KENYATTA UNIVERSITY

RMS 115 ::​Metabolism of

biomolecules
Department of Nursing
Lecture 5
Ojolapatrick@gmail.com
Dr. P. Ojola
Semester-I 2022/2023
 Glycolytic Pathway
glucose
Hexokinase (glucokinase) ATP
glucose-6-phosphate
Glucose phosphate isomerase
fructose-6-phosphate
Phosphofructokinase-1 ATP
fructose-1,6-bisphosphate
Aldolase Aldolase
Triose phosphate isomerase
dihydroxyacetone phosphate glyceraldehyde-3-phosphate NAD+
Glyceraldehyde-3-phosphate
Bisphosphoglycerate mutase dehydrogenase
1,3-bisphosphoglycerate NADH
2,3-bisphosphoglycerate 3-Phophoglycerate kinase ATP

2,3-Bisphosphoglycerate phosphatase 3-phosphoglycerate

Phosphoglycerate mutase
2-phosphoglycerate
Enolase
phosphoenolpyruvate
Pyruvate kinase ATP
Lactate dehydrogenase
lactate pyruvate

NAD+ NADH
 Glycolytic Pathway Disorders
• Hexokinase – rare autosomal recessive, nonspherocytic hemolytic anemia.
• Phosphoglucose isomerase – rare autosomal recessive, hemolytic anemia, less common
neurological problems.

• Phosphofructokinase – (Glycogen storage disease type VII; Tarui disease) rare autosomal recessive,
three subtypes (classic, infantile onset, and late onset), myoglobinuria, hyperuricemia, hemolytic
anemia when erythrocyte isoform is involved. Avoid high carbohydrate meals.

• Adolase – rare autosomal recessive, three genes (ALDOA, mainly muscle; ALDOB, mainly liver, some
kidney and intestine; ALDOC, mainly brain), ALDOA has myopathy and hemolytic anemia. ALDOB
(hereditary fructose intolerance) vomiting, hypoglycemia, failure to thrive, cachexia, hepatomegaly,
jaundice, coagulopathy, coma, renal Fanconi syndrome, severe metabolic acidosis, treat by restricting
fructose.

• Triosephosphate isomerase – rare autosomal recessive, congenital hemolytic anemia,

progressive neuromuscular dysfunction, susceptibility to bacterial infection, and
cardiomyopathy.
• Glyceraldehyde-3-phosphate dehydrogenase – rare autosomal recessive, very little information
available.
 Glycolytic Pathway Disorders
• Bisphosphoglycerate mutase/phosphatase – rare, hemolytic anemia, polycythemia, increased
hemoglobin affinity for O2.

• Phosphoglycerate kinase – rare X-linked recessive, two forms, chronic hemolytic anemia,
myopathic (myoglobinuria) with muscle symptoms especially upon exercise.

• Phosphoglycerate mutase – rare autosomal recessive, mainly affects skeletal muscle.

• Enolase – rare autosomal recessive, affects muscle, exercise intolerance.

• Pyruvate kinase – autosomal recessive, most common inherited cause of nonspherocytic hemolytic
anemia (normochromic, normocytic, and reticulocytosis), pallor, jaundice, fatigue, dyspnea,
tachycardia and splenomegaly. Treatment is primarily supportive, avoid impact sports with
splenomegaly, avoid large doses of salicylates, supplement with folic acid and B vitamins, use blood
transfusions with decreased hemoglobin concentrations.

• Lactate dehydrogenase – rare autosomal recessive, two forms, LDHA is mainly skeletal muscle,
LDHB mainly heart muscle, LDH is tetramer of combination of LDHA and LDHB subunits. LDHA
deficiency symptoms include fatigue, muscle pain, exercise intolerance, rhabdomyolysis, and
myoglobinuria. LDHB deficiency is asymptomatic.
 Pentose Phosphate Pathway
Glucose-6-phosphate
dehydrogenase Lactonase
glucose-6-phosphate 6-phosphoglucono-δ-lactone 6-phosphogluconate
NADP+
NADP+ NADPH 6-Phosphogluconate
dehydrogenase
NADPH
ribulose-5-phosphate
Transketolase

