Clinical biochemistry of

Nervous System
Metabolism overview
• The term metabolism refers to all the chemical
reactions that occur in an organism. Chemical
reaction within cells, collectively known as
cellular metabolism, provide the energy
needed to maintain homeostasis and to
essential functions.
• There are two aspect of metabolism:-
Catabolism the breaking- down process which
provide energy (stored in ATP) and Anabolism
the building up process which requires energy.
All metabolic reaction within the body
whether anabolic or catabolic are catalyzed by
enzymes.
 The essential function of
metabolism
1) Metabolic turnover the periodic breakdown and
replacement of the organic component of a
cell.
2) Growth and cell division.
3) Special processes, such as secretion,
contraction, and the propagation of action
potentials.
• Adult human require 10 – 12 MJ (2400 – 2900
Kcal) ( 1 Kcal = 4.18 Joule) from metabolic
fuel each day.
 40 – 60 % from carbohydrate.

30 – 40 % lipid.

10 – 15 % proteins.
Brain Metabolism

• The brain and other areas of the central nervous

system (CNS) have high ATP requirements.
Although the brain only represents about 2% of
the body’s mass, it consumes around 20% of
the metabolized oxygen and 60% of the
glucose.
• The brain is extremely sensitive to hypoxia, and occlusion
of its blood supply produces unconsciousness in as short a
period as 10 seconds.
• The neurons’ high energy requirements are mainly due to
ATP-dependent ion pumps (particularly Na+/K+ ATPase)
and other active transport processes that are needed for
nerve conduction. Estimated to require up to half the brain
ATP, while other biochemical processes including protein,
lipid and neurotransmitter synthesis together use perhaps
10%.
• It receives 20% of the cardiac output.
• The energy yield by the brain is necessary to:
1. Maintain ionic gradient across the plasma
membrane
2. Effect various storage and transport processes
3. Synthesis of neurotransmitter and other
cellular components: A amnio acids arising in
the brain cells are rapidly incorporated into
proteins and the rate of protein synthesis is
highest during development and decrease in
adult.
• Neurotransmitter recycling, intracellular signaling
and dendritic and axonal transport also require
energy . Even though neurons are responsible for
massive energy consumption, the brain is made up
of many cells, including neurons, glial and
ependymal cells. Every brain cell has a specific
function and thus every brain cell has different
metabolic needs
• Many of these specific functions are
concerned with maintainance of neuronal
transmission. For example, astrocytes play a
central role in supporting neurons
metabolically by producing lactate, through
glycolysis and activation of glycogen
catabolism.
Chemical composition

1. proteins; brain protein include:

• Globulins
• Phosphoprotein
• Nucleoprotein
• Albuminoid
• neurokeratin
2. lipid:
• Brain contain large amount of lipids.
• In adult brain lipids represent more than
half of the solid compounds.
• They represent as:
• Phospholipids e.g. lecithin and cephalins
(40%)
• Glycolipids e.g. glucocerbroside
galactocerebroside (35%)
• Cholesterol (20%)
• Free fatty acids (FFA) present in trace
amount in nervous tissue, most of them
are unsaturated, have long chain 24
carbon atoms e.g. Palmitic acids
• The white matter contains more lipid than
the gray matter.
• All lipids may be synthesized from glucose
and other metabolites provided by the blood.
The brain thus has fatty acid synthesis
capacity, but all fatty acids are used for
membrane lipid synthesis, and not for beta-
oxidation or fat storage
3. carbohydrates:
Brain and nervous system contain a very few CHO
e.g. glycosaminoglycan & mucopolysaccharide.
 Protein and amino acids metabolism:

