158

AMINO ACID METABOLISM

Digestion of proteins: Proteolytic enzymes are secreted as inactive zymogens which are
converted to their active form in the intestinal lumen. This would prevent auto digestion
of the secretory acini. The digestion of protein is effected by enzymes in:
A. Stomach
B. Pancreas and
C. Intestinal cells
Gastric:
a. Gastric HCL makes the food acidic and also denatures proteins
b. In infants rennin coverts casein in milk protein into paracasein for further
digestion
c. Chief cells in gastric mucosa secrete pepsinogen which is converted to pepsin
by gastric HCL.
d. Pepsin breaks down proteins into proteoses and peptones.
Pancreas:
a. Bile provides alkaline pH
b. Cholecystokinin and pancreozymin stimulate pancreatic juice
c. Action of pancreatic juice:
i. Trypsinogen is activated by enterokinase to trypsin which in turn
activate other enzymes ; Premature activation of trypsin may lead to
acute pancreatitis
ii. Chymotrypsin is activated by trypsin to chymotripsin
iii. Procarboxy peptidase is activated by trypsin to carboxy peptidase
iv. Trypsin, chymotripsin and carboxy peptidase digest protein into
smaller peptides
Intestinal juice (succus entericus)
a. Contain amino peptidase, di peptidase and tri peptidase
b. They bring about complete digestion into amino acids.
Absorption of amino acids:
a. Absorption occurs in small intestine as an ATP dependant transport process.
b. Transport is by 5 different carriers:
i.
Neutral amino acids
ii.
Basic amino acids
iii.
Imino acids and glycine
iv.
Acidic amino acids
v.
Beta amino acids
c. The absorption of neutral amino acids is effected by Gamma-Glutamyl cycle;
glutathione reacts with amino acid to form gamma glutamyl amino acid which
is cleaved again to release amino acid across the membrane using 3
molecules of ATP
Clinical applications:
a. Undigested protein may enter circulation in some people to produce food
allergy in adults and cow milk protein allergy in infants
b. E.g. of defects in amino acid transport:
i. Hartnup disease
ii. Cystinuria etc
c. In protein loosing enteropathy there is a huge loss of proteins through GIT
Intracellular digestion:
a. Proteins can be taken up by endocytosis and are fused with lysosomes
b. They are broken down by enzymes known as cathepsins
c. It can also occur by attachment to ubiquitin and digested by proteosomes
Amino acid metabolism in fasting:
a. Muscle releases alanine and glutamine
b. Alanine is taken up by liver
c. Glutamine is taken by kidneys
d. Liver removes amino group and uses the carbon skeleton for
Gluconeogenesis

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e. Brain uses branched chain amino acids for energy
In fed state:
a. Muscles and brain take up branched chain amino acids and release glutamine
and alanine
b. Glutamine is taken by kidney for acid base regulation
c. Alanine is taken up by liver
AMMONIA FORMATION
Questions:
1. How is ammonia produced? How is it detoxified? Give two causes and
effects of hyperammonemia. April 2000; Oct 2000
2. Why ammonia is toxic to the body? What are the ways in which
Ammonia is produced in the body? Add a note on hyperammonemia
conditions. August 2005
3. Write in detail about how ammonia is formed from amino acids,
transported and connected to urea. Feb 2008
Introduction:
1. Ammonia is a compound with the formula NH3. There is no storage form of
amino acids as in the case of carbohydrates (glycogen) and lipids
(triacylglycerol).
2. The excess intake of amino acids are metabolized to provide energy or converted
to glucose or fat. The amino groups are lost as urea and excreted
3. The presence of -amino group keeps amino acids safely locked away from
oxidative breakdown. Removing the -amino group is essential for producing
energy from any amino acid, and is an obligatory step in the catabolism of all
amino acids. Once removed, this nitrogen can be incorporated into other
compounds or excreted, with the carbon skeletons being metabolized
4. Thus the first step in catabolism of amino acid is to remove amino group as
ammonia and detoxification of ammonia by conversion to urea and excretion in
urine.
Amino acid pool:
1. An adult has about 100 g of free amino acids which represent the amino acid
pool of the body. The pool exists in several compartments. Glutamate and
glutamine together constitute about 50%, and essential amino acids about 10%.
2. The concentration of intracellular amino acids is always higher than the
extracellular amino acids. Amino acids enter the cells against a concentration
gradient by active transport.
3. Amino acid pool is contributed by:
a. Turnover of body protein,
b. Intake of dietary protein and
c. The synthesis of non-essential amino acids
Glutamic acid
Deamination
Aminosugars

Asparagine
Pyrimidine
Putrefaction
Glutamine/asparagine

Glutamine
Ammonia pool

Urea

PATHWAYS OF AMMONIA FORMATION

Transamination:
1. The transfer of an amino (- NH2) group from an amino acid to a keto acid is
known as transamination. This process involves the interconversion of a pair of
amino acids and a pair of keto acids, catalysed by a group of enzymes called
transaminases (recently, aminotransferase).

160
2. Transaminases require pyridoxal phosphate (PLP), a coenzyme derived from
vitamin B6.
3. Transamination reactions tend to channel amino groups on to glutamate.
Glutamate is the
4. only amino acid that undergoes oxidative deamination to a significant extent to
liberate free NH3 for urea synthesis.
5. Glutamate plays a central role in amino acid Nitrogen metabolism
6. All amino acids except lysine, threonine, proline and hydroxyproline participate in
transamination.
7. The Ping Pong mechanism is proposed in transamination reaction.
8. Transaminase reactions are reversible
9. Transamination takes place in the cytoplasm of all the cells of the body; the
amino group is transported to liver as glutamic acid which is finally oxidatively
deaminated in the mitochondria of hepatocytes.
10. Example:
1. In the following reaction, aminotransferases act by transferring the amino
group of an amino acid alanine to the pyridoxal part of the coenzyme to
generate pyridoxamine phosphate. The pyridoxamine form of the
coenzyme then reacts with an -ketoglutarate to form an amino acid
glutamine, at the same time regenerating the original form of the
coenzyme. Thus, glutamate, in effect, acts as a collector of nitrogen
from alanine. In this reaction -ketoglutarate becomes glutamate and
alanine becomes pyruvate.
Alanine transaminase + pyridoxal phosphate
Alanine + -ketoglutarate <---------------------------- pyruvate +
glutamate
Transdeamination:
1. The removal af amino groupfrom the amino acids as NH3 is deamination. This is
a coupled reaction; i.e. transamination followed by oxidative deamination and
hence called transdeamination.
2. All amino acids are first transminated to glutamate and then glutamate is
transported to liver where it is deaminated to alpha keto glutarate. In order to
regenerate the amino acceptor, -ketoglutarate, and to provide ammonia for reutilization or disposal it is necessary to deaminate glutamate. This is
accomplished by the action of the enzyme glutamate dehydrogenase (GDH)
which is located in the mitochondrial matrix in liver. The liberated ammonia is
converted to urea in liver (detoxification)
Glutamate dehydrogenase
Glutamate + H2O + NAD+ <--------------------- Alpha ketoglutarate +
NH3+ NADH+ + H+
Allosteric control: The direction of the glutamate dehydrogenase reaction will be
dependent on the energy state of the cell and on the availability of oxidizable
fuel, i.e. amino acids.
3. The purpose of oxidative deamination is to provide NH3 for urea synthesis and aketo acids for a variety of reactions, including energy generation.
Non Oxidative deaminations:
2. Some of the amino acids can be deaminated to liberate NH3 without
undergoing oxidation. Serine, threonine and homoserine are the hydroxy
amino acids. They undergo non-oxidative deamination catalysed by PLPdependent dehydrases (dehydratases).
3. Dehydratase acts on hydroxy amino acids to remove ammonia as follows:
a. Serine glutamate + ammonia
b. Threonine alpha keto butyric acid+ ammonia
4. Desulfhydrase produce pyruvate and ammonia from Cysteine
5. Histidase converts histidine to urocanic acid and ammonia
6. Ammonia is also produced by bacteria in GIT
Minor pathways:

161
7. L-amino acid oxidase acts on amino acid to form ammonia and ketoacid
8. D-amino acid oxidase oxidises glycine to release ammonia
9. Mono amine oxidase can oxidise monoamines to give ammonia
DETOXIFICATION/ DISPOSAL OF AMMONIA
Trapping and transport of ammonia:
1. Ammonia is constantly being liberated in the metabolism of amino acids and
other nitrogenous compounds. At the physiological pH, ammonia exists as
ammonium (NH4 ion).
2. The transport of ammonia between various tissues and the liver mostly occurs in
the form of glutamine or alanine. Alanine is important for NH3 transport from
muscle to liver by glucose-alanine cycle.
3. Glutamine also carries ammonia from peripheral tissues to the kidney, where it
regenerates glutamate and free ammonium ion, which is excreted in the urine.
4. Glutamine synthetase (a mitochondrial enzyme) is responsible for the synthesis
of glutamine from glutamate and ammonia. This reaction is unidirectional and
requires ATP and Mg2+ ions.
Glutamine synthase
Glutamic acid + NH3 + ATP------------------------- Glutamine + H2O +
ADP+Pi
5. Glutamate dehydrogenase is available only in liver. Hence glutamine has to be
transported to liver. In Liver glutamine is reconverted to glutamate and ammonia
is detoxified into urea.
6. Ammonia is highly toxic to CNS and should be eliminated or detoxified
immediately. The intracellular ammonia is immediately trapped by glutamic acid
to form glutamine, in brain cells. The glutamine is then transported to liver,
where the ammonia generated is immediately detoxified into urea.
7. Aspartic acid may also undergo similar reaction to form asparagine.
8. Glutamine can also be deaminated by hydrolysis to release ammonia by
glutaminase, an enzyme mostly found in kidney and intestinal cells.
Disposal patterns of ammonia:
(a) Ammoniotelic : The aquatic animals dispose off NH3 into the surrounding water.
(b) Uricotelic : Ammonia is converted mostly to uric acid e.g. reptiles and birds.
(c) Ureotelic : The mammals including man convert NH3 to urea. Urea is a non-toxic
and soluble compound, hence easily excreted.
Biological significance of transamination:
1. Ammonia is removed
2. Carbon skeleton of amino acid is utilised for further catabolism
3. Non-essential amino acids are synthesised. Eg:
1. Alanine form pyruvate
2. Aspartic acid from oxaloacetate
3. Glutamic acid from alpha keto glutarate
4. Inter conversion of amino acids is possible to equalise the quantities of
non-essential amino acids
Clinical significance:
1. Aspartate amino transferase (AST) and Alanine amino transferase (ALT)
are induced by glucocorticoids and favor Gluconeogenesis.
2. AST is increased in myocardial infarction and ALT in liver disease.
Funetions of ammonia:
1. Ammonia is not just a waste product of nitrogen metabolism. lt is involved
(directly or via glutamine) for the synthesis of many compounds in the body.
These include non-essential amino acids, purines, pyrimidines, amino sugars,
asparagine etc.
2. Ammonium ions (NH4) are very important to maintain acid-base balance of the
body.