fructose-6-phosphate Ribulose phosphate 3 Ribose-5-phosphate

epimerase isomerase

glyceraldehyde-3-phosphate xylulose-5-phosphate ribose-5-phosphate

Transketolase

Transaldolase
erythrose-4-phosphate sedoheptulose-7-phosphate

fructose-6-phosphate glyceraldehyde-3-phosphate
 Pentose Phosphate Pathway
Disorders
• Glucose-6-phosphate dehydrogenase – X-linked recessive, most common disease-producing
enzymopathy, hemolytic anemia most often triggered by bacterial or viral infections, oxidative drugs
(sulfonamides and malarials), or eating fava beans (favism). Treatment is supportive, bed rest and
oxygen, avoid triggers (drugs, diet, environmental).

• Ribose-5-phosphate isomerase – very rare (single report), leukoencephalopathy and peripheral

neuropathy.

• Transketolase – very rare (single report), liver cirrhosis and hepatosplenomegaly.

 Fructose Pathway
fructose

Fructokinase ATP

fructose-1-phosphate
Aldolase B
Triose phosphate
isomerase
dihydroxyacetone
glyceraldehyde glyceraldehyde-3-phosphate
phosphate

Triose kinase

ATP
 Fructose Pathway Disorders

• Fructokinase – autosomal recessive, benign.

• Aldolase B – autosomal recessive, (hereditary fructose intolerance) vomiting, hypoglycemia, failure

to thrive, cachexia, hepatomegaly, jaundice, coagulopathy, coma, renal Fanconi syndrome, severe
metabolic acidosis. Treatment by restricting fructose intake.
Pyruvate Metabolism and Citric Acid Cycle
Lactate dehydrogenase
lactate pyruvate
Pyruvate dehydrogenase
NAD+ NADH
acetyl-CoA
Pyruvate carboxylase
2ATP
NADH
Citrate synthase
oxaloacetate citrate

Malate dehydrogenase Aconitase

NAD+

malate isocitrate
NAD+

Fumarase Isocitrate dehydrogenase

NADH
fumarate α-ketoglutarate
NAD+

Succinate dehydrogenase α-Ketoglutarate dehydrogenase

succinate succinyl-CoA
Succinyl-CoA synthetase
FADH2
FAD+ NADH
GTP GDP
 Pyruvate and Citric Acid Cycle Disorders
• Pyruvate dehydrogenase – rare, mostly sporadic, X-linked recessive (E1 α-subunit), autosomal
recessive (X protein and E3 subunit), developmental delay, intermittent ataxia, poor muscle tone,
abnormal eye movements, seizures (all dependent on amount of residual enzyme activity, <15%
incompatible with life), increased serum and CSF lactate and pyruvate concentrations, increased
serum and urine alanine; for E2 enzyme deficiency, hyperammonemia and increased nonspecific
serum amino acid concentrations; for E2 enzyme deficiency, increased serum branched-chain amino
acids concentrations, increased serum and urine α-ketoglutarate concentrations, enzyme assays on
leukocytes, fibroblasts. Treatment by limiting carbohydrates and increasing fats, supplement with
thiamine, carnitine, and lipoic acid.

• Pyruvate carboxylase – rare, autosomal recessive, poor feeding, vomiting, and lethargy, Mental,
psychomotor, growth retardation, poor or degenerative neurologic development, metabolic acidosis,
increased serum lactate and pyruvate concentrations, increased serum lactate to pyruvate
concentration ratio, decreased serum glucose during fasting, hyperalaninemia, hypercitrullinemia,
hyperlysinemia, and decreased serum aspartic acid concentrations, hyperammonemia, increased CSF
lactate, pyruvate, glutamic acid and proline concentrations, decreased CSF glutamine concentrations,
enzyme assay of leukocytes or culturedfibroblasts, absence of pyruvate carboxylase mRNA. Treatment
with thiamine, lipoic acid, dichloroacetate, citrate, and aspartic acid.
 Pyruvate and Citric Acid Cycle Disorders
• Lactate dehydrogenase – rare autosomal recessive, two forms, LDHA is mainly skeletal
muscle, LDHB mainly heart muscle, LDH is tetramer of combination of LDHA and LDHB
subunits. LDHA deficiency symptoms include fatigue, muscle pain, exercise intolerance,
rhabdomyolysis, and myoglobinuria. LDHB deficiency is asymptomatic.

