Biochemistry of CNS Module

Bahir Dar University
College of Medicine and Health

Sciences Department of Biochemistry
Nervous system Biochemistry

By: Endalamaw Tesfa (PhD fellow)
1 Endalamaw T 7/18/2014
Learning Objectives
At the end of this module students will be able to;
Explain about NS metabolism
Define what are NTs
List the different types of NTs
Describe the synthesis & storage of NTs
Explain about nicotine toxicity
Metabolism of the Brain:
Glucose is the primary fuel for brain
Glucose is transported into brain by GLUT3.
Lipids are unable to pass the BBB
AAs are available in brain in limited quantities
The brain constantly dependent on blood glucose
During development, starvation & intense physical
activity brain use ketone bodies
Brain During fed state:
 Brain didn’t have glycogen store
 Brain consume 20% O2 & 25% glucose at rest
 During fed state, brain uses glucose exclusively
 Brain oxidizing about 140 g/day to CO2 & H2O
 Brain did not contain TAG & FAs stores
 Brain uses energy at a constant rate, since the brain is
vital for the proper operation of all organs
Brain in Fasting
During the initial days of fasting, the brain
continuously uses glucose exclusively as a fuel & this is
maintained by hepatic gluconeogenesis
In prolonged fasting (> 2-3 weeks), plasma ketone
bodies become an important energy source of brain
which deceased protein that undergo catabolism
5 EndalamawT 9/21/2021
Brain in Fasting
Ketone bodies replace glucose and muscle protein.
The metabolic changes that occur during fasting ensure
that all tissues have an adequate supply of fuel molecules.
 The response of the major tissues involved in energy
metabolism during fasting
Definitions of NTs
NTs are chemical compounds released by one neuron
that affects another neuron or an effector organ
The NTs are stored at the presynaptic site in vesicles,
near the plasma membrane of the axon terminal.
NT release in response to the arrival of an action
potential at the synapse
Receptors are mainly located on the postsynaptic
neurons
Hormones & NTs
The distinction between hormones & NTs is
physiological.
NTs is a compound that acts a short distance across a
synapse 12 X 10-6 cm2
Hormones are compound that acts a long distance (20
cm) from the secretory gland to the target cell.
For example, E & NE are both NTs & hormones.
Properties of NTs:
1. NTs are synthesized in the presynaptic neuron
2. Localized in the vesicles of presynaptic neuron
3. Released from the presynaptic neuron under
physiological conditions
4. Rapidly removed from the synaptic cleft and taken by
enzymatic degradation or by diffusion
5. Had receptors on the post-synaptic neuron
6. Binding of NT elicits a Biological Response
Classification of NTs Based on Their
A. Based on Their Function
1. Excitatory NTs:
 Create excitatory postsynaptic potentials
 Stimulate neuron production of an action potential
e.g. Epinephrine, Norepinephrine, Glu, Asp etc
2. Inhibitory NTs:
 Create inhibitory postsynaptic potentials
 Reduce probability that neuron will show an action
potential
 E.g. Gly, GABA, Dopamine , Serotonin
 Some NTs are both inhibitory and excitatory,
depending upon situation and location
B. NTs Based on Their Structure
1. Nitrogen-containing NTs (Classical NTs)
Synthesized in the cytoplasm from AA & intermediates
of glycolysis & TCA cycle
 Mediate rapid synaptic actions
 Acetylcholine
 Biogenic Amines (dopamine, NE, E, serotonin,
histamine)
 Amino Acids (Glycine, Aspartate, Glutamate, GABA)
 Gases
Endalamaw T
(NO, H2Sand CO)
12 7/18/2014
2. Neuroactive Peptides
 They are usually small peptides
 Synthesized within the CNS of rough ER & processed for
secretion by the Golgi apparatus
 Some of these peptides have targets
 Whereas others are released into the circulation to bind to
receptors on other organs (GH & TSH).
 Many neuropeptides are synthesized as a larger precursor,
which is then cleaved to produce the active peptides.
Types of neuroactive peptides
1. Hypothalamic- Releasing Hormones
2. Neurohypophyseal Hormones (ADH & oxytocin)
3. Adenohypophyseal Hormones (e.g., GH,
endorphins, MSH)
4. GI Peptides – (e.g., Gastrin, substance P, insulin,
glucagon, vasoactive intestinal peptide)
5. Others – (angiotensin, bradykinin, sleep peptides)
NT Synthesis
Most of the NTs are synthesized from AAs,
intermediates of glycolysis & TCA cycle, and O2 in the
cytoplasm of the presynaptic terminal
The rate of synthesis is generally regulated to
correspond to the rate of firing of the neuron