• Neurotransmitters are endogenous chemicals

that transmit signals across a synapse from one
neuron (brain cell)to another 'target' neuron.
• Most neurotransmitters are about the size of a
single amino acid, but some neurotransmitters
may be the size of larger proteins or peptides.
Major neurotransmitters
1- Amino acids:
• are inhibitory and excitatory in action ex.
glycine, glutamate (More than half of the
synapses in the brain are Glutaminergic). and
aspartate.
2- Amines:
• Are the modified amino acids (arise from
amino acids by decarboxylation. ex. GABA,
noradrenaline, adrenaline, dopamine and
serotonin.
3- Peptidse: somatostatine
4- Others: Acetylcholine
• Aspartic acids, glutamic acids and their
derivatives N-acety-aspartic acid, glutamine,

glutathione and γ-aminobutyric acid (γ ABA)

are important amino acids in human brain.
• Glutamic acid & glutamine represent about
80% of the total brain amino acids & present
at eight times higher than in the blood.
• Glycine is the simplest of amino acids. It’s an
inhibitory neurotransmitter.

• Glycine is synthesized from serine by the

mitochondrial isoform of serine
• GABA is the major inhibitory neurotransmitter
of the brain, occurring in 30-40% of all
synapses (second only to glutamate as a major
brain neurotransmitter)
• The GABA concentration in the brain is 200-
1000 times greater than that of the
monoamines or acetylcholine
• GABA is somewhat unique among
neurotransmitters insofar as it is commonly
inactivated (after release into the synapse) by
active transport into the astrocyte glial cells that are
closely associated with synapses. Both glutamate
and GABA are synthesized in the brain from the
Krebs citric acid molecule alpha-keto glutarate —
a reaction known as the "GABA shunt".
• So The GABA shunt is a closed-loop process with
the dual purpose of producing and conserving the
supply of GABA.
• GABA is synthesized from glutamic acid and
is catabolized back into the citric acid cycle.
The vitamin B6 derivative pyridoxal
phosphate is a cofactor in the synthesis of
GABA.
• GABA levels rise when the citric acid cycle
activity is low (ie, when cell energy usage is
low), and the resultant generalized GABA
inhibitory effect on the brain neurons can be
protective during hypoxia or ischemia.
• Like glycine, the GABA receptor is connected
to a chloride ion channel, allowing more
chloride ion to enter the cell and thus making
the membrane less likely to depolarize
• glutamate and aspartate function as
neurotransmitters came from the observation
that at low concentrations they excite virtually
every neuron in the CNS. In the adult CNS,L-
glutamate and L-aspartate are the most likely
candidates for neurotransmitter action at
excitatory amino acid receptors, and these
amino acids are used by some of the most
widely distributed neuronal types. Glutamate
and aspartate are present in high
concentrations in the CNS and are released in
a Ca2+-dependent manner. 
• Glutamate and aspartate are nonessential
amino acids that do not cross the blood—brain
barrier and, therefore, are synthesized from
glucose and a variety of other precursors.
Synthetic and metabolic enzymes for
glutamate and aspartate have been localized to
the two main compartments of the brain,
neurons and glial cells. Glutamic acid is in a
metabolic pool with α-ketoglutaric acid and
glutamine.
• A large fraction of the glutamate released from
nerve terminals probably is taken up into glial
cells, where it is converted into glutamine.
Glutamine then cycles back to nerve terminals,
where it participates in the replenishment of the
transmitter pools of glutamate and GABA. At
present, there is little evidence for the
extracellular metabolism of glutamate in the CNS.
 Metabolism of glutamate in synaptic
structures