• α-Ketoglutarate dehydrogenase – autosomal recessive, psychomotor retardation, hypotonia,

ataxia and convulsions (symptoms of Leigh syndrome), sudden death, myocardiopathy, hepatic
disorders, hyperlactacidemia, increased serum glutamine concentrations, increased urine glutaric acid,
enzyme assay of leukocytes, fibroblasts.

• Succinate dehydrogenase – autosomal recessive, four subunit genes (SDHA, SDHB, SDHC, SDHD),
SDHA leads to encephalomyopathy, other genes associated with tumour formation, enzyme assay of
leukocytes, fibroblasts.

• Fumarase – very rare, autosomal recessive, microcephaly, severe developmental delay, distinctive
facial features, brain malformation, seizures, failure to thrive, hypotonia, increased urine fumarate,
succinate, citrate, enzyme assays of cultured fibroblasts, lymphoblasts, or white blood cells, molecular
genetic testing. Treatment is supportive.
 Fatty Acid Metabolism
• Why are fatty acids important to cells?
• fuel molecules
• stored as triacylglycerols
• building blocks
• phospholipids
• glycolipids
• precursors of hormones and other messengers
• used to target proteins to membrane sites
Fatty Acid Metabolism
• What is needed for triacylglycerol breakdown?
• bile salts
• made in liver, stored in gall bladder
• glycocholate
• lipases
• pancreas
• hydrolyze ester bond
Processing of dietary lipids in vertebrates
Lipid Metabolism
Lipid Metabolism
Fatty Acids Cannot be Used to Synthesize
Glucose
• Even though the citric acid cycle intermediate oxaloacetate can be used to
synthesize glucose, Acetyl–CoA cannot be used to synthesize oxaloacetate.
• The two carbons that enter the citric acid cycle as Acetyl–CoA leave as CO2.

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 Pathway Integration

Fatty acid synthesis requires the cooperation of

several metabolic pathways.
 Review of lipid structures:
Fatty acids are stored as triacylglycerols
Glycerol
Fatty acid #2
Fatty acid #1

Fatty acid #3

Glycerol esterification of fatty acids

protects cell membranes from the
amphipathic nature of fatty acids. Soap
is made out of fatty acids and works well
to remove oils from hands and clothes by
forming micelles that trap the lipids in a
water soluble particle.
Lipid Structure
Cholesterol

HO

Fatty Acids Triglycerides

COOH COO

COOH COO

COOH COO

HO
Phospholipid: Lecithin
+ Glycerol HO COO

COO
HO

+ N OPOO
Fatty acid biosynthesis
Fatty acid biosynthesis IS NOT JUST A REVERSAL of the degradation

Takes place in the cytosol Takes place in the mitochondria

Intermediates are linked to the SH group of Intermediates are linked to the SH group of
an acyl carrier protein (ACP) coenzyme A
Many of the enzymes are organized as a No association as a multienzyme complex
multienzyme complex:
fatty acid synthetase
The growing fatty acyl chain is elongated by Removal of 2-carbon units
the sequential addition of 2-carbon units;
the activated donor is malonyl-ACP
Reductant is NADPH NADH is formed

Elongation by the fatty acid synthetase

complex stops upon the formation of
palmitate (C16:0)
Further elongation and insertion of double
bonds are carried out by other enzymes
Fatty Acid Synthesis
• Intermediates in fatty acid
synthesis are linked to an acyl
carrier protein
• role similar to coenzyme A
Introduction
• Overview of fatty
acid synthesis

23
Fatty Acid Metabolism
• What are some of the differences between fatty acid degradation and
synthesis?
• location in cell
• use of acyl carrier protein vs. coenzyme A
• association of synthetic enzymes into complex
• use of NADPH as opposed to NAD+ and FAD
 O AT3 A D3 + 3 i
CH3 C- SCoA + HCO3 -
OH
Acetyl-CoA Biotin, Mn
O
CHOC- SCoA
COO-
Malonyl-CoA
Fatty Acid Synthesis
• What are the steps in fatty acid synthesis catalyzed by the fatty acid
synthase complex?
 Fatty acyl synthase

Note that during biosynthesis all intermediates remain

covalently linked to the fatty acid synthetase complex.
This is a clear example of channeling: the intermediates do not
equilibrate with the bulk phase.
Elongation
• The elongation cycle is repeated six more times, using malonyl–CoA
each time, to produce palmityl–ACP.

