This document provides an overview of neurobiochemistry, including the structure and chemical composition of nerve cells and the general metabolism of the brain. It discusses the structure of neurons and how they transmit signals. The major components of nervous tissue are lipids, proteins, carbohydrates, nucleic acids and minerals. Glucose is the primary fuel for the brain, though ketone bodies can be used alternatively. Amino acids and ammonia are also metabolized in the brain. The document outlines these metabolic pathways and explains how the brain regulates levels of substances like ammonia.

1. Introductory Neurobiochemistry

2. Content
• General Structure of Nerve Cell
• Chemical Composition of Nervous Tissue
• General Metabolism of Brain
• Vitamins and Brain Metabolism
• Transmission of Nervous Impulse
• Neurotransmitters
• Neurotoxins

3. General Structure of a Nerve Cell
• Neuron (Nerve cell) is made up of 3 main parts, cell body,
axon and dendrites.
• The essential function of a nerve cell is to transmit signals
from one end of the cell to the other.
• The signals are received by fine processes known as
dendrites, these are near to the part of the cell containing
the nucleus.
• Also present in the main part of the cell are mitochondria
and bodies called nissil granules.
• The neuron has a fine extension known as an axon,
which is surrounded by a myelin sheath.

4. The axon divides into fine branches which terminate in
structures known as end feet.
The end feet contain chemical transmitters which relay
the signal to neighbouring cells.
There are small gaps between the schwann cells called
nodes of ranvier which expose the neuron.

5. Figure 1: Structure of a Nerve Cell

6. Clinical correlation
• Multiple sclerosis is a disease in which destruction of myelin
sheath occurs and the axon fails to conduct the nervous
impulses.
• The causes of myelin sheath destruction has a genetic
predisposition.
• Deficient oxidation of very long chain fatty acid (VLCFA) by
peroxisomal enzymes leads to this disease, where VLCFA
accumulate and the myelin is destroyed.

7. Chemical Composition of the Nervous Tissue
1. Lipids
• Chemically the brain is characterized by its high content of
lipid which accounts for 56 % of the total dry weight of the
white matter and 32 % that of the grey matter.
• The lipids are of a special nature, containing a large
proportion of shingomyelins and cerebrosides.
• Most of the lipids are metabolically inert, especially the
sphingomyelins of the white matter, which have a structural
rather than a metabolic role.

8. Lipids contd.
• However, there is a small fraction of phospholipids,
particularly the phosphatidic acids (eg phosphatidyl
ethanolamine and phosphoinositols, that turn over
rapidly.
• This high rate of turnover is shared by brain
phosphoproteins and is related to the level of neuronal
activity.
• Unlike lipids in other parts of the body, those in the brain
are not depleted by extreme starvation.

9. • Another major characteristics of the brain is that it
contains about 25 % of the body cholesterol, which is
synthesized insitu, with only small amounts
incorporated from the diet.
• The cholesterol in the brain has an extremely low
turnover number.
• The higher concentration of lipids in the white matter
reflects the high degree of myelinization in that area.
• Myelin is formed by many layers of cell membrane
(derived from Schwann cells) arranged around axons
in a spiral fashion.

10. 2. Proteins
•The brain contains both simple and complex proteins.
•The simple proteins commonly found in the brain are
albumin, globulins and histones
• The albumin and globulin fractions are called
neuroalbumin and neuroglobulins respectively, but
their physico-chemical properties are quite different
from the corresponding albumin and globulin fractions
found in the serum.

11. • The complex proteins include nucleoproteins, lipoproteins,
phosphoproteins and glycoproteins.
• A highly acidic protein termed S-100 is found in large
amounts in the glial cells of the brain and small amounts in
the neurons.
• Glutamic and aspartic acids comprise 30 % of the amino acid
residues.
• The protein is comprised of three non-identical subunits
with high affinity for Ca2+.

12. • Another protein known as 14-3-2 (sequence of elution in
chromatography), is found mainly in neurons and is also
highly acidic, because it contains high proportion of asp and
glu residues.
• The S-100 and 14-3-2 have been implicated in memory
and learning ability of the brain.
•Calmodulin is a protein involved in the Ca2+ activation of
the enzyme cyclic nucleotide phosphodiesterase found in
the brain.
• It is also involved in the Ca2+ dependent release of
acetylcholine and norepinephrine from their vesicular
stores.