162
Toxicity Associated with Ammonia
1. Ammonia is neurotoxic. Marked brain damage is seen in cases of hepatic and
renal failure.
2. Ammonia crosses the brain blood barrier and in the brain it is converted to
glutamate via glutamate dehydrogenase, depleting the brain of -KG. As the KG is depleted, oxaloacetate falls correspondingly, and ultimately TCA cycle
activity comes to a halt.
3.

In the absence of aerobic oxidative phosphorylation and TCA cycle activity,

irreparable cell damage and neural cell death ensue.

4. In addition, the increased glutamate leads to glutamine formation. This depletes

glutamate stores which are needed in neural tissue since glutamate is both a
neurotransmitter and a precursor for the synthesis of -aminobutyrate, GABA,
another neurotransmitter.
5. As glutamine levels raise in the brain the volume of fluid within glial cells
increases resulting in the cerebral oedema seen in infants with hyperammonemia
caused by urea cycle defects.

UREA CYCLE
Question:
1. What is urea? Describe the steps of Urea synthesis. What is the
significance of urea cycle? Name the disorders of urea cycle. September
2002
2. What is transamination and what is its significance? Write the steps of
urea cycle and discuss its control. Describe the enzyme defects in urea
synthesis and their consequences. April 1999
3. Differences between CPSI and CPS II.
Introduction:
1. Urea is also known as carbamide, as established by the World Health
Organization.
2. Urea is an organic compound with the chemical formula (NH2)2CO. Urea is the
end product of protein metabolism. The nitrogen of amino acids, converted to
ammonia, is toxic to the body. lt is converted to urea and detoxified.
3. Urea is synthesized in liver and transported to kidneys for excretion in urine. It is
known as Krebs-Henseleit cyde and Ornithine cycle
4. Urea synthesis is a five-step cyclic process, with five distinct enzymes. The first
two enzymes are present in mitochondria while the rest are localized in cytosol.
5. Urea contains two nitrogen atoms derived from different sources: 1. Ammonia 2.
Aspartic acid
6. Urea and TCA cycle are interlinked to be called a urea bicycle!
Steps:
Steps 1 & 2 are in mitochondria:
1. One molecule of ammonia condenses with CO2 in the presence of 2 ATP to form
carbamoyl phosphate catalysed by carbamoyl phosphate synthase-1 (CPS-1).
This is reversible and allosterically regulated and rate limiting.

163
Carbamoyl phosphate synthase-1
Ammonia + CO2+ 2 ATP ----------------------------------- carbamoyl
phosphate+ 2 ADP +Pi
2. The carbamoyl group is transferred to the NH2 group of Ornithine by ornithine
transcarbamoylasae (OTC) to form Citrulline.
Ornithine transcarbamoylasae
Carbamoyl phosphate + Ornithine----------------------------------------- Citrulline
Further steps occur in cytoplasm:
3. One molecule of aspartic acid is added to Citrulline to form arginosuccinate
which contain 2 c from 2 different sources. 2 ATPs are utilised and catalysed by
arginosuccinate synthetase.
Arginosuccinate synthetase
Citrulline + Aspartic acid + 2 ATP ------------------------------
Arginosuccinate + AMP+pi+H2O
4. Arginosuccinate is cleaved by arginosuccinate lyase to Arginine and Fumarate.
Fumarate enters TCA cycle.
Arginosuccinate lyase
Arginosuccinate ------------------------------------ Arginine and
Fumarate
5. Arginine is hydrolysed to urea and ornithine by arginase. Ornithine enters
mitochondria to continue urea cycle.
6. Fate of Urea: Urea diffuses from the liver, and is transported in the blood to the
kidneys, where it is filtered and excreted in the urine. A portion of the urea
diffuses from the blood into the intestine, and is cleaved to CO2 and NH3 by
bacterial urease.
Energetics of urea cycle: Overall reaction is as follows:
NH3 + CO2 + Aspartate Urea + Fumarate
1. In step 1, 2 ATPs are used;
2. In step 3 One ATP is converted to AMP;
3. Thus 4 high energy bonds are consumed in total.
4. Fumarate is converted to malate and then to oxaloacetate and will yield 1
NADH equivalent to 3 ATPs.
5. The net energy spent is 1 ATP
Regulation of urea cycle:
1. Coarse regulation: During starvation urea cycle is accelerated to meet the
increased rate protein catabolism.
2. Fine regulation:
a. The synthesis of carbamoyl phosphate and the urea cycle are
dependent on the presence of N-Acetylglutamic acid, which
allosterically activates CPS1.
b. Arginine is an activator of N-Acetylglutamic acid synthase; So, Arginine
is not only a substrate for the urea cycle reactions but also serves as
an activator for the urea cycle.
c. Compartmentalization: The inhibitory effect of Fumarate is minimised
by the fact that the enzyme arginosuccinate lyase is in cytoplasm
while Fumarate is in mitochondria.
Integration between urea cycle and TGA cycle:
1. Urea cycle is linked with TCA cycle in three different ways. This is regarded as
bicyclic integration between the two cycles.

164
2. The production of fumarate in urea cycle is the most important integrating point
with TCA cycle. Fumarate is converted to malate and then to oxaloacetate in TCA
cycle. Oxaloacetate undergoes transamination to produce aspartate which enters
urea cycle. Here, it combines with citrulline to produce arginosuccinate.
3. Oxaloacetate is an important metabolite which can combine with acetyl CoA to
form citrate and get finally oxidized.
4. Oxaloacetatec an also serve as a precursor for the synthesis of glucose
(gluconeogenesis).
5. Citric acid cycle is an important metabolic pathway for the complete oxidation of
various metabolitesto CO2 and H2O. The CO2 liberated in TCA cycle (in the
mitochondria) can be utilized in urea cycle.
Disorders of urea cycle:
1. Deficiency of any urea cycle enzyme would result in hyperammonemia.
2. Normal level of ammonia in blood is <50 mg/dl
3. Urea level in blood is 20-40 mg/dl. It is increased in renal failure.
4. The term 'uremia' is used to indicate increased blood urea levels due to renal
failure.
5. Azotemia reflects a condition with elevation in blood urea/or other nitrogen
metabolites which may or may not be associated with renal diseases.
6. Non protein nitrogen (NPN): NPN refers to all the nitrogen-containing
substances other than proteins. These include urea (most abundant),
creatinine, creatine, uric acid, peptides, amino acids etc. In healthy persons,
NPN concentration in blood is 20-4O mg/dl.
7. Blood urea nitrogen (BUN):
a. The molecular weight of urea is 60 and about half of it (28) is
contributed by the two nitrogen atoms. Thus, if blood urea
concentration is 60 mg, then about half of it-28 mg-is blood urea
nitrogen (BUN).
b. Therefore,
i. BUN = NPN
ii. NPN = 2 BUN
c. In some countries, estimations of BUN or NPN are used rather than
blood urea for assessing kidney function.
d. Renal disorders can be:
i. Prerenal: due to increased protein breakdown.
ii. Renal: In renal disorders like acufe glomerulonephritis, chronic
nephritis, nephrosclerosis, polycystic kidney, blood urea is
increased
iii. Post renal: ohstruction in the urinary tract (e.g. tumors, stones,
enlargemenot f prostateg land etc.),
8. Urea cycle disorders: There are six disorders of the urea cycle.

Disease

Enzyme defect

Features

Hyperammonemi
a type I

Carbamoyl
Phosphate synthase1

Increase ammonia level in blood;

mental retardation

Hyperammonemi
a type II

Ornithine
transcarbamoylase

Increase ammonia and glutamine level

in blood;

165
Hyper
ornithinemia

Ornithine transporter
protein

Increased ammonia and ornithine;

Citrulinemia

Arginosuccinate
synthetase

Increased blood level of arginisuccinate

Hyperargininemi
a

Arginase

Increased arginine in blood

Argininosuccinic
aciduria

Argininosuccinate
lyase

Argininosuccinate in blood and urine.

Friable brittle tufted hair (Trichorrhexis
nodosa).

Significance of urea cycle:

1. Urea cycle is connected with vital metabolic reactions in the body.
2. It is integrated with citric acid cycle, which serves as a source of aspartate.
3. Fumarate derived from argino succinate is again integrated with citric acid cycle.
4. The urea cycle operates to eliminate excess nitrogen. On high-protein diets the
carbon skeletons of the amino acids are oxidized for energy or stored as fat and
glycogen, but the amino nitrogen must be excreted. To facilitate this process,
enzymes of the urea cycle are controlled at the gene level.
5. With long-term changes in the quantity of dietary protein, changes of 20-fold or
greater in the concentration of cycle enzymes are observed. When dietary
proteins increase significantly, enzyme concentrations rise. On return to a
balanced diet, enzyme levels decline.
6. Under conditions of starvation, enzyme levels rise as proteins are degraded and
amino acid carbon skeletons are used to provide energy, thus increasing the
quantity of nitrogen that must be excreted.

