemostasis) Prothrombin (II), VII, IX, X, Proteins C and S thrombomodulin to thrombin
- Conversion of blood from liquid state to solid gel state - glutamic acid residues of above proteins are
- Ultimate goal: soluble fibrinogen to insoluble fibrin and carboxylated in reaction involving vitamin K
stabilize (via cross linking) Step 4: Dissolution of the fibrin clot/ tertiary hemostasis
- allows Ca2+ binding b/c of negative charge - Fibrin degredation products and D-dimer levels raised
-> requires thrombin
- 2 pathways
-> forms complex with Ca2+ allowing it to with deep vein thrombosis Tests of hemostatic functions
bind to phospholipids on platelet membrane - estimated to clinical practice to estimate extent
1) Extrinsic Pathway
- activated on injury of patients with thrombosis Bleeding time Clotting time
2) Intrinsic pathway - time from initial injury - time formatin of stable fibrin
Precursors for + Proteins Inactive Plasminogen gets
- important pathological processes e.g. atherosclerosis
II, VII, IX, X C and S incorporated in developing clot to platelet plug formation - Prolonged clotting time
- Both systems involve cascade 1) Tissue plasminogen
- Product formed at each step catalyzes next step - + - indicator of platlet plug indicates defect in coagulation
Plasminogen Activator activator
Glutamyl residue formation pathway
Inhibitor 1 & 2 2) urokinase
Rough endothelial surface 3. Streptokinase - Prolonged bleeding time
- exposure of collagen - Antiplasmin Active plasma (proteolytic indicator of Prothrombin time (PT) or
Warfarin - International normilized ratio (INR)
1) Low platelet count
12 Vitamin K 2) vWf deficiency - Tests extrinsic and common
vWF Def Hemophilia B Fibrin degredation
+ Fibrin 3) Platelet receptor defects coagulation pathway
Hemophilia A products (FDP)
11
INR is very sensitive
Partial thromboplastin time
Mature factors
9 Tissue Injury
II, VII, IX, X indicator of Vit K (APTT)
Thrombin deficiency
(2) 8 - Tests intrinsic and common
- -carboxyl-
pathways
Thromboplastin glutamyl
Proteins Ca2+ (3)
C and S
(Gla) residue Overview:
Phospholipids

Thrombin - 10 7 Vessel Injury

5 Ca2+
(2)
13a: Highly specific transglutaminase Colagen exposure
Ca2+ - forms Gluitamine-Lysine Hemophilia
cross linkage Platelet adhesion Tissue factor
- inherited coagulation disorder (x-linked)
Phospholipids Seratonin
Platelet - Hemophilia A - VIII and Hemophilia B- IX
Ca2+ + Endothelin Platelet activation
2 phospholipid
13 Bleeding me Normal (platelet plug forma on normal)
Platelet count Normal
Ca2+ Vasoconstriction Thrombaxane A2, ADP Clo ng me increased (defect in intrinsic pathway)
Blood coagulation Prothrombin me (INR) Normal (extrinsic and common coagula on pathway normal)
Fibrin 1 Cross Platelet aggregation cascade APTT (Intrinsic pathway) increased (defect in intrinsic pathway)
(1) linked
Fibrinogen: Platelet phosphlipids in clotting Thrombin Von Willebrand Disease
- Plasma protein synthesized in liver Redued blood flow Primary Hemostatic plug - Most common inherited bleeding disorder
- Activation of platelets -> exposure of
- Thrombin cleaves fibrinopeptides of phospholipids on platelet surface Fimbrin - defect in platelet plug formation
fibrinogen forming fibrin Fibrin - instability of Factor VIII
- Provide binding sites for coagulation factors degredation Plasmin Secondary hemostatic plug
- Fibrin Monomers aggregate, linked Presents similar to hemophilia A
via H-bonds (Soft Clot) products (FDP) Bleeding me Prolonged (defect in platelet plug forma on)
“Hard” clot: Via cross linking
- Mediated by Factor XIII activatedby thrombin Platelet count normal
- Covalent cross linking bond APTT (Intrinsic pathway) Prolonged (Factor VIII levels may be low normal)