NTs are transported into storage vesicles by an ATP-
requiring pump
Release from the storage vesicle is triggered by the
nerve impulse that depolarizes the postsynaptic membrane
& causes an influx of Ca+2 ions through voltage-gated Ca+2
channels.
Influx of Ca+2 promotes fusion of the vesicle with the
synaptic membrane & release NT into the synaptic cleft.
The transmission across the synapse is done by binding
of the NT to a receptor on the postsynaptic membrane
 The action of NT is terminated though;
 Reuptake into the presynaptic terminal
 Diffusion away from the synapse
 Enzymatic inactivation
 The enzymatic inactivation may occur;
 In the postsynaptic terminal
 In the presynaptic terminal
 On an adjacent astrocyte or microglial cells
 The BBB affects the supply of precursors of NT
18 synthesis
Endalamaw T 7/18/2014
Acetylcholine (Ach)
It synthesized from acetyl CoA & choline by the
enzyme choline acetyltransferase (ChAT)
It is stored in vesicles & released by Ca+2 -mediated
exocytosis
Choline is taken up by the presynaptic terminal from
the blood
Choline derived from phosphatidylcholine
Membrane lipids are storage sites for choline
Choline is a common component of the diet but also can
be synthesized in human as synthesis of phospholipids.
Choline synthesized via the sequential addition of 3
methyl groups from SAM to the ethanolamine portion of
phosphatidylethanolamine to form phosphatidylcholine.
Phosphatidylcholine is subsequently hydrolyzed to
release choline or phosphocholine
Conversion of phosphatidylethanolamine to
phosphatidylcholine occurs in mainly in liver & brain
This
21 conversion
Endalamaw T requires vitamin B6- & B12 7/18/2014
Inactivation of Ach
Ach is the major NT at the NMJs
Ach is inactivated by acetylcholinesterase
This rapid removal enables the nerves to transmit more
than 100 signals per second
The enzyme is inhibited by a wide range of compounds
Inability to inactivate Ach leads to constant activation
of the nerve muscle synapses that leads to paralysis.
Acetylcholine Synthesis & Degradation
Acetylcholine Receptors
Acetylcholine had two types of receptors
1. Nicotinic acetylcholine receptors (nAChR)
2. Muscarinic acetylcholine receptors (mAChR)
 nAChR are pentameric ligand-gated ion channels & mAChR are
G-coupled receptors
Nicotinic Receptors
Directly coupled to cation channels
Mediate fast excitatory synaptic transmission at NMJ,
Autonomic ganglia and at various sites of CNS
Nicotinic receptors are classified into three
1. Muscle type NM (Muscle nAChR)
2. Neuronal type NN (Neuronal nAChR)
3. Ganglionic type GN (Ganglionic nAChR)
Nicotine is a bitter-tasting compound that naturally
occurs in large amounts in the leaves of tobacco plants
Nicotine binds to nicotinic cholinergic receptors,
facilitating the release of Dopamine, Glu & GABA
Nicotine Toxicity
 Dopamine, Glu & GABA are important for the
development of nicotine dependence and corticotropin-
releasing factor appears to contribute to nicotine
withdrawal
 Nicotine poisoning results from too much nicotine intake.
 Acute nicotine poisoning usually occurs in young
children who chew on nicotine gum or patches
 Nicotine is rapidly absorbed after ingestion & inhalation
 In young children, ingestion of 1 to 2 mg of nicotine has
been associated with signs of toxicity
 Nicotine is primarily metabolized by CYP2A6, and
variability in rate of metabolism contributes to
vulnerability to tobacco dependence, response to smoking
cessation treatment, and lung cancer risk.
Catecholamine Biosynthesis
1. Hydroxylation:
 The reaction involves the conversion of tyrosine, O2 and
tetrahydrobiopterin to dopa & dihydrobiopterin.
 It is irreversible rate limiting step
 This reaction is catalyzed by tyrosine hydroxylase.
 Present in adrenal medulla, brain, and all sympathetically
innervated tissues
 Rate-limiting enzyme & activated by phosphorylation
 Converts tyrosine into DOPA
2. Decarboxylation:
 Dopa decaboxylase catalyze the decarboxylation of
dopa to produce dopamine
 Deficiency of this enzyme causes Parkinson’s disease
 It is irreversible reaction
 PLP is the cofactor for this reaction
 In Dopaminergic neurons stop synthesis at this point,
because these neurons do not synthesize the enzymes
required for the subsequent steps
3. Hydroxylation:
 This is an irreversible reaction
 It is catalyzed by dopamine β- hydroxylase
 It changes dopamine to norepinephrine
 The reactants include dopamine, O2 and ascorbate
 Ascorbic acid serves as the electron donor and is