• Glutamate is synthesized and stored within

synaptic endings of nerve terminals. Synthesis
of transmitter pools of glutamate is likely to
involve two major synthetic pathways. The
conversion of glutamine to glutamate involves
the enzymatic action of glutaminase
•  within the mitochondrial compartment.
Glutamate formation also occurs by a process
of transamination . Newly synthesized
glutamate is then packaged and stored in high
concentration within synaptic vesicles. After
release of glutamate from the nerve terminal
into the synaptic cleft, it is taken up into glial
cells by glutamate transporter-1(GLT-1) and
glutamate—aspartate transporter (GLAST) and
converted into glutamine .
• Glutamine is then cycled back to the nerve
terminal, where it participates in the
replenishment of transmitter stores of
glutamate. Alternatively, some glutamatergic
nerve terminals contain the excitatory amino
acid carrier-1 (EAAC1), which recovers
glutamate directly.
• Aspartate and glutamate stimulate cAMP
formation from ATP in the brain which
activates c AMP dependent protein kinase by
binding to its regulatory subunits and relasing
its active catalytic subunits.
• The active catalytic subunit catalyze the
transfer of phosphate from ATP to specific
theronin or serine. This phosphorylation is:
• Involved in the nerve impulse transmission
across synaptic junction.
• It may act directly on cell’s ion channel.
• It may activate or inhibit enzymes.
• The brain’s uptake of glutamate is approximately
balanced by its output of glutamine.
• Glutamate entering the brain takes up ammonia
and leaves as glutamine.
• In the brain glutamate is a major
neurotransmitter but is toxic in excess
• The glutamate-glutamine conversion in the
brain- the opposite of the reaction in the
kidney that produces some of the ammonia
entering the tubules-serves as a detoxifying
mechanism to keep the brain free of ammonia.
• Glutamine synthetase acts as a catalyst in the
following reaction:
Glutamate + NH3 + ATP Glutamine + ADP
+ Pi.
• The enzyme from mammalian brain has two
important functions: assimilation of ammonia
and biosynthesis of glutamine.
• Ammonia is very toxic to nerve cells, and
ammonia toxication is believed to be a major
cause of the bizarre neurologic symptoms in
hepatic coma. Ammonia may be toxic to the brain
in part because it reacts with α-ketoglutarate to
form glutamate. The resulting depleted levels of α-
ketoglutarate then impair function of the
tricarboxylic acid (TCA) cycle in neurons. (Low
cellular respiration and ATP production)
and perhaps more importantly, there are
decreased levels of GABA and glutamate in
the brain. GABA is a major inhibitory
neurotransmitter, whereas glutamate is a major
excitatory neurotransmitter.
• Ammonia is formed in brain at high rate by three
ways:
1. Deamination of AMP to IMP (Inosine
monophosphate)
2. Deamination of glutamine
3. Deamination of glutamate and oxidative
deamination of adrenaline to nor-adrenaline.
Once ammonia formed, it should be removed as
fast as it formed.
• High ammonia toxicty thought to be due to
shift in the equilibrium of the glutamate
dehydrgenase reaction forward the direction of
glutamate formation
• α-ketoglutarate + NADPH+H+ glutamate
+ NADP+ . This lead to depletion of α-ketoglutarate
which is essential intermediate in TCA cycle resulting in
decrease in cellular oxidation and ATP production.

• Brain particularly more affected by hyperammonemia due

to it depend on the CAC to maintain its high rate of
energy
• Brain contain all the enzyme of urea cycle
except carbamoyl phoshpate synthetase so
urea dose not form in the brain and occur in
the liver only.
 Carbohydrate metabolism

• Glucose is the main source of energy for the

brain
• Brain utilizes 60% of total blood glucose to
provide a fuel for respiration
• The glucose transporter, GLUT-1, is enriched
in the brain capillary endothelial cell and
mediates the facilitated diffusion of glucose
through the blood brain barrier.
• Most of the glucose is metabolism to pyruvate,
which enters the mitochondria of neurons and
glia and is converted to acetyl-CoA before
entering the TCA cycle.
• Only about 13% of glycolytic pyruvate is
converted to lactate under normal condition.
Utilization of glucose in the brain is only via
glycolysis and kerb’s cycle.
• Glycolysis and the TCA cycle are also the
source of non-essential amino acid precursors
used to synthesize the neurotransmitters
glutamate, aspartate, GABA, and glycine.
 Glycogen metabolism
• Primarily glycogen is stored in a strocytes. Brain
tissue cannot store much glucose levels. in brain
are low compared to liver and muscle. Turnover
rate is very rapid; its synthesis and breakdown are
regulated by the two key enzymes coupled to
synaptic activity. During anesthesia they rise
sharply. It is regulated in astrocytes by
norepinephrine and vasoactive intestinal peptide .
monocarboxylate transporters (MCT) phosphoglucomutase (PGM)
glycogen synthase (GS) glycogen phosphorylase (GP) hexokinase
(HK) UDP glucose pyrophosphate (UDPGPP)
• Glycogenolysis produces glucose-6-phosphate. It has been
proposed that glucose-6-phosphate is used to produce
metabolic substrates such as lactate, which can be exported
from a strocytes to neuronal cells. It has also been
proposed that glucose-6-phosphate from glycogen in
astrocytes inhibits glycolysis (by hexokinase inhibition)
and thus, glucose consumption is favored by neurons. In
any case, glycogen is important for brain. Indeed glycogen
metabolism in astrocytes only occurs in mature a strocytic
cells
 Lipid metabolism-Fatty acids