- (amino group of lysine from 1 molecule PT (INR) Normal (extrinsic pathway normal
cov link to amide nitrogen of glutamine) vWF levels LOW
- (XIIIa highly specific transglutaminase)
Functions of liver: Serum bilirubin Serum Enzymes Test for Liver Synthetic Function Tests evalulating metabolic function
- excretion, plasma protein synthesis, - estimate extent of liver damage - Indicator of - All plasma proteins except -globulins
blood clotting, metabolism, detox - difficult to distinguish hepatocellular -> Hepatocellular damage synthesized by liver Blood glucose
- Used in clinic for liver function tests from cholestatic disorder -> Cholestasis - liver is major glucostat
(LFTs) -> elevated in intra and extra hepatic - degree of enzyme rise corresponds Serum Albumin - regulation by storing and releasing
cholestasis to extent of damage - Only synthesized in liver glucose
Liver function tests (LFTs) - Intra-hepatic: observed in viral hepatitis, Chronic liver disease
- Serum bilirubin (total, uncon, con) drug toxicity and cirrhosis Enzymes Indicating Hepatocellular Damage: In chronic liver disease - alter blood glucose level
- Enzymne levels in serum indicating - Extra-hepatic: bile duct/gall bladder Aminotransferases (Transaminases) - low albumin is characteristic
-> Hepatocellular damage obstruction or tumors around bile duct/ - ALT (Alanine Aminotransferase) - contributes to ascites and pedal Blood amonia levels
-> Cholestasis head of pancreas -> More specific for liver cell damage edema - ammonia detoxified to urea in liver
-> GGT (Drugs or Cholestasis) -> Acute Hepatitis, levels are higher Fulminant and end stage liver disease
- Synthetic function Hepatitis - AST (aspartate aminotransferase. Acute hepatitis - impairment of urea formation
-> Albumin -> Increased unconjugated (decreased -> Long standing alcoholic cirrhosis - albumin levels normal - blood ammonia levels rise
-> Clotting factors (PT) liver uptake -> AST:ALT ratio 2:1 - High blood ammonia contributes to
-> alpha feto protein (AFP) -> Increased conjugated ( associated intra- - Levels raised in viral hepatitis, drug Cirrohsis -> Hepatic encephalopathy
- Tests for metabolic functions hepatic cholistasis induced hepatitis, and long standing - -globulins usually elevated in -> altered consciousness
-> serum ammonia obstructive jaundice (levels lower than
-> blood glucose Cholestatic disease hepatitis) Clotting factors (PT) Lipid metabolism
- Serum bilirubin mostly elevated - Liver synthesizes clotting factors - liver secretes VLDL transporting TAG
When do we use LFTs? - Complete obstruction Enzymes Indicating Cholestasis: V, VII, IX, X, protrhombin (II) and fibrin (I) Fatty liver
- Assess intensity and type of -> bilirubin regurgitated in blood (in urine) (Intra and extra hepatic) - Normal prothrombin time: 12-15 s - excessive deposition of TAG in liver
-> Jaundice (hepatic or obstructive) -> urobilinogen absent in urine - ALP (Alkaline phosphatase) - Liver also involved in post translational - damage to hepatocytes by ethanol
- Assess extent of hepatocyte damage -> stercobilin absent in feces (extent of -> secreted by biliary canaliculi vitamin K dependent -carboxylation of results in fatty liver
-> viruses absence depends on severeity) -> Elevated with both intra and extra glutamic acid - caused by:
-> malignancy hepatic obstruction -> factors II, VII, IX and X -> high NADH thus low b-oxidation
-> drugs -> Also Elevated during pregnancy - Important monitor during surgery -> high acetyl CoA thus FA synthesis
- Differentiate between growing children and bone disease - Increase indicates -> decreased VLDL secretion
-> chronic - GGT (Gamma glutamyl transferase) -> Hepatocellular disorders (decrease in because hepatotoxic EtOH effect
-> acute -> secreted by biliary ducts synthesis