oxidized in the reaction
 The products are NE, H2O & dehydroascorbate
4. Methylation:
 This reaction is catalyzed by phenylethanolamine N-
methyltransferase
 NE & S-adenosyl methionine form epinephrine &
S-adenosyl homocysteine
 Epinephrine synthesis is dependent on the presence of
adequate levels of B12 and folate
Catecholamine Biosynthesis
Storage & Release of Catecholamines
Events begin when a message is transmitted from one
neuron to the next by NTs
The message is initiated by calcium ions
 When the concentration in a neuron reaches a certain level
(more than 0.1 mM), the vesicles containing Ach fuse with the
presynaptic membrane of the nerve cells
Then they empty the NTs into the synapse
The messenger molecules travel across the synapse and are
adsorbed onto specific receptor sites
Inactivation of Catecholamines
Catecholamines are inactivated by oxidative
deamination through monoamine oxidase (MAO) &
catechol-o-methyl-transferase (COMT)
MAO is present on the outer mitochondrial membrane
MAO oxidizes the carbon containing amino group to an
aldehyde, thereby releasing NH4+
In the presynaptic terminal, MAO inactivates
catecholamines that are not protected in storage vesicles
There are two isoforms of MAO
MAO-A preferentially deaminates NE & serotonin,
whereas MAO-B acts on phenylethylamines
MAO in the liver and other sites protects against the
ingestion of dietary biogenic amines
COMT can metabolize both intra- or extracellularly & it
is also found in many cells, like; erythrocyte
It works on a broad spectrum of extraneuronal catechols
and those that have diffused away from the synapse
COMT transfers a methyl group from SAM to a
hydroxyl group of catecholamine in the presence of Mg2+,
vitamins B12 and folate
The metabolic products of MAO and COMT are
excreted in the urine as vanillylmandelic acid,
metanephrine & normetanephrine
Cerebrospinal homovanillylmandelic acid is an indicator
of dopamine degradation
Its concentration is decreased in Parkinson’s disease
Inactivation of Norepinephrine
Dopamine (DA)
 Dopamine is a monoamine NT that upon binding to a
dopamine receptor (G-protein coupled) releases a
variety of downstream signals
 Dopamine is mainly synthesized in areas of the CNS
and PNS, such as in the hypothalamus
Actions of Dopamine
 Dopamine released into synaptic cleft
 Once done, dopamine is taken back
into the cell, so not too much is
present in the cleft
 The control mechanism for this
signaling is found in the endorphin
 Endorphin can either enhance of
inhibit the action of dopamine
Functions of Dopamine
Dopamine plays a major role in drug addiction
Dopamine involved in pleasure (cocaine blocks its reuptake)
Dopamine involved in goal-directed behaviors, reward-
learning, sexual responses, sleep-wake cycle and movement
control
Agonists are drugs bind to dopamine receptor and stimulate
dopamine receptor
Antagonists are drugs that bind but don't stimulate
dopamine receptors and prevent the actions of dopamine
Dopamine-Related Diseases
Dopamine deficiency in the striatum or substantia nigra
results in Parkinson’s disease
In this case, movement becomes slow and rigid,
accompanied by muscle tremor
An excessive amount of dopamine leads to
schizophrenia, characterized by altered behavior, &
delusions
A deficiency of dopamine causes depression
Norepinephrine & Epinephrine
Outside the NS, NE, and E act as regulators of CHO &
lipid metabolism
NE & E are released from storage vesicles in the
adrenal medulla in response to fear, exercise, cold and low
levels of blood glucose
They increase the degradation of glycogen and TAG as
well as increase blood pressure and the output of the heart
Norepinephrine (NE)
NE recognized as a secretory product of the adrenal
medulla and a major NT of the postganglionic sympathetic
nerves
Local NT in the peripheral nerves
Acts locally and reaches general circulation only when
intense activation
The synthsesis of catecholamines in the CNS,
sympathetic postganglionic neurons and chromaffin tissue
Carbohydrate Metabolism
Hyperglycemia (α and β receptor)
Glycogenolysis↑↑ (in liver & skeletal muscle) →
plasma glucose↑↑
Gluconeogenesis↑↑ → plasma glucose↑↑
 Insulin secretion↓↓ → plasma glucose ↑↑
α-receptors inhibit β cell insulin secretion
β-receptors stimulate α cell glucagon secretion
Fat Metabolism
 Catecholamines cause lipolysis (β receptor)
The products are used as energy sources
Lipolysis increase → plasma FFA↑↑ → FFA serves as
energy source and precursor for glucose formation