HYPERAMMONEMIA
1. Increased entry of ammonia to the brain is a primary cause of neurological
disorders associated with hyperammonemia.
2. Examples:
a. Congenital deficiencies of urea cycle enzymes,
b. Hepatic encephalopathy - Reye syndrome, several other metabolic
disorders, and some toxic encephalopathies.
3. Congenital Enzyme defects in urea cycle
1. N -acetylglutamate synthetase (NAGS) deficiency (Hyperammonemia type I):
Deficiency of this enzyme results in lack of N -acetylglutamate, which is an
activator of carbamoyl phosphate synthetase. Mode of inheritance is autosomal
recessive.
2. Carbamoyl phosphate synthetase I (CPS I) deficiency: This defect is inherited in
an autosomal recessive pattern. In the presence of N -acetylglutamate,
ammonium ions combine with bicarbonate to form carbamoyl phosphate.
Hyperammonemia develops as early as the first day of life. A majority of affected
infants die in the neonatal period.

166
3. Ornithine transcarbamoylase (OTC) deficiency: In the absence of the enzyme,
accumulated carbamoyl phosphate enters the cytosol and participates in
pyrimidine synthesis in the presence of CPS II. This is the most common urea
cycle defect, with an estimated incidence of 1 case in 14,000 persons. It is
transmitted as an X-linked trait.
4. Argininosuccinic acid synthetase (AS) deficiency: Citrulline combines with
aspartate to form argininosuccinic acid. The AS deficiency results in citrullinemia.
Onset is usually between hours 24 and 72 of life, but late-onset forms have been
described in the literature. The mode of inheritance is autosomal recessive. The
gene for this defect has been localized to chromosome 9.
5. Argininosuccinic lyase (AL) deficiency: This enzyme cleaves argininosuccinic acid
to yield fumarate and arginine. The lack of this enzyme leads to argininosuccinic
aciduria. It is the second most common urea cycle disorder. Symptoms may
appear in the neonatal period or later in life. It also is inherited in an autosomal
recessive pattern. Abnormally fragile hair (trichorrhexis nodosa) has been
observed in these infants as early as age 2 weeks.
6. Arginase deficiency: This enzyme is involved in the final step of the urea cycle
when arginine is cleaved to form urea and ornithine. Its deficiency results in
argininemia, which is the least frequent of the urea cycle disorders.
Hyperammonemia is not severe and the probable cause of neurotoxicity is
arginine.
7. Organic acidemias
a. Usually these disorders are associated with ketosis and acidosis in
addition to hyperammonemia; The proposed mechanism for
hyperammonemia is the accumulation of CoA derivatives of organic acids,
which inhibit the formation of N -acetylglutamate, the activator of
carbamoyl phosphate synthetase in liver.
b. Disorders in this group include the following:
i. Isovaleric acidemia
ii. Propionic acidemia
iii. Methylmalonic academia etc
8. Reye syndrome
1. This is an acquired disorder usually occurring after a viral infection
(particularly influenza A or B or varicella). Statistically, it has some
association with aspirin ingestion.
2. Patients present with symptoms and signs of cerebral and hepatic
dysfunctionvomiting, altered level of consciousness, seizures, cerebral
edema, and hepatomegaly without jaundice.
3. Laboratory studies reveal marked increases in liver transaminases,
hyperammonemia, and lactic acidosis.
9. Drugs
1. Valproate: Therapy with valproate is associated with hyperammonemia,
2. Chemotherapy: Acute hyperammonemia has been reported after highdose chemotherapy such as 5-fluorouracil, resulting in a high mortality
rate.
3. Salicylate: Intoxication with aspirin can present findings similar to Reye
syndrome with an initial respiratory alkalosis and hyperammonemia.
10. Liver disease
1. This is a common cause of hyperammonemia in adults.
2. It may be due to an acute process, for example, viral hepatitis, ischemia,
or hepato toxins.
3. Chronic liver diseases that can cause hyperammonemia include the
following:
1. Biliary atresia
2. Alpha1-antitrypsin deficiency

167
3. Wilson disease
4. Cystic fibrosis
5. Galactosemia
6. Tyrosinemia
4. Hepatic coma:
1. Hyperammonemia is the characteristic feature of liver failure. The
condition is also known as portal systemic encephalopathy.
Normally the ammonia and other toxic compounds produced by
intestinal bacterial metabolism are transported to liver by portal
circulation and detoxified by the liver. But when there is portal
systemic shunting of blood, the toxin bypass the liver and their
concentration in systemic circulation rises.
2. The signs and symptoms are mainly pertaining to CNS dysfunction
(altered sensorium, convulsions), or manifestations of failure of
liver function (ascites, jaundice, hepatomegaly, edema,
hemorrhage, spider naevi).
11. Renal
1. Urinary tract infection with a urease-producing organism, such as Proteus
mirabilis, Corynebacterium species, or Staphylococcus species, can
produce a hyperammonemic state.
DIFFERENCES BETWEEN CPSI AND CPS II:
1. Carbamoyl phosphate is an anion of biochemical significance. In land-dwelling
animals it is an intermediary metabolite participating in the nitrogen disposal
through two different pathways:
a. the urea cycle and
b. the synthesis of pyrimidines
2. Carbamoyl Phosphate Synthetase I Initiates Urea Biosynthesis. Condensation of
CO2 , ammonia, and ATP to form carbamoyl phosphate is catalyzed by
mitochondrial carbamoyl phosphate synthetase I. This rate-limiting enzyme of the
urea cycle, is active only in the presence of N - acetylglutamate
3. A cytosolic form of this enzyme, carbamoyl phosphate synthetase II, uses
glutamine rather than ammonia as the nitrogen donor and functions in pyrimidine
biosynthesis.
4. Compartmentation thus provides two independent pools of carbamoyl phosphate.
5. Differences between CPSI and II:

Site of action
Pathway of
Dependance
Source for N
Inhibitor

CPS-I
Mitochondria
Urea formation
N - acetylglutamate
Ammonia
Nil

Activator:

Nacetylglutamate

Deficiency
Disorder

Hyperammonemia
type I

CPS-II
Cytosol
Pyrimidine symthesis
Nil
Glutamine
UTP (uridine
triphosphate.)
PRPP (phosphoribosyl
pyrophosphate)
nil

ONE-CARBON METABOLISM
1. One carbon groups donate carbon atoms for different type of compounds in amino
acid metabolism.
2. One carbon groups are:
1. Formyl group
2. Formimino group
3. Methanyl group

168

3.
4.
5.

6.

7.

8.

4. Hydroxymethyl group
5. Mrthylene group
6. Methyl group
Except mehyl group others are carried by tetrahydrofolic acid. They are contributed
by by amino acids
Co2 is also a one carbon unit as it participates in carboxylation but not accepted by
many as a one carbon unit.
Formation of one carbon units:
1. The formate released from glycine and tryptophan metabolism combines with
THF to form N10-formyl THF.
2. Histidine contributes formimino fragment to produce N5-formimino THF
3. When serine is converted into glycine N5-N10 methylene THF is formed. As
serine is converted to choline, 3 one-carbon units are used up. During the
conversion of choline to glycine, these methyl groups are recovere. Hence,
this pathway is called the "salvage pathway" for one-carbon units.
4. Choline and betain contribute to the formation of N5-methyl THF
Interconversion of One-Carbon Groups
1. The different one-carbon groups are interconvertible . All one-carbon units are
ultimately siphoned into methyl-THFA. This is because the reductase reaction
is an irreversible step.
2. From methyl-THFA, the B12 co-enzyme accepts the methyl group to form
methyl cobalamin. It then transfers the methyl group to homocysteine to
form methionine. This is one of the few reactions in human metabolism,
where B12 acts as a coenzyme. In B12 deficiency, deficiency of folic acid is
also observed; this is because, the transfer of methyl group from methyl-THFA
does not occur. THFA is not regenerated;
Utilization of one carbon moiety: One carbon units are used to synthesise the
following compounds:
1. C2 of purine
2. Formylation of Methionyl t RNA
3. C8 of purine
4. Glycine
5. Pyrimidine nuceleotide
6. Serine
7. Choline
8. Transmethylation reactions including creatine, choline and epinephrine
synthesis
9. Excreted as carbon dioxide
Role of methionine and B12:
1. Active methionine is a methyl donor; after release of methyl group it
becomes homocysteine. Reconversion of homocysteine to methionine using
N5-methyl THF is a reaction which is catalyzed by a B12-containing
methyltransferase
2. B12 coenzyme accepts methyl group from methyl THFA to form methyl
cobalamin.
3. In B12 deficiency this transfer cannot occur and hence THFA (Folic acid) cannot
be regenerated. So folic acid deficiency coexists with B12 deficiency a
condition called folate trap.