13. 3. Carbohydrates
• The brain tissue contains a very small store of glycogen
compared with other tissues.
• It is important to note that the brain cells of foetus and infants
contain much more glycogen than those of adults.
• However, during development of the infant, the glycogen
content in the brain decreases and later becomes constant as
in adult humans.
• Brain tissue also contains intermediates of glucose
metabolism such as lactate, pyruvate and glyceraldehyde
• Because of blood brain barrier most of the other
carbohydrates are absent or present in negligible amount.

14. 4. Nucleic acids
•The adenine nucleotides (ATP, ADP, AMP and cyclic
AMP) make up about 80-85 % of the total free
nucleotides in the brain.
•The other major fraction is the guanine
nucleotides 20-25%.
•Distribution of these nucleotides is about the same
in both the grey and white matter of the brain.

15. 5. Minerals
•Mg, Cu, Ca, Mn, Fe, Na and K in the brain are
relatively equally distributed in the grey and white
matter respectively.
•In humans, the cerebral concentrations of the ions
Na, K, Ca, Cl and bicarbonate are different from
their plasma concentration

16. General Metabolism of the Brain
•To provide energy, substrates must be able to cross the
endothelial cells that line the blood vessels in the brain
(called the blood brain barrier, BBB).
• Normally, glucose serves as the primary fuel.
• However, ketone bodies play a significant role as
alternative source of fuel during a fast.

17. 1. Fat Metabolism
•The brain has no significant stores of triacylglycerol
and the oxidation of fatty acids obtained from blood
makes little contribution to energy production
because fatty acids do not efficiently cross the
blood brain barrier.

18. 2. Carbohydrates
• Brain differs from other organs in that virtually only glucose can
act as a metabolic fuel. The nervous tissue oxidizes glucose and
releases energy in mainly three interrelated phases namely
glycolysis, TCA cycle and ETC.
• Glucose is completely oxidized to CO2 and H2O with the release of
energy.
• Glucose oxidation in the brain accounts for 25 % of the body’s
total oxygen consumption.
• Since the brain has stores of glucose and glycogen sufficient for
only ten second’s activity, the brain is critically dependent upon
the glucose supplied by the blood. In the absence of adequate
supply of glucose to the brain only a few carbohydrates have been
shown to act as substrates of brain energy metabolism.

19. Carbohydrate Metabolism Contd.
Compounds such as maltose, fructose, galactose and
intermediate metabolites such as lactate, pyruvate and
glyceraldehyde were shown to do so only after their conversion
to glucose elsewhere in the body.
The brain can utilize mannose directly in the absence of glucose
because it can easily cross the BBB like glucose.
• Small falls in the concentration of blood glucose can be
compensated by increases in the cerebral flow, but more severe
falls (for e.g by an overdose of insulin) can lead to onset of a
coma that is potentially fatal. Unless the supply of glucose is
restored to normal within an hour or so, the brain may suffer
irreversible damage.

20. However, the irreversible damage (cerebral failure) does not
occur with long-term hypoglycaemia such as starvation
because ketone bodies are utilized as the brain’s metabolic
fuel.
This is related to their increased concentration in the brain.
• During anoxia (absence of oxygen) and hypoxia (low oxygen),
the rate of glycolysis is increased.
• This is attributed to the activation of hexokinase and
phosphofructokinase.
• All these are mechanisms to supply the brain with glucose,
because blood glucose is critical to the survival of the brain.

21. Metabolism of Proteins (Amino Acids)
• The concentration of free amino acids in human brain tissue is
eight times higher than the amount of found in plasma.
• The free amino acids in the brain are utilized in the synthesis
of proteins and biologically active amines and in other
metabolic processes.
• The concentration of the individual amino acids is also
different for example aspartic and glutamic acid concentrations
are 300 times greater in brain than in plasma.
• Glutamate plays an important role in brain metabolism. It is
involved in synthesis of gama amino butyric acid (GABA),
detoxification of ammonia and can act as a neurotransmitter.