- Monitoring drug therapy of -> synthesis induced by alcohol and -> cholestasis (decrease Vit K absorption
hepatotoxic drugs drugs no bile and vit K fat soluble
- Follow up and prognosis of liver -> Used to differentiate between hepatic
diseases and non hepatic ALP elevation
- Elevation in both ALP and GGT
Signs and symptoms during physical -> Cholestasis usually present
exam and possible causes -> Ultrasound performed to assess
Special tests evaluating liver function:
- Jaundice - alpha feto protein (AFP)
Intra or Extra hepatic biliary stasis
-> acute hepatitis -> tumor marker for liver cancer
-> Dilated biliary tree = extrahepatic
-> biliary obstruction - Fe, transferrin and ferritin
-> no dilation = intrahepatic
-> advanced chronic liver disease -> hemochromatosis
- Abdominal pain and fever - Ceruloplasmin
-> cholesystitis -> Wilson’s disease
-> inflammatory liver diseaseo - 1-antitrypsin
- Stigmata of chronic cirrhosis -> 1-antitrypsin deficiency
-> spider angioma
-> palmar erythema
-> gynecomastia
-> testicular atrophy
- complications of liver disease
-> advanced liver disease
-> encephalopathy, ascites, GI bleeding
(esophageal varicies), coagulation
disorders
 NADPH NADP+, H+ CYP450:
Xenobiotics
- Heme containing enzyme induced by EtOH and drugs
- Not normally found in human body - CYP450 reductase works with CYP450 Different CYP450
- Drugs, food additives or pollutants -> Providing NADPH - Hundreds of isoforms grouped into
FAD RH O2 ROH, H2O
- Primarily modified in liver or in GIT, -> two e- taken up and bound to FAD then FMN 6 major groups
e- - CYP3A4
lungs, brain, kidney, skin -> Donates 1 e- at a time to heme group of CYP450
-> 1/3 of CYP450 in liver
- Drug metabolism - Reaction very complex and radicals generated
FMN Fe-heme -> acts on more than half of therapeutic drugs
-> expose functional group (hydroxyl) - CYP2E1
Induction of CYP450
-> makes molecule more polar for - Done by drugs of specific CYP450 that metabolize them -> specific for EtOH metabolism
excretion in kidney - induction complex, but increase of transcription
Cytochrome Cytochrome
- Two phases of metabolism P450 reducase P450 - Phenobarbital leads to 3-4 fold increase in 4-5 days
-> stimulates heme synthesis
-> Phase II: usually follows I, but may -> drug should be avoided with AIP
start here -> bad to elevated ALA levels (similar to GABA) Acetaminophen Detoxification
- Normally conjugates with glucuronate or sulfate and excreted in urine
CYP2E1 - Occurs to lesser extent, with CYPE1
- Part of MEOS system in liver (microsomal EtOH oxidizing - With chronic alcoholics
Phase I: involving cytochrome Phase II: system -> more processed by CYP2E
P450 (CYP 450) - Often after Phase I - Induced during chronic ethanol consumption -> produces NAPQ1 (TOXIC!) but can still be detox by GSH
- ER membranes - In cytosol - Poisoning treated with acetadote
-> Hydroxylation or many other -> UDP-glucuronic acid Drug interactions -> binds directly to NAPQ1 and provides cysteine for glutathione synth
reactions by microsomal -> PAPS (sulfate) - Grapefruit juice
-> inactiavtes CYP3A4
Cytochrome P450 -> Glutathione 60% 30%
-> statins less inactiavted by enzyme
-> Amino acids -> leads to liver damage
Glucuronate Acetaminophen Sulfate (SO4)
- Tamoxifen (breast cancer treatment) 10% (normally)
-> needs activation by cytochromes in liver
Acetadote
-> inhibition of CYP450 leads to less effectiveness CYP2E1 EtOH
(N-acetyl-cysteine)
+
Treatment with more than 1 drug
- One drug can induce CYP3A4 leading to different
+
metabolism of another drug Mercaptopuric Glutathione
-> DANGEROUS! S-transferase
NAPQ1 Cell Death
acid
Ethanol Metabolism: Toxicity of acetaldehyde in chronic - Ex. Warfarin less effective with phenobarbital