A reduced production of NE results in obesity
Protein Metabolism
Protein degradation↓, plasma AA levels decreased
Epinephrine acting on β-adreno receptors decreases the
release of AAs from muscle via proteolysis inhibition
This increases the energy available
Serotonin
Serotonin had multiple roles like; mood stabilization, feelings of
well-being and happiness.
90% of all serotonin in human body in the GIT, 8% in blood
platelets & 2% in CNS
Neurons in brain make their own; none from body crosses Blood
Brain Barrier (BBB).
Serotonin is synthesized from Tryptophan AA
Its deficiency causes mood disorders, anxiety & sleep disorder
The synthesis of serotonin involve two reactions
Serotonin function
Serotonin Biosynthesis:
1.Tryptophan Hydroxylase;
High serotonin levels within neuron do not inhibit
enzyme synthesis-serotonin just builds up
 Rate of enzyme activity can be modulated by cAMP
 Also, can be modulated by O2 levels in blood; more
O2, more serotonin synthesis
2.5-hydroxytryptophan( 5HTP) Decarboxylase:
Enzyme production and serotonin synthesis is rapid
Can't manipulate serotonin by manipulating this
enzyme.
Release of serotonin is Ca+2 dependant, Ca+2 must come
into trigger release.
Inactivation & Breakdown
Action terminated by active reuptake process into
neurons and ganglia.
 Then broken down by MAO.
MAO breaks down 5HT into several things.
 5-hydrozindoleacetic acid (5HIAA) is a metabolite that
is often used to index activity in system
The NT melatonin is also synthesized from tryptophan.
 Melatonin is produced in the pineal gland in response
to the light–dark cycle, its level in the blood rising in a
dark environment.
It is probably through melatonin that the pineal gland
conveys information about light–dark cycles to the body,
organizing seasonal and circadian rhythms.
Melatonin also may be involved in regulating
reproductive functions.
Synthesis & Inactivation of Serotonin
Tyramine & Tryptamine
Tyramine:
Synthesized by the decarboxylation of tyrosine in kidneys
and GIT by intestinal bacteria, has limited biological role.
At high levels, it increase blood pressure.
Tryptamine:
The decarboxylation product of tryptophan is tryptamine.
It is synthesized in kidneys, liver & GIT bacteria.
The biological significance of tryptamine is that it is the
precursor for serotonin synthesis.
Decarboxylation of
Lys & Arg changed into
corresponding diamines
cadaverine &
Putrescine respectively
Which are largely
excreted in feces, but are
essentially non-toxic.
Cadaverine & Putrescine
 Cadaverine synthesized from lysine AA by lysine
decarboxylase
 Putrescine is formed by the decarboxylation of ornithine
and arginine
 Both are foul-smelling compounds produced when AAs
decompose in decaying animals
 Over expression of lysine decarboxylase leads to
accumulation of cadaverine in growing cells
 In plants, cadaverine involved plant growth and
development, cell signaling, stress response, and insect
defense
Cadaverine Metabolism
Octopamine
 It is a biogenic monoamine
structurally and functionally
related to NE.
 It is synthesized from tyramine by
the tyramine β-hydroxylase
 Octopamine has no physiological
role in vertebrates, making it the
focus of much pesticide research.
 Octopamine may function as a
cotransmitter together with NE in
the peripheral sympathetic NS
 Octopamine may function as a
neurotransmitter in lower animals.
Oxytocin
 Oxytocin is a hormone and a neurotransmitter produced
in the hypothalamus and released during sex, childbirth,
and lactation
 It has physical and psychological effects in influencing
social behavior and emotion.
 Oxytocin is prescribed as a drug for obstetric and
gynecological reasons and used in childbirth
Oxytocin Targets
Glutamate
It is an excitatory NT within the CNS.
Glutamate is synthesized from α-ketoglutarate
Synthesized from glutamine in neurons by glutaminase
Taken up by neurons and glutaminase in mitochondria
convert it to glutamate
Most important NT for brain function
High levels of extracellular glutamate are toxic to neurons
Released from neurons after trauma & cannot cross BBB
Synthesis of Glutamate
Glutamate dehydrogenase, which reduces -ketoglutarate to
glutamate, by incorporating free NH3 into the carbon backbone.
The second route is through transamination reactions in
which an amino group is transferred from other AAs to -
ketoglutarate to form glutamate.
Glutamate is stored in vesicles, and its release is Ca2+ -
dependent.
It is removed from the synaptic cleft by high-affinity uptake