• A thioesterase then cleaves the palmityl–CoA from the ACP.

34
 Palmitic acid
modifications

Cell makes a pool of

palmitic acid that it can
elongate and/or
desaturate in the ER.

Elongation system is
very similar to synthesis:
2C units added from
malonyl-CoA.
Origin of the reactants for fatty acid biosynthesis
Oxaloacetate + NADH + H+  Malate + NAD+
Fatty acid biosynthesis occurs in the cytopl. malate dehydrogenase
cytosol except in plants where it takes
place in the chloroplasts.
What is the origin of NADPH?
• pentose-P pathway
• conversion of cytoplasmic NADH to
cytoplsamic NADPH
What is the origin of ATP?
Glycolysis

NADH + OAA + NADP+  Pyruvate + NADPH + H+ + CO2

cytoplasma mitochondria
4 glucose 8 pyruvate 8 acetyl-CoA

8 ATP 8 (NADH + H+)

8 (NADH + H+) 24 ATP (ox- phos)
Fatty Acid Metabolism
• Which enzyme plays a key role in regulating fatty acid metabolism?
• acetyl CoA carboxylase
• Global control of ACC by glucagon, epinephrine and insulin
• insulin activates
• glucagon and epinephrine inactivate
Biosynthesis of triacylglycerols

In humans and other vertebrates,

carbohydrates, fats or proteins in excess of
energy needs are stored in the form of
triacylglycerols to withstand periods of
fasting.
Biosynthesis of triacylglycerols
Breakdown of Triacylglycerols
• In the adipose tissue, lipases are activated by hormone
signaled phosphorylation

40
Fatty acid oxidation
• Each round in fatty acid degradation involves four reactions

41
Mobilization of stored triacylglycerols
The use of glycerol
 Stages of fatty acid oxidation

Stage 1:
Removal of successive 2-carbon units in the form of
acetyl-CoA.
During each cycle of -oxidation, 1 mole of NADH
and FADH2 are formed.
Stage 2:
The acetyl-CoA generated is further oxidized in the
citric acid cycle
Stage 3:
The NADH and FADH2 formed in stage 1 and stage 2
generates ATP through oxidative phosphorylation
Fatty acid degradation: the -oxidation

Important:
Not water but free coenzyme A is used to
split off the carboxyl terminal 2-carbon atom
fragment of the original fatty acid as acetyl-
CoA. The other product formed is again an
activated fatty acid that can enter the next
round of the -oxidation.

Activation of fatty acids only

occurs once, irrespective of the number of
carbon atoms originally present.
Example of the successive removal
of 2-carbon atoms in each cycle of
the -oxidation of palmitate
(C16:0) with the concomitant
formation of acetyl-CoA

Palmitoyl-CoA + 7 CoA
+ 7 FAD + 7 NAD+ + 7 H2O

8 acetyl-CoA + 7 FADH2 + 7 NADH + 7H+

Get surprized:
calculate the number of ATPs formed
through the oxidation of palmitate !!
Fatty Acid Degradation
• What are the products of fatty acid degradation?
• For a C16 fatty acid
• 8 acetyl CoA
• 7 FADH2
• 7NADH + 7 H+
• How much energy does this generate?
• 7 x 1.5 ATP = 10.5
• 7 x 2.5 ATP = 17.5
• 8 x 10 ATP = 80
• Total = 108 ATP – 2 ATP (activation) = 106 ATP
Ketone Bodies
• Use of fatty acids in the citric acid cycle requires carbohydrates for the
the production of oxaloacetate.

• During starvation or diabetes, OAA is used to make glucose

• Fatty acids are then used to make ketone bodies (acetoacetate and
D–3–hydroxybutarate)

48
Ketone bodies: condensation products of acetyl-CoA

Ketone bodies, acetoacetate

and 3–hydroxybutarate are
formed from Acetyl–CoA
Ketone Bodies as a Fuel Source
• The liver is the major source of ketone bodies.
• It is transported in the blood to other tissues

• Acetoacetate in the tissues

• Acetoacetate is first activated to acetoacetate by transferring the CoASH from
succinyl–CoA.