22. • The toxic compound ammonia is produced in the brain
during metabolism mainly from the action of adenylate
deaminase.
• It is transported to the brain when the ammonia level in
blood is high.
• The rate of urea formation in the brain is too low for the
removal of ammonia due to absence of carbamoyl
phosphate synthetase (first enzyme in urea cycle). Ammonia
is removed from brain tissue by the (a) formation of
glutamate from alpha-ketoglutarate and ammonia as well as
the (b) formation of glutamine from glutamate and
ammonia.
• Thus, provided there is an adequate supply of alpha-
ketoglutarate the concentration of ammonia in brain tissue
will be kept low (Figure 2 below ).

23. Fig. 2: Metabolism of amino acids contd.

24. Metabolism of amino acids contd.
• If the concentration of ammonia in the brain is high,
convulsions may result.
• Any tendency for the concentration of ammonia to rise is
counteracted by the conversion of glutamate to glutamine by
glutamine synthetase and the conversion of -ketoglutarate to
glutamate by glutamic dehydrogenase.
• It follows, therefore, that in the brain, ammonia must be
removed as fast as it is formed (above reactions).
• The function of ammonia in the metabolism of the brain is
not entirely understood, but it is clear that elaborate chemical
devices exist to keep its concentration within close limits.

25. Metabolism of amino acids contd.
Carbon dioxide fixation
•Any extensive removal of ammonia converting -
ketoglutarate to glutamtate drains away intermediates
from the citric acid cycle and thus affect energy supply
to the brain.
• Such depletions may be made up by carbon dioxide
fixation by: malic enzyme, pyruvate carboxylase and
phosphoenolpyruvate carboxykinase which allows
pyruvate to be converted to malate.
• Pyruvate carboxylase is mainly responsible for the
fixation of carbon dioxide in the brain.

26. Fig. 3: Conversion of Malate and Pyruvate

27. Metabolism of amino acids contd.
•Transamination reaction between glutamate and
oxaloacetate gives -ketoglutarate and aspartate,
potential sources of energy.

28. Fig. 4: Transamination reaction between glutamate and
oxaloacetate

29. • Another conversion undergone by glutamate in the brain is
decarboxylation to give -aminobutyric acid.
• Removal of -aminobutyric acid is effected by deamination to form
succinic semialdehyde and ammonia.
• Succinic semialdehyde can be oxidized to succinate and hence to
oxaloacetate, which by condensation with acetyl CoA can eventually
give -ketoglutarate.
• The -ketoglutarate generated combines with ammonia to give
glutamate and hence gamma aminobutyric acid.
• Provided that any dicarboxylic acid drained out of the cycle can be
replaced by CO2 fixation, the -aminobutyric acid cycle will operate as
long as C2 units are supplied.

30. Fig. 5: Decarboxylation Reaction

31. Vitamins and Brain Metabolism
•Dietary deficiencies of vitamins that provide coenzymes
for reactions supplying energy to the brain can lead to
the development of nervous disorders.
• This is not hardly surprising when one considers the high
rate of metabolism of the brain and the rapid
deterioration of brain function when the supply of
glucose is restricted.

32. 1. Thiamine (Vitamin B1)
•Thiamine pyrophosphate (TPP) is a coenzyme required for
the decarboxylation of pyruvate during its conversion to
acetylCoA.
•TPP plays a role in acetylcholine synthesis and
transmission of nerve impulse.
• Thus, in thiamine deficiency, the citric acid cycle, (the main
source of energy for cerebral activity) is inhibited, hence
pyruvate and lactate accumulate.
• The human brain contains about 5 moles of thiamine/g
of tissue and it retains this more tenaciously than any
other organ.

33. Thiamine deficiency contd.
• Thus, during the first 15 days of a diet deficient in
thiamine, the brain retains its normal content of the
vitamin while other tissues have only some 30 % of
their original content.
•After 15 days, the brain thiamine begins to fall and
leads to a condition known as beriberi which is
associated with neurological disorders, edema,
muscles weakness and patients may even die if not
treated.