Fatty acids metabolism

• Brain is unable to utilize fatty acids as a source
of fuel since the fatty acids complexed to
albumin are unable to traverse the blood brain
barrier. But, brain can effectively utilize
acetoacetate.
• While glucose is the preferred energy
substrate, neurons and glia will metabolism
ketones for energy under fasting-induced
reduction of blood glucose.
• Alfa- oxidation of fatty acids is relatively
minor in terms of total energy production, it is
metabolism of branched-chain fatty acids in
the diet. Phytanic acid can not be oxidized by
β-oxidation because of the presence of the 3-
methyl group. It is metabolized by an α-
hydroxlation followed by dehydrogenation
and decarboxylation.
• Patients with a rare genetic called Refsum’s
disease lack the peroxisomal α-hydroxylating
enzyme and accumulate large quantities of
phytanic acid in their tissues and sera. this
lead to serious neurological problem such as
retinitis pigmentosa, peripheral neuropathy,
cerebellar ataxia, and nerve deafness.
 Cholesterol metabolism

• Cholesterol is synthesized in the brain during

growth stage, with increasing age the level of
hydroxy methylglutaryl CoA reductase (HMG
CoA reductase) reduces and the brain becomes
less capable of cholesterol synthesis.
• Brain lipid not depleted by starvation, unlike the
lipid in other parts of the body.
 Ketone bodies
• Ketone bodies are three chemicals that are
produced when fatty acids are broken down in
excess. Consisting of acetoacetate and β-
hydroxybutyrate, Acetone.
• Major energy source(75%) for brain during
starvation.
• Catabolism of fat in the liver. Their
concentration in blood is inversely related to
that of glucose.
• After the diet has been changed to lower blood
glucose for 3 days, the brain gets 30% of its
energy from ketone bodies.
• After 40 days, this goes up to 70% (during the
initial stages the brain does not burn ketones,
since they are an important substrate for lipid
synthesis in the brain).
• Ketone bodies are transported into brain
through the blood brain monocarboxylic
transportd (MCTs) whose expression is
regulated in part by circulating ketone and
glucose levels.
• Β-OH is the predominant. Rapidly oxidized to
acetyl-CoA in the mitochondria through an
enzymatic series involving 3-hydroxybuyrate
dehydrogenase, SCOT (succinyl-CoA-acetoacetate-
CoA transferase) and mitochondrial acetyl-CoA
thiolase
• Acetone is anon-enzymatic byproduct of ketone
body synthesis and is largely excreted in the urine or
exhaled from the lungs.
• Ketone bodies are more energetically efficient
than either pyruvate or fatty acide because
they are more reduced (greater
hydrogen/carbon ratio) than pyruvate and do
not uncouple the mitochondrial proton
gradient as occurs with fatty acid metabolism.
• In contrast to glucose, ketone bodies by-pass
cytoplasmic glycolysis and directly enter the
mitochondria where they are oxidized to acetyl-
CoA. The amount of acetyl-CoA formed from
ketone body metabolism is greater than that
formed from glucose metabolism.
• Ketone body metabolism can also reduce
production of damaging free radicals.
• Ketone bodies not only function as an energy
substrate, but also as intermediates for the
synthesis of lipids and neurotransmitters