• It is then split into two Acetyl–CoA by a thiolase reaction

50
Cholesterol synthesis
• Synthesis of cholesterol takes place in cytosol.

• The carbon skeleton of cholesterol is formed from acetyl

CoA. The pathway of cholesterol biosynthesis has over 30
steps.

• The rate determining step of cholesterol synthesis and the

major control point is the conversion of β-Hydroxy β-
methylglutaryl-CoA (HMG-COA) to mevolonic acid.

• Some intermediate steps of cholesterol synthesis are

mevolonic acid— squalene— zymosterol—cholesterol.
 HMG CoA Reductase
(More Than Cholesterol Synthesis)
Acetyl CoA

HMG CoA (β-Hydroxy β-methylglutaryl-CoA)

HMG CoA Reductase
Isopentenyl
Mevalonate
adenine
(transfer RNA)
3renylation of Farnesyl 3yrophosphate
signalling peptides
(ras, rho, etc.) Ubiquinones
(CoQ-10, etc.)
Dolichols Cholesterol
Inhibition of other key products of mevalonate may relate to
nonlipid effects & rare side effects of statins.
Cholesterol Ester Synthesis
Acyl-Cholesterol Acyl Transferase (ACAT)
Cholesterol

COOH HO
Cholesterol
Ester

COO

Lecithin-Cholesterol Acyl Transferase (LCAT)

Lysolecithin COO COO

COO COO

+ N OPOO + N OPOO
The fate of cholesterol

1. It can be incorporated
into a cell membrane.
2. It may be acylated to
form cholesteryl ester
for storage.
3. It is precursor of steroid
hormone (estrogen,
testosterone)
4. It is a precursor of bile
acids.
 Vitamin D
The fat-soluble vitamins, A, D, E, and K, are all derived from
isoprene units. Vitamins A and D are precursors of hormones.
Vitamin D3, also called cholecalciferol, is normally formed in the
skin from 7-dehydrocholesterol in a photochemical reaction driven
by UV light absorption. Vitamin D3 itself is not biologically active,
but is converted by enzymes in the liver and kidney to 1,25-
dihydroxyvitamin D3 (calcitriol). Calcitriol is a hormone that
regulates calcium uptake in the intestine and calcium levels in
kidney and bone. The deficiency of vitamin D leads to defective
bone formation and the disease rickets, for which administration of
vitamin D produces a dramatic cure. Vitamin D2 (ergocalciferol) is a
commercial product formed by UV irradiation of ergosterol from
yeast, which resembles vitamin D3. It is further processed to a
calcitriol-like active hormone. Vitamin D2 is added to milk and
butter as a dietary supplement. Calcitriol regulates gene expressing
by interacting with specific nuclear receptor proteins.
 Vitamin A
Vitamin A1 (retinol) derivatives function as a hormone and as the
visual pigment of the vertebrate eye. The vitamin A derivative,
retinoic acid, is a hormone that regulates gene expression by binding
to nuclear receptor proteins. Retinoic acid is required for the
development of epithelial tissues, including the skin. It also is the
active ingredient in the drug tretinoin (Retin-A) used in the
treatment of acne and wrinkled skin. Retinal, another vitamin A
derivative, is the pigment that initiates the response of rod and
cone cells of the retina to light, producing a neuronal signal to the
brain. Good sources of vitamin A are fish liver oils, liver, eggs,
whole milk, and butter. In vertebrates, ß-carotene, the pigment
that gives carrots, sweet
potatoes, and other yellow
vegetables their characteristic
color, can be enzymatically
converted to vitamin
A1 .Deficiency of vitamin A leads
to dryness of the skin, eyes, and
mucous membranes; retarded
development and growth; and
night blindness, an early symptom
commonly used in diagnosing a
vitamin A deficiency.
 Other Isoprenoids (I)
Vitamin E is the collective name for a group of closely related lipids
called tocopherols, all of which contain a substituted aromatic ring
and a long isoprenoid side chain. As hydrophobic molecules,
tocopherols associate with cell membranes, lipid deposits, and
lipoproteins in the blood where they react with and destroy oxygen
radicals and other free radicals that would otherwise react with
and damage unsaturated fatty acids in membrane lipids. Good
sources of vitamin E include vegetable oils, eggs, and wheat germ.
Laboratory animals fed vitamin E-depleted diets develop scaly skin,
muscular weakness and wasting, and sterility. In humans, vitamin E
deficiency is rare, and the principal symptom is fragile red blood
cells.
 Other Isoprenoids (II)
Vitamin K is a cofactor that is required for the synthesis of
prothrombin, a blood protein essential in blood coagulation. Vitamin
K deficiency slows blood clotting and therefore can be fatal.
Vitamin K1 (phylloquinone) is present in green leafy vegetables. A
related molecule that is biologically active, vitamin K2 (menaquinone)
is formed by bacteria living in the intestine of vertebrates. The
drug warfarin is a synthetic compound that inhibits the synthesis of
active prothrombin by competing with vitamin K for binding to the
enzyme that modifies prothrombin. Warfarin is an important
anticoagulant drug which is used to treat patients prone to
thromboses. It also is used as a rat poison, causing death by
internal bleeding.
 Other Isoprenoids (III)
Ubiquinone (also called coenzyme Q) and plastoquinone are
isoprenoids that function as lipophilic electron carriers in oxidation-
reduction reactions used for ATP synthesis in mitochondria and
chloroplasts, respectively. Both molecules can carry either one or
two electrons and either one or two protons. Dolichols carry the
sugar units that are added to glycoproteins and glycolipids during
their synthesis. Hydrophobic dolichol molecules are anchored to the
membrane where these sugar-transfer reactions take place.
Summary of lipid metabolism
Eicosanoid Hormones
• Eicosanoid horomones are synthesized from arachadonic acid (20:4).
• Prostaglandins
• 20-carbon fatty acid containing 5-carbon ring
• Prostacyclins
• Thromboxanes
• Leukotrienes
• contain three conjugated double bonds