Glycine
Questions:
1. Describe glycine metabolism. Write the various compounds formed from
glycine.- April 2000
1. Discuss the metabolism of GLYCINE. Add a note on metabolic disorders
associated with glycine metabolism.
S.N:
2. creatine and creatinine synthesis - Nov 1998; March 2002
3. Creatine April 2000

169
1. Introduction:
a. Glycine is the organic compound with the formula NH2CH2COOH. It is the
smallest of the 20 amino acids commonly found in proteins. Collagen
contains about 35% glycine. In its crystallized form glycine is a free-flowing,
sweet-tasting crystalline material. It is a non- essential and glucogenic amino
acid.
b. Glycine is actively involved in the synthesis of many specialized products like
heme, purines, creatine etc. in the body.
c. It is incorporated into proteins & used in the synthesis of serine and glucose
d. It participates in one-carbon metabolism.
2. Biosynthesis:
1. It is biosynthesized in the body from the amino acid serine. The enzyme
Serine hydroxymethyltransferase catalyses this transformation by removing
one carbon atom
Serine + tetrahydrofolate Glycine + N5,N10-Methylene
tetrahydrofolate + H2O
2. Glycine synthesis is also effected by glycine synthase from CO2, NH4 and one
carbon unit .
CO2 + NH4+ + N5,N10-Methylene tetrahydrofolate + NADH + H+ <
Glycine + tetrahydrofolate + NAD+
3. Glycine is also synthesised from threonine by threonine aldolase.
Threonine Glycine + Acetaldehyde.
4. Glycine amino transferase can catalyze the synthesis of glycine from
glyoxylate and glutamate or alanine.
3. Utilization/ degradation of glycine:
1. Glycine undergoes oxidative deamination by glycine synthase to liberate
NH4+, CO2 and one carbon fragment as N5, N10-methylenTe HF. This glycine
cleavage system has a multi-enzyme complex
Glycine + THF + NAD+
5, 10-methylene-THF + + CO2 +
NH3 + NADH
2. Glycine is converted to serine by serine hydroxy methyl transferase; serine is
again converted to pyruvate by serine dehydrogenase ; pyruvate serves as a
precursor for glucose
3. Serine is degraded to glyoxylate which undergoes transamination to give
back glycine. Glyoxylate is converted to oxalate, an excretory product and
formate which enters one carbon pool
4. Synthesis of specialized products from glycine: Glycine is used in the
biosynthesis of:
1. Creatine & Creatine phosphate
2. Creatinine
3. Heme
4. Purine nucleotides
5. Glutathione
6. Conjugating agents
7. Neurotransmitter
1. Creatine and creatine phosphate synthesis: (S.N)
1. Creatine is present in the tissues like muscle, brain, blood etc. as the high
energy compound, phosphocreatine and as free creatine.
2. Creatine is biosynthesized from three different amino acids - arginine,
glycine, and methionine. The rest is taken in by alimentary sources. Ninetyfive percent of creatine is later stored in the skeletal muscles. Creatine kinase
is stored in muscle as high energy phosphate.
3. Steps:
1. The amidino group argenine is transferred to glycine to form guanido
acetic acid, catalysed by amido transferase in kidney and pancreas
and not liver.
amido transferase

170

2.

3.
4.

5.
6.
7.
8.
9.

Argenine +Glycine ------------------------Guanido acetic acid+

Ornithine
2. Guanido acetic acid is methylated to S-adenosine methionine (SAM)
by methyl transferase to form creatinine. This reaction occurs in liver.
Methyl Transferase
Guanido acetic acid + S-adenosyl methionine --------------------
Creatine + S-adenosyl homocysteine
3. Creatine is phosphorylated to creatine phosphate by creatine kinase
Creatine kinase
Creatine + ATP -------------------- Creatine phosphate+ ADP
The reverse of this reaction yields energy for muscle contraction and
is called Lohmanns reaction
4. Creatine phosphate is converted spontaneously to creatinine and
excreted in urine
Creatine phosphate ----------- Creatinine + Pi + H2O
4. Clinical application of creatine:
1. Normal serum creatinine level is 0.7 to 1.4 mg/dl
2. Serum creatine level is 0.2 to 0.4 mg/dl
3. Urine contains negligible amount of creatine but increased in muscular
dystrophies
4. Creatine level is an indicator of kidney function
5. Creatine kinase level is increased in myocardial infarction
Heme synthesis:
Delta amino levulinic acid (ALA) a key enzyme in heme synthesis is formed by
condensation of glycine with succinyl CoA catalysed by ALA synthase.
Synthesis of purines: The whole molecule of glycine is added to purine ring during
its synthesis
Glutathione synthesis: Glutathione is formed by glutamic acid, Cysteine and
glycine. It is a tripeptide.
-Glutamyl synthase
Glutamate+Cysteine+ATP-------------------Glutamylcysteine+ADP+Pi
Glutathione synthase
-Glutamylcysteine+Glycine+ATP-----------------------------
Glutathione
Conjugating agent: Glycine is used to conjugate bile acid to form bile salts.
Cholic acid + Glycine--- Glycocholic acid
Chenodeoxycholic acid + Glycine- --- Glycochenodeoxy cholic acid
Benzoic acid: Glycine is used for detoxification of benzoic acid to form hippuric acid
in liver.
Neurotransmitter: Glycine acts as neurotransmitter in brain stem and spinal cord;
high levels cause over excitation.
Constituent of protein: Glycine is found in polypeptides at beta bonds or loops; in
collagen every 3rd amino acid is glycine.
Glycine metabolic disorders:
1. Defect in glycine cleavage system increases blood level of glycine and result
in mental retardation and seizure.
2. Glycinuria: This is a rare disorder. Serum glycine concentration is normal,
but very high amount of it (normal O.5-1 g / day) is excreted in urine. lt is
believed that glycinuria is due to a defective renal reabsorption. Glycinuria is
characterized by increased tendency for the formation of oxalate renal
stones.
3. Primary hyperoxaluria: It is transmitted as an autosomal recessive trait. It is
caused by a deficiency of the peroxisomal liver-specific alanine: glyoxylate
aminotransferase, which normally converts glyoxylic acid to glycine. When
the pathway is blocked because of a deficiency or absence of this enzyme,
the result is high levels of glycolic and oxalic acid, which readily convert to

171
oxalate; this is then excreted in the urine. This leads to nephrocalcinosis and
the eventual development of end-stage renal failure. Management:
1. Increase intake of water
2. Reduce dietary intake of oxalate by minimizing the intake of leafy
vegetables, tea, spinach etc.
4. ln vitamin B6 deficiency, urinary oxalate is elevated which can be corrected
by B6 supplementation. However, B6 administration has no effect on
endogenous hyperoxaluria.
SERINE
1. Serine is an aliphatic hydroxy amino acid; It is non essential; It is glucogenic
2. Sources:
a. Phosphoglycerate by dehydrogenation, transamination and removal of
phosphate group.
b. Glycine by reversal of serine hydroxy methyl transferase reaction.
c. Alanine by transmethylation of hydroxy pyruvate with alanine.
3. Catabolism:
a. Deamination to pyruvate
b. Transamination to hydroxy pyruvate
c. Glucogenic pathway
4. Metabolic functions:
a. Donates one carbon group to its pool; serine hydroxymethyl transferase
as on serine and removes one carbon group as Methylene THF and
glycine is formed.
b. Serine combines with homocysteine to form Cysteine and homoserine.
c. Serine can be converted to alanine by dehydration followed by
transamination
d. Its analogues are used as drugs; azaserine is anticancer and cycloserine is
antituberculous.
5. Choline synthesis:
a. Serine is decarboxylated to ethanolamine by decarboxylase and 3 methyl
groups are added to form choline
b. Choline is precursor of acetyl choline a neurotransmitter.
c. Choline is one carbon donor.
6. Selenocysteine is produced by replacing the oxygen of serine by selenium;
selenocysteine participates in scavenger reactions and selenoprotein-P is an
antioxidant.
7. Serine is a component of phosphoproteins, glycoprotein and many enzymes like
trypsin etc
Alanine
1. Alanine is non-essential & glucogenic amino acid.
2. It is formed by transamination of pyruvate by alanine amino transferase (ALT) +
pyridoxal phosphate.
Pyruvate + Glutamate ---------------------------- Alanine + Alpha keto glutarate
3. In starvation glucose alanine cycle plays an important role.
4. Liver takes alanine from skeletal muscle for this cycle.
SULPHUR CONTAINING AMINO ACIDS: METHIONINE, CYSTEINE AND CYSTINE
Qestions:
1. Name the sulphur containing amino acids. Outline the metabolism of
any one of them.- October 1999
2. What is the active form of methionine and how it is formed? Enumerate
the steps of methionine metabolism and write the disorders associated
with its metabolism. February 2007
3. Describe the pathways of methionine metabolism. Add a note on
metabolic functions of methionine and cysteine. AUGUST 2008
S.N:

172
4.
5.
6.
7.

Metabolically important products formed from methionine. Oct 2003

Transmethylation November 1994; April 2001
Active methionine. April 1998
Metabolic role of methionine-April 2001

METHIONINE
Introduction:
1. The sulphur containing amino acids are methionine, cysteine and cystine.
2. Among these, only methionine is essential. It is a sulphur containing, essential,
and glucogenic amino acid.
3. Metabolism is divided into 3 parts:
a. Activation and Transmethylation reactions
b. Conversion to Cysteine and cysteine
c. Degradation and conversion of Cysteine into various products
Steps:
1. Activation of Methionine: Methionine is activated to S-adenosyl methionine (SAM)
by transferring the adenosyl group to sulphur atom
Methionine s-adenosyl transferase
Methionine + ATP> S-adenosyl methionine + PPi+Pi
2. Methyl transfer or transmethylation: From S-adenosyl methionine the methyl
group is transferred to a methyl acceptor and gets converted to S-adenosyl
homocysteine. In SAM, due to the presence of a high energy bond, the methyl group
is labile, and may be transferred easily to other acceptors.
Methyl transferase
S-adenosyl methionine + Methyl acceptor > S-adenosyl homocysteine
3. Formation of Homocysteine: Adenosyl group is removed from to form
homocysteine. Thus, Methionine is also the source of homocysteinea metabolite
associated with atherosclerotic vascular disease.
Adenosine homocysteinase
S-adenosyl homcysteine > Homocysteine+ Adenosine
4. Fate of Homocysteine :
a. Synthesis of methionine: Homocysteine is methylated to methionine from
a one carbon pool with the help of B12.
Methyl transferase
Homocysteine+ CH3(1 C pool) +B12 > Methionine
b. Homocysteine degradation to Cystathionine: Homocysteine condenses
with serine to form cystathionine and is catalysed by pyridoxal phosphate
dependant cystathinine-beta synthase. Absence this enzyme will lead to
homocystinuria.
Cystathionine-beta synthase
Homocysteine+ Serine -> Cystathionine
c. Synthesis of Cysteine: Cystathionine is hydrolysed by cystathionase to
form Cysteine and Homoserine and is called trans-sulphation reaction.
Cystathionase
Cystathionine + H20 -> Cysteine + Homoserine
d. Final oxidation: Homocysteine is deaminated and then decarboxylated to
propionyl CoA. It enters TCA as succinyl CoA to give glucose.
Clinical significance:
1. Homocysteine and heart attacks:
i. Homocysteine is an intermediate in the synthesis of cysteine from
methionine.
ii. Elevation in plasma homocysteine (normal <15 pmol/l) has been
implicated in coronary artery diseases, although the mechanism is not
known.
iii. lt is believed that homocysteine reacts with collagen to produce
reactive free radicals, besides interfering with collagen cross links.