34. 2. Pyridoxal phosphate (Vitamin B6) PLP
• A phosphorylated form of Vitamin B6, pyridoxal phosphate is
involved in several important reactions in brain tissue.
These reactions include:
• The transamination occurring between glutamate and
oxaloacetate
• The decarboxylation of glutamate to -amino butyric acid,
• Conversion of 5-hydroxytryptophan to 5-hydroxytryptamine
(serotonin) and of
• Dopa (3,4-dihydroxyphenylanine) to dopamine all require
pyridoxal phosphate as coenzyme

35. Fig. 6: Conversion of Tyrosine to Dopa (3,4-dihydroxyphenylanine) to dopamine
Phenylethanolamine
N-acetyltransferase
Tyrosine
hydroxylase

36. PLP deficiency contd.
• Vitamin B6 deficiency is characterized by convulsions
and peripheral neuropathy which may result from a
diminished ability to form -aminobutyric acid,
serotonin and catecholamines (dopamine, nor-
epinephrine and epinephrine)
• Biochemical importance of Pineal gland, (Synthesis
of serotonin and melatonin)

37. Fig. 7: Biosynthesis of Melatonin (MLT)

38. 3. Nicotinic acid (Vitamin B3)
• Nicotinic acid synthesized from tryptophan is a component of
Nicotinamide Adenine Dinucleotide (NAD) and Nicotinamide
Adenine Dinucleotide Phosphate (NADP) and hence linked with
reactions supplying energy for cerebral activity.
• A large number of enzymes (oxidoreductases) are dependent
on NAD and NADP as coenzymes
• Its deficiency leads to a syndrome called pellagra
characterized by dermatitis, diarrhea and dementia associated
with degeneration of nervous tissue, if not treated leads to
death.

39. Transmission of the Nervous Impulse from one Nerve cell to Another
Resting and Action Potential
•Na+ and K+ ions are involved in the excitation and
transmission of nerve impulses.
• The potential differences between the interior and
exterior of resting nerve cell is about -6omv with the
inside negative and the outside positive.
• The potential difference is mainly the result of the
large amounts of K+ on the inside of the cell relative to
the outside of the cell.

40. • If a nerve cell is stimulated, the membrane is depolarized and
the potential difference between the inside and outside of the
cell changes and this is called action potential.
• There is increase in the permeability of the membrane to Na+
and the inside of the cell becomes positive with respect to the
outside and the membrane potential difference is restored to
the resting potential (-60mv) by increasing the influx of K+ to
the inside of the cell and exflux of Na+.
• This involves energy expenditure by the Na+_ ATpase.

41. Na+++++++++ Na+-------------+++++ K+
K+- - - - - - - - - +++++++++- - - - - -
_ _ _ _ _ _ _ ++++---------- K+
+++++++++ Na+---------+++++
sodium pump
Resting potential membrane becomes permeable to Na+
Action potential.
Fig. 8: Resting potential and Action potential.

42. Neurotransmitters
•Nerve impulses are communicated across synapses
by chemical transmitters, which are small, diffusible
molecules.
• Neurotransmitters are the chemicals that
communicate information throughout our brain and
body.

43. •The presynaptic membrane is separated from the post
synaptic membrane by a gap of about 500A unit called
the synaptic cleft.
• The end of the presynaptic axon is filled with synaptic
vesicles containing the neurotransmitter.
•Arrival of nerve impulse leads to the release of the
neurotransmitter into the cleft.
• The neurotransmitter then diffuses to the post synaptic
membrane where they combine with specific receptors.
• This produces depolarization of the postsynaptic
membrane, which is propagated along the electrically
excitable membrane of the second nerve cell.

44. Presynaptic
membrane
Postsynaptic
membrane
Synaptic cleft (500oA)
Ca2+ bind
Direction of
nerve impulse
Synaptic vesicle (containing neurotransmitters)
Receptors for neurotransmitters
Fig. 9: Transmission of Nerve Impulse

45. •Ca2+ then bind with the protein bound membranes of
the synaptic vesicles allowing the vesicles to “dock”
with the pre synaptic membrane resulting in the
creation of a fusion pore.
•The vesicular stores then release their contents to the
synaptic cleft through the fusion pore.
•A large number of chemicals are used as
neurotransmitters.
• Except for acetylcholine, they are either amino acids
or their derivatives.

46. Properties of Neurotransmitters
1. Synaptic vesicles of the presynaptic neurons must contain the substance, it
must be released at the appropriate time in response to stimulation and the
quantity released must be sufficient to induce the appropriate response in
the postsynaptic cell.
2. Ionto-phoresis of the substance into the synaptic cleft must induce the
same response as does stimulation of the pre-synaptic nerve.
3. The substances must be removed or degraded rapidly resulting in
restoration of the resting membrane potential.
4. The same response must be obtained when the chemical is experimentally
placed on the target.