- Uptake starts in stomach ethanol abuse in liver: -> thus higher dosage of Warfarin for patients GSH
- Efficient on empty stomach (70%) - Inhibits VLDL release perscribed with both
- Metabolism mainly with hepatocytes - Binds to GSH -> if pt comes off phenobarbital, can lead to
Kidney, Urine
- Metabolized to acetaldehyde, then to - Very high Acetaldehyde excessive bleeding
acetate -> inhibits relase of proteins
- Metabolized to acetaldehyde by -> including clotting factors
Acetyl CoA
->alcohol dehydrogenase, - In periphery
MEOS at high EtOH and by catalase -> Toxic for brain and other organs AMP
Acetyl CoA
Synthetase - Used mainly in muscle
- Main enzyme at low EtOH levels (80%) CoASH + ATP - irreversible
- Seven isozymes Acetaldehyde Acetate - enters TCA cycle
- Metabolism varies with individual - Enzyme has low activity
- liver isozyme has low Km (high affinity) in hepatocytes

NAD- NADH

Alcohol Dehydrogenase
(ADH) NAD- NADH

Acetaldehyde Methanol or Ethylene glycol

EtOH NAD- NADH Acetaldehyde DH-1 Acetate
- Both substrates in cytosol for alcohol DH
Disulfam (antabuse) - Treatment is EtOH or Fomepizole
- inhibits acetaldehyde DH -> comp inhibitor
MEOS Disulfiram -> both have higher affinity
- Side effects
(antabuse) - Also sodium bicarb to reverse acidosis
-> flushing, nausea
-> meant to prevent EtOH consump - Severe cases: hemodialysis needed
NAD- NADH - Dangerous if large EtOH intake
- Large Km Methanol
- generates cytosolic acetaldehyde - oxidzed to form formaldehyde
at high ethanol levels Acetaldehyde
DH-2
Acetate -> by Alcohol DH
-> highly toxic
- prod leads to
-> mental and visual disturbance
High cytosolic NADH/NAD+ ratio, gluconeogensis cannot use precursors Mitochondrial acetaldehyde (DH-2) -> irreversible blindness (severe)
- Lactate stays in blood - small Km, fast reaction
- Glucogenic aa cannot be used (Malate - OAA) - forms NADH and acetate in Ethylene glycol
- Glycerol released by fat, cannot be used for gluconeogensis mitochondria - metabolized to glycoaldehyde
- 40% asians have less active form - then to TOXIC oxalate
- antifreeze
Lactate Malate Glycerol 3-P Ctysolic acetaldehyde (DH-1) - leads to
NAD+ NAD+ NAD+ - cytosolic isoform -> kidney failure and death
- higher Km, formed in cytosol -> due to formation of Ca oxalate

NADH NADH NADH

Pyruvate OAA DHAP
 Vitamins: only insoluble cofactor Ergocalciferol (D2)
- chemically unrelated organic compounds Vitamin K DIET
- cannot be synthesized - Coenzyme for post translational modification of
- supplied by diet clotting factors Adults 25-Hydroxylase
- Diet and synthesized by intestinal bacterial flora
Precursors for Cholecalciferol (D3) (LIVER)
25-hydroxycholecalciferol
- Perform specific cellular functions II, VII, IX, X - Caused by
- Forms -> fat malabsorption
- 13 necessary for health Glutamyl residue + 1-hydroxylase
-> Phylloquinone (dietary plant source) -> prolonged use of broad spectrum Sunlight Parathormone,
- classified according to solubility Vit K (rate limiting step)
-> Menaquinone (intestinal bacteria) (Glu) antibiotics Low plasma calcium
ACTIVE Warfarin (KIDNEY)
- Characterized by 7-dehydrocholesterol
Fat soluble Vitamins: Role of vitamin K & -Carboxylation -> Hematuria (SKIN) -
Liver microsomal
-
- absorption dependent on normal fat digest - Vit K required as cofactor for hepatic synthesis Epoxide -> Melena (black tarry stools) 1,25-dihydroxycholecalciferol
- Maldigestion/malabsorption of fat results in of Prothrombin (II), VII, IX, X, Proteins C and S g-carboxylase -> Ecchymoses (bleeding)
reductase
Vitamin D (CALCITRIOL)
- glutamic acid residues of above proteins are -> Bleeding gums
secondary deficiency - D3 in animals (cholecalciferol) (Active form)
carboxylated in reaction involving vitamin K Vit K