173
iv. Homocysteine is also involved in the aggregation of LDL particles. All
this leads to an increased tendency for atherogenesis, and
consequently heart complications.
v. Supplementation of diet with folic acid, vitamin B12 and vitamin B6
have some beneficial effects in lowering plasma homocysteine levels.
2. Homocystinurias:
i. Homocystinurias are a group of metabolic disorders characterized by
the accumulation and increased urinary excretion of homocysteine
and S-adenosyl methionine. Plasma concentration of methionine is
increased.
ii. Homocystinuria type I is due to a defect in the enzyme cystathionine
synthase. Accumulation of homocystetne results in thrombosis,
osteoporosis and mental retardation. Further, the deficiency of
cystathionine is associated with damage to endothelial cells which
might lead to atherosclerosis.
iii. The other homocystinurias are associated with enzyme defects in the
conversion of homocysteine to methionine by remethylation.
iv. Homocystinuria ll : N5-N10 methylene THF reductase.
v. Homocystinuria lll : N5-N10 methylene THF homocysteine
methyltransferase. This is mostly due to impairment in the synthesis
of methylcobalamin.
vi. Homocystinurla lV: N5- Methyl THF homocysteine methyl transferase.
This is primarily due to a defect in the intestinal absorption of vitamin
B12.
3. Cyanide-nitroprusside test:
i. It is a screening test. 5 ml urine saturated with sodium chloride, 4
drops of ammoniacal silver nitrate. After 1 min, KCN (potassium
cyanide) is added drop by drop until solution is clear. Then 4 drops of
freshly prepared sodium nitroprusside is added.
ii. A magenta-red colour appearing within 2-3 min and persisting for at
least 2-3 min is indicative of the presence of
homocystine/homocysteine in urine. Specific amino aciduria may be
confirmed by chromatography.
TRANSMETHYLATION REACTION; ACTIVE METHIONINE (Short notes)
1. The transfer of methyl group (-ch3) from one active methionine to an acceptor is
called trans-methylation.
2. Active methionine:
a. Methionine reacts with ATP forming S - adenosylmethionine (SAM) which is
called active methionine.
b. Methionine has to be activated to S-adenosyl methionine (SAM) to donate the
methyl group.
c. The synthesis of S- adenosyl methionine occurs by transfer of an adenosyl
group from ATP to sulphur atom of methionine and the sulphur atom becomes
sulfonium atom and is catalysed by methionine s adenosyl transferase. SAM
is a sulfonium compound. This reaction is also unusual since all the three
phosphates of ATP are eliminateda s pyrophosphates (PPi) and inorganic
phosphates (Pi). Three high energy phosphates 3 ATn arc consumed in the
formation of SAM.
Methionine s-adenosyl transferase
Methionine + ATP> S-adenosyl methionine + PPi+Pi
3. Functions of S- adenosyl methionine (active methionine)
a. S-adenosyl methionine is highly active due to its positive charge.
b. SAM is the main source of methyl groups in the body. The enzymes involved
in the transfer of methyl group are collectively known as Methyl Transferase.
c. From S-adenosyl methionine the methyl group is transferred to a methyl
acceptor and gets converted to S-adenosyl homocysteine
Methyl transferase

174
S-adenosyl methionine + Methyl acceptor > S-adenosyl homocysteine
d. In this reaction methionine is regenerated by converting homocysteine to
methionine by remethylation.
e. S-Adenosylmethionine is also involved in the synthesis of polyamines
(spermidine, spermine).
4. Creatine, epinephrine, choline, phosphatidyl choline, melatonin etc are formed by
transmethylation.
5. Significance of transmethylation:
a. Transmethylation is of great biological significance since many compounds
become functionally active only after methylation.
b. Methylation protects proteins from immediate degradation.
c. In plants, S-adenosylmethioninies the precursor for the synthesis of a plant
hormone, ethylene, which regulates plant growth and development and is
involved in the ripening of fruits.
CYSTEINE
S.N:
1. Glutathione role in amino acid synthesis August 2005
2. Give an account of the formation and fate and metabolic role of Cysteine.
Nov 1995
3. Give a concise account of the formation, fate and metabolic role of
Cysteine. November 1995
Introduction:
1. Non-essential and glucogenic; Present in hair and nails as keratin
2. Homocysteine formed from methionine is a precursor for the synthesis of
cysteine. Homocysteine condenses with serine to form cystathionine.
Biosynthesis:
1. It is formed by carbon skeleton contributed by serine and sulphur from
methionine as follows: Methionine is activated to S-adenosyl methionine (SAM)
by transferring the adenosyl group to sulphur atom.
Methionine s-adenosyl transferase
Methionine + ATP> S-adenosyl methionine + PPi + Pi
2. From S-adenosyl methionine the methyl group is transferred to a methyl acceptor
and gets converted to S-adenosyl homocysteine
Methyl transferase
S-adenosyl methionine + Methyl acceptor > S-adenosyl homocysteine
3. Adenosyl group is removed from to form homocysteine.
Adenosine homocysteinase
S-adenosyl homocysteine > Homocysteine+ Adenosine
4. Homocysteine condenses with serine to form cystathionine and is catalysed by
pyridoxal phosphate dependant cystathinine-beta synthase. Absence this
enzyme will lead to homocystinuria.
Cystathionine - beta synthase +PLP
Homocysteine+ Serine -> Cystathionine
5. Cystathionine is hydrolysed by cystathionase to form Cysteine and Homoserine
and is called trans-sulphation reaction.
Cystathionase
Cystathionine + H20 -> Cysteine + Homoserine
Degradation/reactions of Cysteine:
1. Transamination:
a. Cysteine transaminates to form beta mercapto pyruvic acid and finally to
pyruvate.
b. Sulphur may be eliminated as H2S or as sulphite.
c. Cysteine on decarboxylation gives beta mercapto ethanolamine. This is
used for synthesis of co-enzyme A
2. Formation of glutathione: Glutathione is formed from Cysteine as follows:
Cysteine + Glutamate > gamma glutamyl cysteine
Glutamyl cysteine + glycine glutathione
3. Production of cysteic acid taurine & pyruvate:

175
a. The enzyme cysteine dioxygenase oxidizes cysteine to cysteine sulfinate
which, on further oxidation, is converted to cysteic acid. The latter
undergoes decarboxylation to produce taurine which conjugates with bile
acids.
b. Cysteic acid can also be degraded to pyruvate, which is glycogenic.
4. Formation of sulfate PAPS:
a. Cysteine sulfinate cleaves off alanine to produce sulfite which is
converted to sulfate and excreted in urine. Some amount of sulphate
condenses with ATP to form active sulfate or 3'-phosphoadenosine S'phosphosulfafe (PAPS).
b. Active sulphate (PAPS) is utilized for the synthesis of
mucopolysaccharides (sulfation), besides being used in detoxification.
Sulfate is also a structural component of some proteins, lipids etc.
5. Keeping the correct structure of proteins: Cysteine residues in polypeptide chains
form disulfide bridges to make active proteins, e.g. insulin and immunoglobulins.
Protein disulfide isomerase forms these disulphide bonds.
6. Formation of Taurine:
i. Cysteine is oxidized to cysteic acid and then decarboxylated to form
taurine. Alternatively cysteine is oxidized to cysteine sulfinic acid. It is
then decarboxylated by a decarboxylase to hypotaurine which in turn is
oxidised to taurine. Taurine is used for conjugation of bile acids.
Taurine + Cholyl CoA Taurocholate + CoA-SH
ii. Taurine is a modulator of calcium fluxes, calcium binding and
movement. In the CNS it is an inhibitory neurotransmitter.
7. N-Acetyl cysteine (NAC) is believed to improve the body levels of glutathione.
Hence it is used as an adjuvant in the treatment of injury by free radicals.
Glutathione and NAC have therapeutic effects in chronic hepatitis B patients.
8. In erythrocytes, the rate of GSH synthesis is determined by the availability of Lcysteine. There is a significant decline in the influx of L-cysteine in erythrocytes
during aging in humans. Cysteine supplementation has been shown to
ameliorate several parameters that are known to degenerate during human
aging; this has led to an interesting hypothesis that aging could be a cysteine
deficiency syndrome.
Clinical importance:
1. Cystinuria:
a. It is one of the inborn errors of metabolism included in the Garrod's
tetrad. It is an autosomal recessive condition. The disorder is attributed to
the deficiency in transport of amino acids.
b. Cystinuria is characterized by increased excretion of cysteine (25-40
times normal). A specific carrier system exists in kidney tubules for the
reabsorption of amino acids, namely cysteine, ornithine, arginine and
lysine.
c. In cystinuria, this carrier system becomes defective leading to the
excretion of all these four amino acids in urine. This leads to precipitation
and formation of cystine stones in kidney and urinary tract.
d. Treatment is to increase urinary volume by increasing fluid intake.
Solubility of cystine is increased by alkalinization of urine by giving
sodium bicarbonate.
e. Cyanide-nitroprusside test:
2. Cystinosis (cystine storage disease):
a. Cystine crystals are deposited in many tissues and organs of
reticuloendothelial system throughout the body. These include spleen,
lymph nodes, liver, kidney, bone marrow etc. A defect in the Iysosomal
function is said to be the primary cause of this disorder. The affected
patients die usually within l 0 years, mostly due to renal failure. A defect
in the enzyme cysteine reductase is believed by some as the etiology.