47. •Substances besides acetylcholine that have been
identified by these criteria as neurotransmitters include
dopamine, epinephrine, norepinephrine, serotonin, -
amino butyric acid (GABA), glycine and glutamate.
• The neurotransmitters epinephrine and norepinephrine
function as both systemic hormones and transmitters.
• Dopamine, epinephrine and norepinephrine are
synthesized from tyrosine.
•They are also referred to as catecholamines.

48. Synthesis of Acetylcholine
• Acetylcholine is synthesized from choline and acetyl
coenzyme A, the reaction is catalyzed by choline acetyl
transferase (choline acetylase).
• The enzyme is synthesized in the ribosomes, acetyl CoA
is formed in the mitochondria, choline is derived from
extracellular fluid.
• Glucose, oxygen and sodium ions are necessary for
optimal acetylcholine synthesis.
• Acetylcholine synthesis occurs in the axon terminals.

49. Fig 10: Synthesis of Acetylcholine

50. Inactivation of Acetylcholine
• Acetylcholine is inactivated by an enzyme cholinesterase.
• The permeability properties of the postsynaptic membrane
are restored and the membrane becomes repolarized.
• Acetylcholinesterase is located in the synaptic cleft, where it
is bound to collagens and glycoaminoglycans.
• The rate of hydrolysis of acetylcholine by cholinesterase is
extremely high.
• Acetylcholine reacts with a specific serine residue on the
active site of acetylcholinesterase to form acetyl-enzyme
intermediate and choline is released.
• The acetylated cholinesterase is very unstable and reacts with
H2O to form acetate and regeneration of the free enzyme.

51. Fig. 11: Inactivation of Acetylcholine
Enz-Ser CH3-C O-CH2-CH2-N-(CH3)3
OH +
HO-CH2-CH2-N-(CH3)3
Enz-Ser
+
=O
+
+
C-CH3
=O
Acetylated Cholinesterase
is very unstable
Choline
Enz-Ser OH + CH3-C
=O
O-
Acetate
Free enzyme regenerated
H2O
H+
Acetylcholine
Free enzyme

52. Inhibitors of the Acetylcholine Receptors
• Neuromuscular transmission can also be impaired by compounds
that act directly on the acetylcholine receptors by inhibiting it.
• Curare (arrow poison) whose active component is d-tubocurarine
inhibits the depolarization of the end plate by competing with
acetylcholine.
• In contrast compounds such as decamethonium bind to the
receptor and cause a persistent depolarization of the end plate.
• Succinylcholine a muscle relaxant causes persistent depolarization.
It is used in surgical procedures because its activity is reversible
due to the rapid hydrolysis of the compound after cessation of
administration.
• (CH3)3 N+ (CH2)10 N+ - (CH3)3

53. Clinical Correlation (Neuromuscular Disorder)
• Myasthenia Gravis is an acquired autoimmune disease
characterized by muscle weakness due to decreased
neuromuscular signal transmission.
• The neurotransmitter involved is acetylcholine
• Antibodies against the AChR interact with it and inhibit its
function, either its ability to bind acetylcholine or its ability to
undergo conformational changes necessary to effect ion
transport.
• Thymus gland produces antibodies (IgG) against the AChR
Treatment: Use of anticholinesterase, immunosuppresant
drugs, steriods and surgical removal of thymus gland

54. Toxins that Affect Nerve Impulse
Tetrodotoxin and Saxitoxin
• Tetrodotoxin: Is a potent (non protein) poison from the puffer fish that
blocks the conduction of nerve impulse along axons which leads to
respiratory paralysis
• It has no effect on resting membrane potential.
• It is effective only when applied to the external surface of the
membrane.
• The toxin specifically prevents the increase in sodium conductance
following the partial depolarization of the membrane.
• The passive entry of sodium ions is blocked by binding to Na+ channels
without affecting the active extrusion of the Na+ by sodium pump.
• Also it does not affect the increase in K conductance.

55. •Tetrodotoxin contains a guanidine group and at the pH of
the extracellular fluid, is in cationic form.
• This positively charged group of the toxin interacts with
a negatively charged carboxyl group at the mouth of the
channel.
• In effect, it is a competitive inhibitor of Na+
Saxitoxin which is produced by marine dinoflagellate is
another non-protein toxin.
• It differs from tetrodotoxin in that its molecule contains
two guanidine groups instead of one, thus it is bulkier.