68
Eicosanoid Hormones

69
Eicosanoid Hormones

70
Eicosanoid Hormones

71
 Aspirin and Prostaglandins
Aspirin inhibits prostaglandin synthesis by
acetylating cyclooxygenase, an enzyme necessary
for prostaglandin synthesis
 Fatty acid/β-Oxidation
Very long chain = C14 to 20
palmitate
Long chain = C10 to 14
carnitine shuttle

palmitoyl-CoA (C16) FAD

Medium chain = C6 to 10
Acyl-CoA dehydrogenase
FADH2
trans-� 2-enoyl-CoA

enoyl-CoA dehydratase
acetyl-CoA
C4 C6 C8 C10 C12 L-3-hydroxyacyl-CoA NAD+

L-3-Hydroxyacyl-CoA dehydrogenase
NADH
3-ketoacyl-CoA

myristoyl-CoA (C14) thiolase CoASH

acetyl-CoA
 β-Oxidation Disorders
• Medium-chain acyl CoA dehydrogenase – autosomal recessive, preprandial irritability, lethargy,
jitteriness, sweating, seizures, tachypneic, somnolent, mildly enlarged liver, decreased serum bicarbonate
concentration, increased serum anion gap, hypoglycemia, hypoketonuria, hyperammonemia, increased
urine monocarboxylic fatty acids and dicarboxylic organic acids (adipic, C6; suberic, C8; sebacic, C10; and
dodecanedioic,C12), enzyme assay, molecular genetic testing. Treatment with increased calories from
carbohydrates and protein, limited fats, avoid periods of fasting.

• Very long-chain acyl CoA dehydrogenase – autosomal recessive, cardiomyopathy, hypotonia,

hepatomegaly, hypoketotic hypoglycemia, increased serum C14:1, C14:2, C14, and C12:1 straight-chain
acyl-carnitine esters, 3-hydroxy-acyl carnitine esters, and unsaturated acyl-carnitine esters, enzyme assays,
molecular genetics testing. Treatment with increased calories from carbohydrates and protein, medium-
chain triglycerides, avoid periods of fasting.