176
GLUTATHIONE
1. Glutathione is gamma glutamyl cysteinyl glycine. Glutathione is generally
abbreviated as GSH, to indicate the reactive SH group. Glutathione (abbreviated
GSH) is a tripeptide composed of glutamate, cysteine and glycine that has numerous
important functions within cells.
2. Glutathione synthesis: Glutathione is formed by glutamic acid, Cysteine and
glycine. Both steps need hydrolysis of one ATP each.
-Glutamyl synthase
Glutamate+Cysteine+ATP--------------------Glutamylcysteine+ADP+Pi
Glutathione synthase
-Glutamylcysteine+Glycine+ATP----------------------------- Glutathione
3. Role of Glutathione:
1. Glutathione is involved in amino acid transport across cell membranes (the glutamyl cycle) It reacts with the amino acid to form gamma glutamyl amino
acid. This is catalyzed by gamma glutamyl transferase. The glutamyl amino
acid is then cleaved to give the free amino acid. The net result is the transfer
of an amino acid across the membrane
2. Co-enzyme Role: Metabolic role of GSH is mainly in reduction reactions. The
hydrogen released is used for reducing other substrates. A few examples are
shown below:
i. Maleyl acetoacetate fumaryl acetoacetate
ii. Cysteic acid taurine
3. RBC Membrane Integrity: Glutathione is present in the RBCs. This is used for
inactivation of free radicals formed inside RBC. This is called free radical
scavenging. The occurrence of hemolysis in GPD deficiency is attributed to
the decreased regeneration of reduced glutathione.
4. Met-hemoglobin: The met-Hb is unavailable for oxygen transport. Glutathione
is necessary for the reduction of methemoglobin (ferric state) to normal Hb
(ferrous state).
2Met-Hb-(Fe3+) + 2GSH 2Hb-(Fe2+) + 2H+ +GS-SG
5. Conjugation for Detoxification:
a. Glutathione helps to detoxify several compounds by transferring the
cysteinyl group, the reaction is catalyzed by glutathione-S- transferase
(GST). Eg.
1. Organo phosphorus compounds b. Halogenated compounds
2. Nitrogenous substances (chloro dinitro benzene)
3. Heavy metals
4. Drug metabolism.
6. Activation of Enzymes: Many enzymes having SH groups in the active site
are kept in the active form by the glutathione. Such enzymes are active in the
reduced form. Glutathione keeps the enzymes in reduced, active state.
GLUTAMIC ACID
Introduction:
It is a non-essential amino acid. It plays a prominent role in amino acid
metabolism. It is involved in transfer of amino group for urea synthesis.
Biosynthesis:
1. -ketoglutarate, an intermediate in TCA cycle is an immediate precursor for
glutamate formation.
Amino acid+ a-ketoglutarate > Glutamic acid + a-keto acid
2. It is also formed from the metabolism of histidine, proline and arginine.
Glutamate in specialized products:
1. Glutamate is converted to glutamine.
2. Glutathione is a tripeptide that contains glutamate.

177
3. N-Acetylglutamate is an allosteric regulator of carbamoyl phosphate synthase l,
the first enzyme in urea synthesis.
4. Glutamate is present in the clotting factors (ll, Vll, lX, X) as y-carboxyglutamate
and is involved in coagulation.
Degradation of glutamate:
1. Oxidative deamination:
Glutamate dehydrogenase
Glutamate + H2o + NAD+ --------------------------> Alphaketoglutarate + NH3+
NADH+ + H+
2. Glucogenic: Glutamate enters TCA cycle to form oxaloacetate for glucogenic
pathway.
3. NAG: glutamic acid forms N-acetyl glutamate a positive modifier of Carbomyl
phosphate synthase-1
Glutamic acid +Acetyl CoA> NAG + CoASH
4. Glutamine: The intracellular ammonia is immediately trapped by glutamic acid
to form glutamine which is a transporter of ammonia in a benign form.
Glutamine synthase
Glutamic acid+NH3 + ATP --------------------------------> Glutamine+ H2O+ADP+Pi
5. Gamma carboxy glutamic acid is present in prothrombin and is involved in
coagulation.
6. Excitatory neurotransmitter: nitric oxide is formed by glutamate stimulating
NMDA receptors in neurons; nitric oxide increases cyclic GMP and neurons are
excited.
7. Glutathione: It is a tri peptide containing glutamate and is necessary for folic
acid synthesis.
8. Gamma amino butyric acid:
a. Glutamic acid on decarboxylation gives rise to Gamma amino butyric acid
(GABA). GABA can be metabolized to succinate. GABA is an inhibitory
neurotransmitter.
b. CABA undergoes transamination followed by oxidation to form succinate
which enters TCA cycle.(GABA shunt)
c. Functions of GABA: lt is one of the major inhibitory neuro transmitters in
the brain. GABA regulates the activity of neurons by discouraging the
transmission signals. lt is believed that GABA opens chloride channels and
increases the permeability of post-synaptic membranes. Thus GABA
functions as an inhibitory neurotransmitter. Decreased CABA levels will
cause convulsions. Sodium valproate inhibits GABA oxidase and is used as
an anticonvulsant.
d. Vitarnin B6 deficiency and GABA : GABA synthesis requires pyridoxal
phosphate, a coenzyme of vitamin B6. In B6 deficiency, the production of
GABA is reduced. The result is neuronal hyper excitability, causing
convulsions.
GLUTAMINE
1. It is a glucogenic amino acid; it is synthesized from glutamic acid. It helps to fix
ammonia into a nontoxic form and protects neural tissues from toxicity.
2. Biosynthesis:
The intracellular ammonia is immediately trapped by glutamic acid to form
glutamine which is a transporter of ammonia in a benign form
Glutamine synthase
Glutamic acid+NH3 + ATP ---------------------------
Glutamine+ H2O+ADP+Pi
3. The glutamine synthase reaction is important because it produces glutamine, which
carries ammonia from peripheral tissues to the kidney, where it regenerates
glutamate and free ammonium ion, which is excreted in the urine. In renal tubular

178
cells Glutamine is hydrolyzed to glutamate and ammonia by glutaminase. Ammonia
helps to buffer H+ in urine.
4. Glutamine is hydrolysed to glutamate and NH3. Glutamic acid is then deaminated to
alpha ketoglutarate and enters TCA cycle for further catabolism.
5. The N atoms 3 and 9 of purines are derived from glutamine
6. Glutamate dehydrogenase is available only in liver. Hence glutamine has to be
transported to liver for its catabolism.
7. It provides N atoms to pyrimidine and provides NH2 to guanine and cytosine.
8. Glutamine is conjugating agent to form phenyl acetyl glutamine.
9. It donates amino group to amino sugars and amide group of nicotinamide
10. Functions:
Glutamine has a variety of biochemical functions including:
1. A substrate for DNA synthesis
2. Major role in protein synthesis
3. Primary source of fuel for enterocytes
4. Precursor for rapidly dividing immune cells, thus aiding in immune
function
5. Regulation of acid-base balance in the kidney by producing ammonium
6. Alternative source of fuel for the brain and helps to block cortisol-induced
protein catabolism
7. As a carrier of ammonia from extra hepatic tissues.

1.
2.
3.
4.
5.
6.
1.
2.
3.
4.
1.
2.
3.
4.
5.
6.
1.
2.
3.
4.
5.
1.
2.

ASPARTIC ACID
It is non-essential glucogenic amino acid.
Aspartate on transamination gives rise to oxaloacetate which initiates TCA cycle.
Malate - aspartate shuttle transfers the cytoplasmic NADH into mitochondria for
oxidation in the electron transport chain.
In urea cycle it contributes its alpha amino group to urea molecule.
The carbon skeleton of Aspartate can enter glucogenic pathway as Fumarate.
Citrulline + Aspartate > Arginine + Fumarate
It is used for synthesis of purines and pyrimidine.
ASPARAGINE
Aspartate reacts with ammonia to form asparagine similar to glutamine.
Asparagine can be hydrolyzed to Aspartate and NH3 by Asparaginase.
L. Asparaginase is an anti leukemic drug.
It is glucogenic.
LYSINE
It is an essential amino acid.
It does not undergo transamination.
It id mainly ketogenic.
The epsilon amino group of lysine forms Schiff linkage attaching coenzymes to
proteins.
It is present in collagen
It is a precursor of Carnitine
ARGININE
It is a basic, semi essential amino acid.
It contains guanidium group.
In urea cycle arginase splits arginine into urea and ornithine.
Arginine reacts with glycine to form guanido acetic acid which is methylated to
creatine.
It is a precursor of nitric acid an important signal molecule.
NITRIC OXIDE
NO has potent biological functions. It is a highly reactive free radical with half life 0.1
sec.
Synthesis: NO is formed from arginine by nitric acid synthase. The enzyme uses
NADPH and molecular oxygen
Arginine + O2 + NADPH > NO + Citrulline + H2O+ NADP

