Biochemistry

PROTEIN METABOLISM(incomplete)
Phenylketonuria- An overview
Explain why phenylketonurics are warned against eating products containing the artificial
sweetener aspartame (Nutrasweet; chemical name L-Aspartyl-L-Phenylalanine methyl ester)?
Discuss the biochemical defect, clinical manifestations, laboratory diagnosis and treatment of
Phenylketonuria.
Aspartame contains Aspartic acid and phenyl alanine. The patients suffering from Phenylketonuria
have high levels of phenyl alanine, any further increase in phenylalanine can prove harmful to the
patient.
(See the details below )
Phenylketonuria (PKU)
Phenylketonuria (PKU) is an inherited error of metabolism caused by deficiency of the enzyme
phenylalanine hydroxylase. Loss of this enzyme results in mental retardation, organ damage, and
unusual posture and can, in cases of maternal PKU, result in severely compromised pregnancy.
Incidence
Classic PKU and the other causes of hyperphenylalaninemia affect about one of every 10,000 to
20,000 Caucasian or Oriental births. The incidence in African Americans is far less. These disorders
are equally frequent in males and females.
Biochemical defect
Deficiency of the enzyme phenylalanine hydroxylase or of its cofactor (Figure-1)  causes
accumulation of phenylalanine in body fluids and the central nervous system (CNS).

 
 
Figure-1- showing the conversion of phenyl alanine to Tyrosine. The reaction is catalyzed by phenyl
alanine hydroxylase . The enzyme requires tetrahydrobiopterine as a cofactor.
Overview of Phenyl alanine metabolism –Phenyl alanine is metabolized through formation of
Tyrosine. The first enzyme in the catabolic pathway for phenylalanine (Figure-1 and
2), phenylalanine hydroxylase, catalyzes the hydroxylation of phenylalanine to tyrosine.
Phenylalanine hydroxylase inserts one of the two oxygen atoms of O 2 into phenylalanine to form
the hydroxyl group of tyrosine; the other oxygen atom is reduced to H 2O by the NADH/NADPH also
required in the reaction. This is one of a general class of reactions catalyzed by enzymes
called mixed-function oxidases , all of which catalyze simultaneous hydroxylation of a substrate by
O2 and reduction of the other oxygen atom of O 2 to H2O. Phenylalanine hydroxylase requires a
cofactor,tetrahydrobiopterin, which carries electrons from NADH/NADPH to O 2 in the hydroxylation
of phenylalanine. During the hydroxylation reaction the coenzyme is oxidized to dihydrobiopterin
(Figure-2). It is subsequently reduced again by the enzyme dihydrobiopterin reductase in a reaction
that requires NADH/NADPH.
 

Figure-2- Showing the metabolism of phenylalanine . The different enzyme deficiencies cause

different disorders  with different clinical manifestations. Under normal conditions phenylalanine
is catabolized to produce fumarate and acetoacetate, thus it is both glucogenic as well
as ketogenic.
 
The severity of hyperphenylalaninemia depends on the degree of enzyme deficiency and may vary
from very high plasma concentrations (>20mg/dL, or >1200µM, “classic PKU”) to mildly elevated
levels (2–6mg/dL or 120–360µM). In affected infants with plasma concentrations over 20mg/dL,
excess phenylalanine is metabolized to phenylketones (phenylpyruvate and phenyl acetate 
through a secondary pathway of phenylalanine metabolism. In this minor pathway phenylalanine
undergoes transamination with pyruvate to yield phenylpyruvate (Figure 3) Phenylalanine and
phenylpyruvate accumulate in the blood and tissues and are excreted in the urine: hence the name
of the condition, phenylketonuria. Much of the phenylpyruvate is either decarboxylated to produce
phenylacetate or reduced to form phenyllactate. Phenylacetate is excreted in  conjugation form
with Glutamine that imparts a characteristic odor (Mousy odor) to the urine and that has been used
to detect PKU in infants. The accumulation of phenylalanine or its metabolites in early life impairs
the normal development of the brain, causing severe mental retardation. Excess phenylalanine
may compete with other amino acids for transport across the blood-brain barrier, resulting in a
depletion of some required metabolites.