- allows Ca2+ binding b/c of negative charge Effect of Warfarin - D2 in Plants (ergocalciferol) Deficiency
INACTIVE
Water Soluble vitamins -> forms complex with Ca2+ allowing it to Mature factors - K antagonist - Causes
- B complex bind to phospholipids on platelet membrane II, VII, IX, X - blocks activity of liver epoxide reductase Mechanism of calcitriol
-> nutritional
-C -> prevents regeneration of reduced Vit K -> inadequate exposure to sunlight
-carboxyl- - binds to intracellular receptor proteins
Deficiency in neonates Binding -> No recycling of Vit K -> Chronic renal disease (Renal Rickes),
glutamyl - complex interacts with DNA in nucleus of
- Hemorrhagic disease of newborn of Ca2+ -> reduced clotting factors and delayed chronic liver disease (decreased vit D
(Gla) residue
Vitamin deficiency -> bleeding various sites including skin, umbilicus prothrombin time (INR) target cells (intestine) hydroxylation
- Primary and viscera - selectively stimulate or repress gene
-> Dietary deficiency -> intracranial bleeding - most serious expression (similar to steroids) Rickets:
- Sterile intestines - Vit D def in children
-> Starvation Complex then binds to
-> no synthesis of vitamin K phospholipids on platelet - decreased Ca++ absorb from diet
-> Malnutrition Actions: (Increase plasma calcium) -> increased parathyroid hormone
-> routine intramuscular injections of Vit K membrane
- Secondary - Intestine -> increased demineralization of bone
-> Reduced intake -> stimulates absorption of Ca++ and - soft pliable bones
(dental problems, chronic Phosphate via synthesis of Ca++ - bow-leg deformity
disease, morning sickness) binding protein - Pigeon chest deformity
- frontal bossing
-> Malabsoprtion - Bone
(diarrhea, genetic defect) Diet: -> mobilize Ca++ and Phos from bone Osteomalacia
-> Increased requirements Retinol esters -> Parathormone required - Vit D def adults
(pregnancy, post op, periods - Kidney - Bones demineralized
of rapid growth) Intestinal Retinoic acid DNA -> susceptible to fracture
Retinol + FFA -> inhibit Ca++ excretion
mucosa (In Nucleus) - Can be secondary to dietary, renal disease
-> increased loss Cellular RBP -> parathyroid dependent
Resterification or liver disease
(lactation)
Transcription
CM oxidized
activation
Vitamin E Vitamin C (Ascorbic Acid)
LIVER
Retinol Retinol - TOCOPHEROL most active form - Water soluble
Stored - Anti-oxidant (lipid soluble) - collagen synthesis and wound healing
RBP Cellular RBP e.g. Keratin -> prevents peroxidation of lipids -> cross linking collagen
-> Scavanges free radicals generated -> coenzyme for hydroxylation of proline
Vitamin A deficiency
- normal diet adequate (only seen with and lysine residues in collagen
- most commonly dietary (fat free diets) - water soluble anti-oxidant
fat malabsorption
- Malabsorption of fats -> scavenger of free radicals
Vitamin A: Absoprtion and transport of Vit A Mechanism of action of retinoic acid -> regenerates anti-oxidant form of
Vit E and Vit C work together
- Collectively called retinoids 1) Diet contains retinol esters in epithelial cells Signs and symptoms Vitamin E
- Vit E
- Retinol - transport and storage 2) hydrolysis by intestinal mucosa releasing - similar to steroid - Night blindness (earliest symptom -> Works in cell membranes
- 11-cis retinal - required for vision retinol and FFA 1) Retinol enters target cell - Xeropthalmia - dry cornea - Vit C Deficiency
- Retinol and Retinal 3) Re-esterification and secretions in CMs 2) oxidized to retinoic acid in cytosol -> Works in cytosol or cell organelles -Scurvy
- Bitot’s spots - increased keritinization -> Perifollicular hemorrhages (fragile
-> can be easily interconverted taken up by liver and and stored 3) retinoic acid enters nucleus with help - Keratomalcia - corneal erosion and Deficiency: blood vessels)