179
3. Mechanism of action:
a. Nitric oxide promotes the synthesis of cGMP. lt is believedt hat some of
the actions of NO are mediated through cGMP and protein kinase C. in
smooth muscle.
b. Dephosphorylation of myosin light chain occurs leading to relaxation of
smooth muscle.
4. Physiological actions:
a. NO functions as a vasodilator and causes relaxation of smooth
muscles.Deficiency cause hypertension and excessive production leads to
hypotension as occurs in septic shock.
b. lt is a key molecule in the regulation of blood flow and the blood pressure
c. NO acts as an inhibitor of platelet aggregation and adhesion.
d. lt functions as a messenger molecule of the nervous system
(neurotransmitter).
e. NO mediates the bactericidal actions of macrophages.
f. It is involved in the erection of penis.
g. In CNS NO stimulates releasing hormones like CRH, GHRH etc.
5. Therapeutic actions:
a. It is used in treating angina pectoris in the form of nitroprusside and nitroglycerin
which release NO.
b. Inhalation of NO reduces pulmonary hypertension.
c. It is useful in treating impotence: eg. sildenafil (Viagra)
POLYAMINES
1. Polyamines are putrescine, spermidine and spermine.
2. They are aliphatic amines.
3. They are synthesized from Ornithine by ornithine decarboxylase with coenzyme
pyridoxal phosphate.
4. Difuromethyl ornithine inhibits polyamine synthesis (Suicidal inhibition)
5. Polyamines are involved in cell proliferation, production and stabilization of ribosome
and DNA
6. Polyamines are growth factors for culture tissue
7. It is increased in cancer tissues.
AROMATIC AMINO ACIDS
Questions:
1. What are aromatic amino acids? Describe the metabolism of Phenyl
Alanine. April 2000
2. Name Aromatic Amino Aids. Write about metabolism of phenylalanine.
November 2001
3. Describe the metabolism of phenyl alanine in the body and discuss the
inborn errors associated with the metabolism. Feb 2005
4. Describe the metabolism of phenyl alanine and tyrosine in the body. Add a
note on the inborn errors of metabolism associated with them. Nov 1991
5. Name the aromatic amino acids. Describe the metabolism of any one of
them. Indicate the genetic errors in this pathway. April 1995
6. What are aromatic amino acids? Describe the metabolism of any one of
them. Name inborn errors of metabolism connected to these amino acids.
Nov 2001
7. Name inherited disorders associated with Tyrosine metabolism noting the
enzyme deficiency. April 2001
8. Describe the metabolism of tyrosine. Name the biologically important
compounds derived from tyrosine. What are the inborn errors of
metabolism of this amino acid? April 2001
9. Describe the metabolism of tryptophan and add a note on inborn errors
associated with it. Feb 2006
10.Inborn errors of Phenyl Alanine and Tyrosine. April 2000
11.Enzyme defects and biochemical consequences of two inborn errors of
phenyl alanine metabolism. Oct 2003
Introduction:

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Aromatic amino acids are amino acids which include an aromatic (indole) ring.
Examples include: phenylalanine,tryptophan, and tyrosine; histidine is also
considered as aromatic amino acid.
Tyrosine
Conversion of phenyl alanine to tyrosine:
1. Phenylalanine and tyrosine are structurally related aromatic amino acids.
Phenylalanine is an essential amino acid while tyrosine is non-essential. Both are
glucogenic and ketogenic.
2. The only function of phenyl alanine is its conversion to tyrosine. If tyrosine is
supplied adequately the requirement of phenyl alanine becomes minimal. Hence
tyrosine has sparing action on phenyl alanine.
3. Phenyl alanine is converted to tyrosine by phenylalanine hydroxylase using NADPH,
and tetra hydrobiopterin as coenzymes. Phenylalanine hydroxylase is a mixedfunction oxygenase. One atom of oxygen is incorporated into water and the other
into the hydroxyl of tyrosine. The reductant is the tetrahydro folate related cofactor
tetrahydrobiopterin, which is maintained in the reduced state by the NADH- de
pendent enzyme dihydrobiopterin reductase (DHPR).
CATABOLISM OF TYROSINE AND PHENYLALANINE
Introduction:
1. Tyrosine is an aromatic amino acid. It is synthesized from phenylalanine, and so
is a non-essential amino acid. The need for phenylalanine becomes minimal, if
adequate tyrosine is supplied in the food.
2. The metabolism of phenylalanine and tyrosine is considered together
3. Degradative pathway of phenylalanine and tyrosine are the same, since
phenylalanine is converted to tyrosine and then metabolized.
Step 1: Phenylalanine to tyrosine: The reaction involves addition of a hydroxyl
group to the aromatic ring, by phenylalanine hydroxylase. It needs NADPH,
NADH and tetrahydrobiopterine as co-enzymes. As this is an irreversible
reaction, tyrosine cannot replenish phenylalanine. Hence, phenylalanine is
essential in food. phenylalanine hydroxylase deficiency blocks the conversion
of phenylalanine to tyrosine resulting in the disorder phenylketonuria (PKU).
phenylalanine hydroxylase
Phenyl alanine + O2 + tetrahydrobiopterin + NADPH + H+ >Tyrosine+H2O + dihydrobiopterin + NADP
Step 2:
Transamination: Degradative pathway of phenylalanine and tyrosine are
the same, since phenylalanine is converted to tyrosine and then metabolized.
Tyrosine is transaminated to give para hydroxy phenyl pyruvic acid by tyrosine
transaminase. It is pyridoxal phosphate dependent. It is induced by
glucocorticoids. Tyrosine is transaminated to parahydroxypyruvic acid by
tyrosine transaminase and pyridoxal phosphate.
Phenylalanine
Phenyl alanine hydroxylase
Tyrosine
Tyrosine transaminase + PLP

A-Ketoglutarate
Glutamic acid
Para hydroxy phenyl pyruvic acid

Step 3:
Production of homogentisic acid : Parahydroxyphenylpyruvic acid is
converted to homogentesic acid. The reaction involves parahydroxypy
pyruvate hydroxylase, a copper containing enzyme and Ascorpic acid.
Parahydroxy phenyl pyruvic acid
O2

Para hydroxy phenyl pyruvic acid

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CO2

hydroxylase + Ascorbic acid

Dihydroxy phenyl acetic acid (homohentesic acid)

Step 4:
Cleavage of aromatic ring: Homogentisic acid oxidase opens the ring. It is
also a di-oxygenase with an iron atom at the active site. The product is 4maleyl acetoacetate.
Dihydroxy phenyl acetic acid (homohentesic acid)
homogentisic acid oxidase
O2
4- Maleyl acetoacetate
Step 5: Isomerization: It then undergoes cis to trans isomerisation to form fumaryl
acetoacetate by an isomerase. The isomerase requires glutathione (GSH) as a
cofactor.
Maleyl acetoacetic aid
Maleyl acetoacetate isomerase
Fumaryl acetoactetic acid
Step 6:
Hydrolysis: Fumaryl aceto acetate is then hydrolysed by hydrolase. This
results in the production of a glucogenic product (fumarate) and a ketone
body (acetoacetate). Hence phenyl alanine and tyrosine are partly glucogenic
and partly ketogenic.

Fumaryl acetoactate
Maleyl acetoacetate hydrolase
H2O
Acetoacetate + Fumarate
(Glucogenic)
(Ketogenic)
Products of Tyrosine:
1. Melonin
2. Catecholamines
3. Throxine
Melanin
Synthesis: Steps
1. Melanin is hydroxlised to dihydroxy phenyl alanine (DOPA) by tyrosinase a
copper containing enzyme.
2. DOPA is converted to DOPA quinone again by tyrosinase.
3. DOPA quinone undergoes a series of steps involving decarboxylation and
oxidation and finally the indole quinone formed is polymerized to melanin.
Clinical application of melanin:
1. Copper deficiency: Since tyrosinase is a copper containing enzyme, there may
be disturbances in pigmentation during copper deficiency. Hair synthesized at
the time of deficiency may be depigmented. If copper deficiency is
intermittent, alternate black and white regions may be seen in the hair (flag
sign).
2. Malignant melanoma: Melanoblasts, especially in junctional naevi, may
multiply to give rise to malignant melanoma. Melanogen may be excreted
through urine in such conditions. Urine on standing bcome black due to
melanin.

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3. Leukoderma is due to absence of tyrosinase and melanin forming cells.
4. Albinism is due to absence of tyrosinase in melanocytes all over the body.
5. Graying of hair is also due to the disappearance of melanocytes from the hair
root.
Catecholamine
How are catecholamines synthesised? Pon May 2010
Synthesis:
1. They are epinephrine, nor- epinephrine and dopamine
2. Dopamine synthesis: Dopamine is a neurotransmitter in extra pyramidal system;
deficiency causes parkinsonism.
Tyrosine hydroxylase DOPA decarboxylase
Tyrosine > DOPA > Dopamine
3. Nor-epinephrine : It is a neuro transmitter.
Dopamine hydroxylase
Dopamine -> nor-epinephrine
4. Epinephrine (adrenalin) : produced at adrenergic nerve endings
N-methyl transferase
Nor epinephrine -> epinephrine
Actions of epinephrine:
1. Epinephrine and nor-epinephrine increase the blood pressure.
2. Adrenaline also increases the rate and force of myocardial contraction.
3. Epinephrine causes relaxation of smooth muscles of bronchi.
4. Adrenaline is anti-insulin in nature; it increases glycogenolysis and stimulates
lipolysis.
5. Adrenaline is released from adrenal medulla in response to flight, fight, fright,
exercise and hypoglycemia.
Degradation:
1. Half lif is 2-5 minutes
2. Catabolised by catechol-o-methyl transferase to metanephrine.
3. Mono amine oxidase converts metanphrine to vanilyl mandelic acid.
4. VMA is excreted in urine which helps in diagnosis of pheochromocytoma and
neuroblastoma.
Thyroxine:
1. It is synthesized by iodination to form 3,monoiodotyrosine and then to 3,5
diiodotyrosine; further coupling leads to tri and tetra iodo tyrosine (T3 and
T4)
2. Tyrosine on decarboxylation gives rise to tyramine by intestinal bacteria;
tyramine is presents in chocolates and may cause migraine.
Inborn errors:
1. Phenylketonuria:
1. Autosomal recessive
2. phenyl alanine hydroxylase is deficient
3. incidence is 1 in 500 births (WHO)
4. phenylalanine is not converted to tyrosine and gets transformed into phenyl
ketones (lactate, pyruvate and acetate)
5. Symptoms: mental retardation, hyperactivity, convulsions, hypo pigmentation
and mousy body odor.
6. Lab. Diagnosis:
1. > 20 mg/dl of phenyl alanine in blood is diagnostic of PKU
2. Guthrie test: it is a screening test; bacillus subtilis needs
phenylalanine for growth.
A drop of blood is obtained by pricking the heel of a newborn . The
blood is collected on a piece of filter paper and placed on an agar gel
plate containing Bacillus subtilis. The amount of growth, measured as