systems present in nerve terminals and glial cells.
Synthesis of Glutamate & GABA
γ-Aminobutyric Acid (GABA)
It is a major inhibitory NT in the CNS
It is synthesized by the decarboxylation of glutamate by
the enzyme glutamic acid decarboxylase (GAD)
It plays functional a role in many neurologic &
psychiatric disorders
GABA is recycled in the CNS by a GABA shunt, which
conserves glutamate & GABA
Much of the uptake of GABA occurs in glial cells.
The GABA shunt in glial cells produces glutamate,
which is converted to glutamine and transported out of the
glial cells to neurons, where it is converted back to
glutamate
 Glutamine thus serves as a transporter of glutamate
between cells in the CNS
 Glial cells lack GAD and cannot synthesize GABA
Histamine
Histamine is derived from the decarboxylation of the
AA histidine by mast cells & by certain neuronal fibers.
Histamine is stored within the nerve terminal vesicle.
 Depolarization of nerve terminals activates the
exocytotic release of histamine by voltage-dependent as
well as a calcium-dependent mechanism.
The first step in the inactivation of histamine in the
brain is methylation.
The enzyme histamine methyltransferase transfers a
methyl group from SAM to a ring nitrogen of histamine to
form methylhistamine.
The second step is oxidation by MAO-B, followed by an
additional oxidation step.
In peripheral tissues, histamine undergoes deamination
by diamine oxidase, followed by oxidation to a carboxylic
acid
Biogenic amine regulating physiological function in the
gut & acting as a NT
Histamine causes several allergic symptoms.
1. It contributes to an inflammatory response.
2. It causes constriction of smooth muscle.
3. Is cause second type of allergic response
Histamine Metabolism
Aspartate
Aspartate is an excitatory NT
It is synthesized by transamination from OAA
Aspartate synthesis uses Oxaloacetate that must be
replaced through anaplerotic reactions.
Aspartate cannot pass through the BBB
Glycine
Glycine is the major inhibitory NT found in the spinal
cord, brainstem and retina
Glycine in neurons is synthesized from serine by the
enzyme serine hydroxy methyltransferase in the presence
of folic acid.
Serine, in turn, is synthesized from the intermediate 3-
phosphoglycerate in the glycolytic pathway.
The action of glycine is probably terminated via uptake
by aEndalamaw
72 high-affinity
T transporter. 7/18/2014
Glycine Biosynthesis
Endorphins
It is an inhibitory NTs similar to opioids
It is a group of NTs that are involved in pain
perception and relief
It is primary produced in the hypothalamus and
pituitary gland in response to pain
Deficiency of endorphins leads to depression, anxiety,
mood swing, headache etc
Nitric Oxide (NO)
 NO is synthesized from L- arginine by NO synthase
It is produced by vascular endothelium and smooth
muscle, cardiac muscle, macrophage & other cell types.
NO is a gas and cannot be stored in the tissue
It needs molecular oxygen and NADPH to be
synthesised
Functions of NO:
NO important for vasodilation & neural transmission
NO activates a soluble guanylate cyclase
Inhibition of platelet adhesion to the vascular
endothelium (anti-thrombotic)
It act as anti-inflammatory
NO responsible for the relaxation of smooth muscle and
the subsequent dilation of vessels
 Scavenging superoxide anion
Nitric Oxide Synthesis
NO is synthesized by nitric oxide synthases (NOS)
These enzymes convert arginine into citrulline, & NO
O2 and NADPH are necessary co-factors.
There are three isoforms of NOS named according to
their activity or the tissue.
Neuronal NOS (nNOS or NOS1)
Endothelial NOS (eNOS or NOS2)
Inducible NOS (iNOS or NOS3)
nNOS& eNOS) are synthesis NO in response to
increases in intracellular calcium levels.
Increases in cellular calcium lead to increases in levels
of calmodulin and the increased binding of calmodulin to
eNOS and nNOS leads to a transient increase in NO
production by these enzymes.
iNOS synthesis NO independent of the level of
calcium in the cell.
iNOS is able to bind tightly to calmodulin even at very
low cellular concentration of calcium.

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Bahir Dar University

College of Medicine and Health

Nervous system Biochemistry

It is a group of NTs that are involved in pain

perception and relief

It is primary produced in the hypothalamus and

pituitary gland in response to pain

Deficiency of endorphins leads to depression, anxiety,

mood swing, headache etc

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