- Retinoic acid 4) Plasma Retinol binding protein (liver) from cellular retinoid binding protein ulceration -> Sore, spongy gums (bleeding)
- Hemolytic anemia
-> epithelial growth and transports to extra hepatic tissues 4) Retinoic acid binds to nuclear receptors - Increased risk of pulmonary infections -> Loose teeth
-> abnormal cell membrane
differentiation 5) Tissue contain cellular retinol binding forming activated receptor complex - Immune deficiency - weakened innate - Reduced deep tendon reflexes -> Bleeding into joints
-> steroid hormone like effects protein carrying retinol into cell 5) binds to chromatin activating transcription immunity -> b/c axonal degeneration -> frequenct bruising
-> irreversible (i.e. Keratin) -> impaired wound healing
- Also less fertility, slowed growth and -> similar to K but different
skin problems
Sources:
- liver, kidney, egg, cream, yum Retinal pigment epithelium Photoreceptor (Rod) cell Vitamins
Treatment
- Yellow veggies and fruit - Retinoic acid is used to treat:
Light
11-cis retinal 11-cis retinal -> severe acne
Fucntion: Water-soluble Fat-soluble
-> psoriasis - A: Retinol, beta carotenes
- Vision - All-trans retinoic acid
Oxidation Rhodopsin - D: cholecalciferol
-> 11-cis retinal is component of Neuronal -> treatment of acute promyelocytic
Opsin (visual pigment) - K: phylloquinones, menaquinones
rhodopsin 11-cis retinol signal leukemia
- Maintenance of epithelia Non-B-complex - E: locopherols
Opsin - C: Ascorbic acid B-complex
-> especially mucus secreting cells Toxicity
(retinoic acid) - Must be careful during pregnancy
- Growth(retinoic acid) All-trans retinyl ester All trans retinal
Vision -> may be teratogenic (cong malf ) Energy releasing: Hematopoietic Other
- Reproduction (retinol) -> spontaneous abortions - B1: Thiamine (RBC/neural development) - B6: pyridoxine
All-trans retinol All-trans retinol - Hypervitaminosis A - B2: Riboflavin - Folic acid
from capillary -> raised intracranial pressure - B3: Niacin - B12
-> headaches mimicing brain tumors - Biotin
- Pantothenic acid
Vitamin B Complex Water soluble vitamins usually NOT stored- Vitamin B3 (Niacin) Vitamin B12: 2 Major reactions
- Thiomine Daily supplements essential Iron
- Coenzyme forms 1) Homocysteine methyltransferase Copper: - Important co-factor in redox reactions
- Riboflavin -- Exception! B12 stored in liver - Important for heme synthesis and redox reactions
-> NAD+ - Synthesis of methionine 1) Cytochrome C
- Niacin - Absorbed into mucousal cells after conversion of
-> NADP+ - Also converts methyl tetrahydrofolate to THF -> Complex IV of ETC
- Pyridoxine ferric to ferrous (absorbable)
- Coenzymes in oxidation-reduction (Active form required for DNA synthesis) 2) Superoxide dismutase
- Biotin - Converge happens in stomach because:
reactions 2) Methylmalonyl CoA mutase -> Detox free radical oxidase
- Pantothenic acid (CoA) 1) low pH
1) NAD - Dehydrogenases - Odd number chain FA 3) Lysyl oxidase
- Cobalamin 2) Vitamin C
2) NADP - reactions in HMP shunt and -> Synthesis of collagen
- Folic Acid - Heme iron easier in meat than inorganic Fe (plants)
fatty acid synthesis Deficiency: 4) Tyrosinase
- Absoprtion TIGHTLY regulated
Folate trap -> Melanin synthesis
-> High body iron stores, less iron absorbed
Vitamin B1 (Thiamine) Therapeutic uses: - methyltetrahydrofolate (not THF) 5) Dopamine -hydroxylase
- TPP - coenzyme form - Treatment of type IIb hyperlipoproteinemia - results in macrocytic anemia -> Neurotransmitter synthesis
Iron transport and storage
- Functions -> inhibits lipolysis in adipose tissue - Cu2+ forms ceruloplasmin in liver
- Ceruloplasmin (ferroxidase)