• Long-chain 3-hydroxyacyl CoA dehydrogenase – autosomal recessive, cardiomyopathy, hypotonia,

hepatomegaly, hypoketotic hypoglycemia, decreased serum carnitine, increased serum 3-
hydroxydicarboxylic derivatives of the C16:0, C18:1, and C18:2 species, increased urine 3-hydroxylated
dicarboxylic acids, enzyme assay, molecular genetics testing. Treatment with increased calories from
carbohydrates and protein, medium-chain triglycerides, avoid periods of fasting.
 Cholesterol Pathway
Δ7-reductase
3-hydroxy-3-methylglutaryl CoA 7-dehydrocholesterol cholesterol

HMG CoA reductase

Δ24-reductase Δ24-reductase
mevalonate
Δ7-reductase
Mevalonate kinase 7-dehydrodesmosterol desmosterol

phosphomevalonate Δ5-dehydrogenase

cholesta-7,24-dien-3β-ol
Δ8,Δ7-isomerase
isopentenyl pyrophosphate

lathosterol zymosterol

farnesyl pyrophosphate

Squalene synthase

squalene lanosterol
 Cholesterol Pathway Disorders
• Mevalonate kinase – rare, autosomal recessive, less- and more-severe types, less-severe
(Hyperimmunoglobulinemia D syndrome) has fever episodes with lymphadenopathy, abdominal pain,
joint pain, diarrhea, skin rashes, and headache, more-severe (Mevalonic aciduria) has (fever or no
fever) developmental delay, progressive ataxia, progressive problems with vision, and failure to gain
weight and grow at the expected rate, unusually small, elongated head, increased serum
immunoglobulins A and D concentrations (less-severe type), increased urine excretion of mevalonic
acid, enzyme assays. Treatment is supportive.

• 7-Dehydrocholesterol reductase (3β-Hydroxysteroid-Δ7-reductase) – autosomal recessive

(Smith-Lemli-Opitz syndrome), dysmorphic facial features, microcephaly, second-toe and third-toe
syndactyly, intrauterine growth retardation, short stature, abnormally low weight for height,
hypotonia, distinctive shrill cry, decreased serum cholesterol concentrations, increased serum
dehydrocholesterol concentrations. Treatment is supportive.

• Δ8,Δ7-isomerase – X-linked dominant (CHILD syndrome), dysmorphic facial features, microcephaly,

second-toe and third-toe syndactyly, intrauterine growth retardation, short stature, abnormally low
weight for height, hypotonia, distinctive shrill cry, decreased serum cholesterol concentrations,
increased serum dehydrocholesterol concentrations. Treatment is supportive
Disorders of Cholesterol and Lipoproteins in 3
Categories
• Specific Familial/Genetic Disorders
• These comprise a small minority of patients
• Secondary to other Diseases
• Diabetes, Hypothyroid, Nephrotic syndrome, Renal Failure, Lupus
• Dietary/Polygenic --(most common)
• This is the great majority of patients with elevated cholesterol/LDL
 Steroid Pathway
cholesterol

Desmolase (CYP11A1)
17-Hydroxylase (CYP17A1) 17-Hydroxylase (CYP17A1)
pregnenolone 17α-hydroxypregnenolone dehydroepiandrosterone

3β-Hydroxysteroid 3β-Hydroxysteroid 3β-Hydroxysteroid

dehydrogenase dehydrogenase dehydrogenase
progesterone 17α-hydroxyprogesterone androstenedione
17-Hydroxylase (CYP17A1) 17,20-Lyase (CYP17A1)
Aromatase
21-Hydroxylase 21-Hydroxylase
(CYP21A2) (CYP21A2) 17-Ketoreductase
11-deoxycorticosterone 11-deoxycortisol testosterone estrone

11-Hydroxylase 11-Hydroxylase 17-Keto-

(CYP11B1) (CYP11B1) Aromatase
reductase
corticosterone
estradiol
Aldosterone synthase
5α-Reductase
(CYP11B2)
aldosterone cortisol dihydroxytestosterone
 Steroid Pathway Disorders
• Desmolase – very rare (lipoid adrenal hyperplasia), autosomal recessive poor weight gain, vomiting,
males are undervirilized, dehydration, hyperpigmentation, increased serum ACTH, hyponatremia,
hyperkalemia, metabolic acidosis. Treatment with saline and fludrocortisone, female also with
estrogen replacement.