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the diameter of the colony, is roughly proportional to the amount of
phenylalanine in the serum.
3. Ferric chloride test: Phenylketones will give a transient blue green
color on adding a drop of ferric chloride to urine sample.
7. Treatment:
i. Early detection by routine NB screening
ii. Low phenyl alanine diet Eg. Tapioca
2. ALKAPTANURIA
1. Alkaptonuria (black urine disease or alcaptonuria) is a rare inherited
genetic disorder of phenylalanine and tyrosine metabolism. Incidence is 1 in
250,000 births.
2. This is an Autosomal recessive condition that is due to a defect in the enzyme
homogentisate oxidase, which participates in the degradation of tyrosine.
3. As a result, a toxic tyrosine byproduct called homogentisic acid (or alkapton)
accumulates in the blood, and is excreted in urine in large amounts. It
blackens the urine on standing.
4. Excessive homogentisic acid causes damage to cartilage (ochronosis, leading
to osteoarthritis) and heart valves as well as precipitating as kidney stones.
5. Treatment is by low protein intake restricting phenylalanine content.
3. ALBINISM:
1. Autosomal recessive; 1 in 20,000 births
2. Enzyme tyrosinase is absent
3. Hypo pigmentation of iris, skin and hairs.
4. Photophobia and nystagmus and skin melanomas are common.
5. In less severe tyrosinase positive cases the uptake of tyrosine by
melanocytes is defective.
4. HYPERTYROSINEMIAS:
1. Hepatorenal tyrosinemia: also called tyrosinosis; Autosomal recessive; the
enzyme fumaro acetoacetate hydrolase is deficient; cabbage like odor and
hypoglycemia is common; death occurs early. Increased levels of tyrosine and
methionine in blood. Treatment: dietary restriction of tyrosine and
methionine.
2. Occulo cutaneous tyrosinemia: Tyrosine transaminase ids deficient; mental
retardation, palmar keratosis, corneal lesions and photophobia are common;
treatment by ascorbic acid and restriction of proteins.
5. Tyrosinosis or tyrosinemia type I:
This is due to the deficiency of the enzymes fumarylacetoacetate hydroxylase
and/or maleylacetoacetate isomerase. Tyrosinosis is a rare but serious disorder. lt
causes liver failure, rickets, renal tubular dysfunction and polyneuropathy.
Tyrosine, its metabolites and many other amino acids are excreted in urine.
6. Tyrosinemia type ll
This disorder-also known as Richner-Hanhart syndrome, is due to a defect in the
enzyme tyrosine transaminase. The result is a blockade in the routine
degradative pathway of tyrosine. Accumulation and excretion of tyrosine and its
metabolites are observed. Tyrosinemia type ll is characterized by skin
(dermatitis) and eye lesions and, rarely, mental retardation. A disturbed selfcoordination is seen in these patients.
TRYPTOPHAN
Questions:
1. Name aromatic amino acids. Describe the metabolism of tryptophan.
Name the important compounds synthesized from it and metabolic
disorders. Sep 2002
2. Describe the metabolism of tryptophan and add a note on inborn errors
associated with it. Feb 2006; Feb 2007
1. Tryptophan was the first to be identified as an essential amino acid. lt contains an
indole ring and chemically it is s-amino B-indole propionic acid. Tryptophan is both

184
glucogenic and ketogenic in nature. lt is a precursor for the synthesis of important
compounds, namely NAD+ and NADP+ (coenzymes of niacin), serotonin and
melatonin.
2. Compounds synthesized from tryptophan:
1. Alanine
2. Acetoacetyl CoA
3. Formyl group(1 C unit)
4. Niacin and NAD
5. Serotonin
6. Melatonin
7. Hydroxy indole acetic acid
8. Indican
3. The metabolism of tryptophan is divided into:
1. Kynurenine pathway
2. Nicotinic acid pathway
3. Serotonin pathway.
Kynurenine pathway:
1. This is the major pathway and mostly occurs in liver leading to oxidation of
tryptophan and the synthesis of NAD+ and NADP+
2. Tryptophan is oxidized to by tryptophan pyrrolase and the indole ring is cleaved
to formyl kynurenine.
3. Formylkynurenine is hydrolyzed by formamidase to form kynurenine and to
liberate formate which enters the 1 C pool.
4. Kynurenine has different fates. It is hydroxylated to form 3-hydroxykynurenine.
3-hydroxykynurenine is split by kynureninase (+ pyridoxal phosphate) to form
alanine that enters glucogenic pathway. B6 deficiency blocks this pathway. In B6
deficiency, 3-hydroxykynurenine is diverted to form 3-hydroxyxanthranilate.
Symptoms of pellagra will develop.
5. 3-hydroxyxanthranilate is cleaved by an oxidase to form an unstable
intermediate called 2-amino 3-carboxy muconate semialdehyde, which has 3
fates as follows:
i. To form quinolinate for NAD+ synthesis.
ii. To form picolinate
iii. To form 2-aminomuconate semialdehyde which enters glutarate
pathway and finally to acety CoA.
Nicotinic acid pathway:
1. Tryptophan is not a precursor for the synthesis of free niacin. Quinolinate undergoes
decarboxylation and is converted to nicotinate mononucleotide by the enzyme
quinolinate phosphoribosyl transferase (QPRT). The synthesis of NAD+ and NADP+
from nicotinate mononucleotide is similar to that from niacin.
2. The development of pellagra like symptoms in the maize eating population is due to
tryptophan deficiency in maize.
3. Hydroxy anthranilate production is dependent on pyridoxal phosphate. Hence in
vitamin B6 deficiency, nicotinamide deficiency is also manifested.
3-hydroxy anthranilic acid
quinolinic acid
CO2
Nicotinic acid
PRPP > PPi
Nicotinate mononucleotide
ATP> PPi
Desamido - NAD
Glutamine>Glutamic acid
ATP> AMP+ PPi
NAD

185
ATPADP+pi
NADP+
Serotonin pathway:
1. Serotonin is produced in the brain, mast cells, platelets and GIT mucosa.
2. Biosynthesis:
a. Tryptophan is hydroxylated by tryptophan hydroxylase with the coenzyme
tetra hydrobiopterine.
b. 5-hydroxy tryptophan is decarboxylated to 5-hydroxy tryptamine
(serotonin) by PLP dependant decarboxylase.
Functions of Serotonin:
c. Serotonin is an important neurotransmitter. The effect of serotonin is
dependent on the amount of serotonin available at the synaptic site. Part
of the serotonin released is again taken up (reuptake). Selective serotonin
reuptake inhibitors (SSRI) are widely used in the treatment of psychiatric
disorders.
d. After food rich in carbohydrate insulin secretion enhances tryptophan
uptake and conversion to serotonin explaining food induced sleep.
e. Serotonin is involved in mood, sleep, appetite and temperature
regulation.
Catabolism:
a. Serotonin is conjugated to sulphate or glucuronic acid and excreted in
urine.
b. MAO converts serotonin to 5-hydroxy indole acetic acid; (HIAA) hence
MAO inhibitors will cause mood elevation. Reserpine increases the
degradation of serotonin, hence acts as a depressant drug. Lysergic acid
diethylamide (LSD) competes with serotonin and, therefore, acts as a
depressant
Carcinoid tumor:
c. It is a cancer arising from small intestine and secretes serotonin in large
quantities.
d. Flushing, sweating, diarrhea and hypertension are the symptoms.
e. Diagnosed by urinary HIAA and serum serotonin levels which are
elevated.

1.
2.
3.

1.
2.

MELATONIN
Pineal gland secretes melatonin and is connected with biological rhythm.
Serotonin is acetylated and then methylated with the help of S-adenosyl methionine
to form melatonin.
Inborn errors: HARTNUP DISEASE:
1. Autosomal recessive.
2. Tryptophan and other neutral amino-acids are not absorbed in the small
intestine , and are converted by gut bacteria convert to indolic compounds
that are toxic to the CNS.
3. Renal tubular transport is defective and causes gross aminoaciduria.
4. The renal loss of amino-acids plus poor absorption from the gut causes
protein malnutrition.
5. Abnormal tryptophan transport leads to niacin deficiency or pellagra.
6. There is a wide clinical spectrum but most patients are asymptomatic.
7. Symptoms are dermatitis and ataxia.
8. diagnosis by amino aciduria and indole compounds in urine detected by
Obermeyer test.
9. Treatment by high protein diet.
HISTIDINE
Histidine has an imidazole ring.
It is an essential amino acid

186
3. It is responsible for maximum buffering action.
4. Catabolism:
1. It is non oxidatively deaminated by histidase to form urocanic acid.
2. Urocanic acid is hydrated to imidazolone propionic acid.
3. imidazolone propionic acid is hydrolysed to formimino glutamic acid.
4. formimino glutamic acid is cleaved to N5-formimino-THFA and glutamic acid.
5. Glutamic acid is is transaminated to alpha keto glutarate which can be
converted to glucose.
6. Hence it is glucogenic.
7. Histidine contributes to one carbon pool.
8. Histidine can also undergo transamination with pyruvate to form imidazole
pyruvate and alanine.
9. Histidine is decarboxylated to histidine decarboxylase to form histamine.
Histamine
1. Once formed, histamine is either stored or rapidly inactivated.
2. Most histamine in the body is generated in granules in mast cells or in white
blood cells called basophils.
3. Actions:
a. Blood vessels: Causes vasodilatation,
b. CVS: Fall in BP; increased capillary permeability.
c. Smooth muscle: Broncho constriction, bronchial smooth muscle
contraction
d. Exocrine: stimulate gastric acid secretion
e. Anaphylaxis: plays a role in the manifestations of anaphylaxis
4. ANTIHISTAMINES:
1. These are drugs which block the actions of histamine.
2. They control allergic and anaphylactic reactions.
3. In common use, the term antihistamine refers only to H1 antagonists, also
known as H1 antihistamines.
4. H2 receptors are present in gastric mucosa. H2 antagonists are used to
reduce the secretion of gastric acid.
5. HISTIDINEMIA: Autosomal recessive; Histidase is deficient; histidine
accumulates in blood; imidazole pyruvic acid excreted in urine; symptoms:
mental retardation.