-> Oxidative decarboxylation of alpha keto acids -> reduces productino of FFA Methylmalonic aciduria -> copper transport protein in liver
-> release of ferrous iron from intestinal cells
-> Helps maintain neural membranes and normal - Neruological manifestations -> helps in iron metabolism
-> forms ferric iron - needed for blood transport
nerve conduction Niacin deficiency - Methylmalonate levels high in circulation Copper metabolism:
- Transferrin
-> PDH, -Keto Acid DH, BC(alpha-keto)A DH - Dietary supplementation is useful with inherited Cu2+ Low Cu2+ -> transport protein for ferric ion in blood plasma
-> Coenzyme for transketolase in Pentose Pellagra: disorder - Iron stored as ferritin and hemosiderin (ferric) in
phosphate shunt - Chracterized by 3 D’s Absorbed Menke’s 1) liver
- B1 supplemenetation for Maple syrup urine disease 1) Dermatitis- necklace like skin damage Pernicious anemia 2) RES
- refined foods: 2) Diarrhea - Lack of intrinsic factor from gastric
-> polished rice, white flour, white sugar Stomach and intestine
3) Dementia parietal cells High Cu2+ Iron Deficiency:
-> are defficienct 4) Death (if not treated) - Most common cause is improper absorption
Wilson’s albumin bound - Most common nutritional deficiency
- Can be caused by corn based diet - Macrycytic anemia - At risk: infants, pregnant moms and blood doners
Thiamine deficiency (corn deficienct ion niacin and tryptophan) -> Macrocytes in peripheral blood - Chronic bleeding is underlying factor
- Patients with Hartnup’s disease can have -> Megaloblasts in bone marrow ATPase Liver
BeriBeri: pellagra-like symptoms - Megaloblastic anemia Degraded and Cu2+
Forms ceruloplasmin Clinical features:
- affects highly aerobic tissue (Brain, cardiac muscle) -> defect in tryptophan absorption -> Due to 2nd deficiency of folate secreted into bile
1) Hypochromic microcytic - Iron deficiency anemia
- Polyneuropathy - Patients with carcinoid syndrome may also - Neuropsychiatric symptoms
Secreted 2) Fatigue and pallor
-> disruption of motor, sensory and reflex arcs have pellagra -> Myelin degeneration both motor and sensory Endocytosed 3) Weakness
-> Progress to Dry Beri Beri (paralysis) -> Due to methylmalonyl accumulation 4) Brittle nails
- Cardiovascular symptoms Treatment: -> May be present in absence of anemia 5) Pica - appetite for soil
-> Web Beri Beri
Pedal - Tryptophan
-> used to synthesize NAD+ and NADP+
1) Cu2+ transport protein
2) helps in Fe metaboism
Aged ceruloplasmin
Hereditory Hemochromatosis
Werneke-Korsakoff syndrome: Plasma - Autosomal recessive - Most common Genetic disorder
- Associated with chronic Alcoholism Folic Acid - excessive absorption of iron
- Ophthalmoplegia and nystagmus - One Carbon Metabolism Cu2+ Deficiency: Nutritional
Vitamin B6 (pyridoxine) - Accumulation parenchymal organs, most importantly:
-> to and fro movement of eyeballs - important in purine and pyrimidine synthesis Signs and symptoms
- AKA pyridoxine, pyridoxal, pyridoxamine 1) Liver
- Ataxia, confusion, disorientation and memmory loss -> e.g. thymidylate (DNA synthesis) 1) Microcytic anemia
- PLP (pyridoxal phosphate) precursor 2) Pancrease
- Confabulation (telling stories) - Most cells receive folate as methyl THF -> smaller RBCs
- Co-enzyme for -> Bronze diabetes (Skin Fe, low insulin b/c iron
- Diagnosis -> conversion to THF requires B12 -> ceruloplasmin (ferroxidase) required for iron
1) Transamination ( amino acid metabolism) disrupts Beta cells in pancrease)
-> incrase in erythrocyte transketolase activity on metabolism
2) Amino acid decarboxylation (synthesis of - HFE gene
TPP addition Deficiency: 2) Degradation of vascular tissue
neurotransmitters) -> on basolateral surface of intestinal crypt
- Dietary inadequacy (green leafs) -> decreased lysyl oxidase activity -> senses iron balance