• 17-Hydroxylase – very rare (congenital adrenal hyperplasia), autosomal recessive, patients with XX
or XY karyotypes are phenotypic females or ambiguous genitalia, hypertension, hypokalemia,
metabolic alkalosis, increased serum progesterone, corticosterone, and deoxycorticosterone
concentrations, decreased 17-hydroxyprogesterone, estrogens, and androgens concentrations.
Treatment with glucocorticoid and estrogen replacement, salt restriction, diuretics as appropriate.

• 3β-Hydroxysteroid dehydrogenase – very rare (congenital adrenal hyperplasia), autosomal

recessive, ambiguous genitalia or female genitalia, hyperpigmentation, increased serum 11-
deoxycortisol and deoxycorticosterone, increased ratio of 24-hour urine metabolite of 11-
deoxycortisol to metabolite of cortisol. Treatment with glucocorticoid and mineralocorticoid therapy
as appropriate.

@DELIGATE
 Steroid Pathway Disorders
• 21-Hydroxylase – very rare (most common congenital adrenal hyperplasia), autosomal recessive,
males have failure to thrive, recurrent vomiting, dehydration, hypotension, hyponatremia,
hyperkalemia, shock, accelerated growth and skeletal maturation; in addition, females have
ambiguous genitalia at birth, later in childhood with precocious pubic hair, clitoromegaly, increased
serum 17-hydroxyprogesterone concentrations, increased urine pregnanetriol concentrations.
Treatment with glucocorticoid and mineralocorticoid therapy as appropriate.

• 11-Hydroxylase – very rare (congenital adrenal hyperplasia), autosomal recessive, androgen excess,
masculinization of female newborns and precocious puberty in male children, hypertension, increased
serum 11-deoxycortisol and deoxycorticosterone, urine 17-ketosteroids, dehydroepiandrosterone,
dehydroepiandrosterone sulfate, and androstenedione, and testosterone. Treatment with
glucocorticoid replacement and antihypertensive therapy.

• Aromatase – very rare, autosomal recessive, virilization manifests as pseudohermaphroditism in

female infants, affected males do not present with obvious defects at birth, tall stature, delayed
skeletal maturation, delayed epiphyseal closure, bone pain, eunuchoid body proportions and excess
adiposity, increased serum testosterone concentrations. Treatment with estrogen replacement.
 Steroid Pathway Disorders
• Aldosterone synthase – rare, autosomal dominant, autosomal recessive, severe salt-wasting in
infancy or stress-induced hyperkalaemia and postural hypotension in adulthood, increased serum
renin activity, decreased serum aldosterone concentrations, increased serum 18-
hydroxycorticosterone. Treatment with mineralocorticoid therapy (fludrocortisone) and sodium
supplementation.
• 5α-Reductase – rare, autosomal recessive, ambiguous genitalia, clitoral-like phallus, markedly bifid
scrotum, pseudovaginal perineoscrotal hypospadias, rudimentary prostate, uterus and fallopian tubes
are absent, testes are intact and usually found in the inguinal canal or scrotum, amniocentesis or
chorionic villus sampling show XY karyotype, fluorescent in situ hybridization results positive for sex-
determining region, increased serum testosterone-to-dihydrotestosterone ratio, molecular genetics
studies. Treatment considerations of gender assignment.
• 17-Ketoreductase – rare, autosomal recessive, characterized by clitoromegaly, posterior
labioscrotal fusion and perineal blind vaginal pouch, testes are inguinal or in the labioscrotal folds,
internal urogenital tract (epididymides, vasa deferentia, seminal vesicles, ejaculatory ducts) well
developed; prostate and Müllerian structures are absent, baseline and post-human chorionic
gonadotropin stimulation hormonal evaluation shows increased androstenedione and decreased
testosterone concentrations, with an increased androstenedione-to-testosterone ratio. Treatment
considerations of gender assignment.
 Sphingolipid Storage Diseases
Disease Symptom Sph. Lip Enzyme
Tay-Sachs Blindness, Ganglioside -hexose-
muscles weak GM2 aminidase A
Gaucher’s Liver & spleen Gluco- -glucosidase
enlarge, MR cerebroside
Krabbe’s demyelation, Galacto- -galactosidase
MR cerebroside
Nieman- MR Sphingomyelin Sphingomyelinase
Pick