3) Condesation (ALA synthase)
- impaired absorption 3) Defects in hair -> defect causes loss of sensing = high Fe absorbtion
4) Conversion of homocysteine to cysteine
Vitamin B2 (Riboflavin) - increased requirment in pregnancy
- Coenzyme forms - Methotrexate (Folate antagonist) Menke’s syndrome (Menke’s kinky hair syndrome) Tissue damage
Deficiency
-> FMN (flavin mononucleotide) - B12 deficiency (Folate trapping) - Inherited (X-linked) defect in copper absorption - Lipid peroxidation through free radicals
-> FAD (flavin dinucleotide) from GI tract - DNA damage
Isoniazid (anti-TB drug)
- Participates in oxidation Megaloblastic anemia - Low plasma and tissue copper
- inactivates Pyridoxine
1) TCA cycle + complex 1 (ETC) - Macrocytes in peripheral blood smears
2) beta oxidation (Succinate DH, MCAD - Supplements given with drug
- Megaloblasts in bone marrow
- Hair twisty grayish and kinky
- Leads to aneurysms and cerebral dysfunction
Clinical features:
1) More common in males (age 40)
PDH, (Fatty) Acyl CoA DH...etc) - Due to 2) Liver damage - cirrhosis; hepatocellular carcinoma
Signs and symptoms
-> deminished synthesis of purines and pyrimidines Wilson’s Disease *** 3) Diabetes - destruction of pancrease
- Microcytic anemia (ALA synthase)
Riboflavin deficiency -> Inability of cells to synthesize DNA - Autosomal recessive 4) Cardiac dysfunction
- Peripheral neuropathy
- Nutritional signs and symptoms -> Delayed mitosis; larger cells - copper metabolism disorder 5) Acute synovitis
- Increased risk of cardiovasc disease
1) cheilosis - areas of pallor, cracks - toxic levels of Cu2+ in liver brain and eye 6) Brownish skin pigmentation (Bronze color of skin)
-> due to high plasma homocystine
and fissures at angles of mouth Treatment: - Chromosome 13 (30 mutations identified)
- Seizures
2) Glossitis - inflammation and atrophy - Megaloblastic anemia - Defect in Cu2+ transporting ATPase in liver
of tongue -> never treat with only THF - protein needed to attach Cu2+ to ceruloplasmin
Treatment: Diet:
3) facial dermatitis -> include B12 until cause established -> also excrete Cu2+ into bile Stomach:
- Children with homocystinuria respond to Fe2+
dietary B6 supplements
- Pregnancy - accumulation in liver spills into plasma and other Fe3+ Low pH
-> Increased requirement tissue (Ferric) Vit C (Ferrous)
Biotin (biocytin) -> prevent neural tube defects Intestinal
1) RBC damage - hemolysis
- Prosthetic group for most carboxylation -> recommended at time of conception Mucosa
2) KF rings (eye) - deposition into cornea)
reactions -> and during first trimester Ceruloplasmin
3) Brain - neuro damage - causing neuropsychiatric
- Enzymes requiring biotin: (ferroxidase)
symptoms (basal ganglia
1) Pyruvate carboxylase - (gluconeogesis) -Conversion and
Lab diagnosis
2) Acetyl-CoA carboxylase - (FA synth) release
1) decreased serum ceruloplasmin
3) Propionyl-CoA carboxylase - (Odd chain) Liver or RES
2) increased urinary excretion of copper
3) increased hepatic copper content
Deficiency Fe3+
- Inherited deficiency leads to multiple Nutritional anemias: Ferritin and
carboxylase deficiency Hemosiderin (ferric)
Microcytic (MCV < 80) Normocytic (MCV 80-100) [storage] Transferrin
- Avidin
- Due to reduced synthesis of 1) protein calorie malnutrition
-> present in raw egg white
-> inhibits biotin heme
Macrocytic (MCV > 100)
- Also seen in lead poisoning
- reduced cell division Microcytic anemia - Cu2+, Fe2+, Lead, PLP
Treatment: 1) Deficiency in iron
1) Deficiency in B12
- Biotin supplementation improves symptoms 2) Deficiency in copper Macrocytic - B12, Folate
2) Deficiency in folate
in children with mult. carboxylase deficiency 3) Deficiency in pyridoxine Normocytic - protein/calorie malnutrition