 
Figure-3- Alternative pathways for catabolism of phenylalanine in phenylketonurics. Phenylpyruvate
accumulates in the tissues, blood, and urine. Phenylacetate and phenyllactate can also be found in
the urine.
Clinical manifestations
CLASSICAL  PKU
 The affected infant is normal at birth.
 Mental retardation may develop gradually and may not be evident for the first few months.
It is usually severe, and most patients require institutional care if the condition remains
untreated. Mental retardation is due to direst toxic effect of phenyl alanine as well as due to
impaired formation of catecholamines .
  Vomiting, sometimes severe enough to be misdiagnosed as pyloric stenosis, may be an
early symptom.
  Older untreated children become hyperactive with purposeless movements, rhythmic
rocking, and athetosis.
 On physical examination these infants are fairer in their complexion (Figure-5) than
unaffected siblings. There is impaired formation of melanin, since tyrosine is a precursor of
melanin (Figure-4).
 Some may have a seborrheic or eczematous rash, which is usually mild and disappears as
the child grows older.
 These children have an unpleasant odor of phenyl acetic acid, which has been described
as musty or mousy.
 There are no consistent findings on neurologic examination. However, most infants
are hypertonic with hyperactive deep tendon reflexes.
  About 25% of children have seizures, and more than 50%
have electroencephalographic abnormalities.
  Microcephaly, prominent maxilla with widely spaced teeth, enamel hypoplasia, and growth
retardation are other common findings in untreated children.

 
 
 
 
 
 
 
 
 
 
Figure-4- showing the metabolic  role of tyrosine. There is impaired formation of melanin and
catecholamines , manifested by blond hair, lighter skin and mental retardation.
MILDER FORMS OF PKU
1.Non-PKU Hyperphenylalaninemia.
In any screening program for PKU, a group of infants are identified in whom initial plasma
concentrations of phenylalanine are above normal (2mg/dL, 120µM) but less
than 20mg/dL (1200µM). These infants do not excrete phenylketones. Clinically, these infants may
remain asymptomatic but progressive brain damage may occur gradually with age. These patients
have milder deficiencies of phenylalanine hydroxylase or its cofactor tetrahydrobiopterin(BH4) than
those with classic PKU.
2.Hyperphenylalaninemia from Deficiency of the Cofactor Tetrahydrobiopterin (BH4)-
In 1–2% of infants with hyperphenylalaninemia, the defect resides in one of the enzymes
necessary for production or recycling of the cofactor BH4 .These infants are diagnosed as having
PKU, but they deteriorate neurologically despite adequate control of plasma phenylalanine. BH4 is
the cofactor for phenylalanine, tyrosine, and Tryptophan hydroxylase. The latter two hydroxylase are
essential for biosynthesis of the neurotransmitters dopamine and serotonin.
Plasma phenylalanine levels may be as high as those in classic PKU or in the range of milder forms
of hyperphenylalaninemia. Neurologic manifestations, such as loss of head
control, truncal hypotonia (floppy baby), drooling, swallowing difficulties, and myoclonic seizures,
develop after 3 months of age despite adequate dietary therapy.
3. Maternal Phenylketonuria
A number of women with Phenylketonuria who have been treated since infancy will reach
adulthood and become pregnant. If maternal phenylalanine levels are not strictly controlled before
and during pregnancy, their offspring are at increased risk for congenital defects and Microcephaly.
After birth, these children have severe mental and growth retardation. Pregnancy risks can be
minimized by continuing lifelong phenylalanine-restricted diets and assuring strict phenylalanine
restriction 2 months prior to conception and throughout gestation.
 
Figure-5- showing  blond hair and eczematous rashes in a child suffering from PKU
DIAGNOSIS
Because of gradual development of clinical manifestations of hyperphenylalaninemia, early
diagnosis can only be achieved by mass screening of all newborn infants.
NEONATAL SCREENING FOR HYPERPHENYLALANINEMIA
 The bacterial inhibition assay of Guthrie,(Figure-6) which was the first and still the most
widely used method for the purpose, is being replaced by more precise and quantitative
methods (fluorometric and tandem mass spectrometry).
 Blood phenylalanine in affected infants with PKU may rise to diagnostic levels as early
as 4hr after birth even in the absence of protein feeding. It is recommended, however, that
the blood for screening be obtained in the first 24–48hr of life after feeding protein to
reduce the possibility of false-negative results, especially in the milder forms of the
condition
 Plasma Phenyl Alanine levels In infants with positive results from the screen
for hyperphenylalaninemia, diagnosis should be confirmed by quantitative measurement of
plasma phenylalanine . A normal blood phenylalanine level is about 1 mg/dl. In classic
PKU, levels may range from 6 to 80mg/dl, but are usually greater than 30mg/dl. Levels are
somewhat less in the other disorders of hyperphenylalaninemia.  .
  Identification and measurement of phenylketones in the urine has no place in any
screening program. However, in countries and places where such programs are not in
effect, identification of phenylketones in the urine by ferric chloride may offer a simple test
for diagnosis of infants with developmental and neurologic abnormalities.
 Once the diagnosis of hyperphenylalaninemia is established, deficiency of cofactor
(BH4) should be ruled out in all affected infants.
 BH4 loading test. An oral dose of BH4 (20mg/kg) normalizes plasma phenylalanine in
patients with BH4 deficiency within 4–8hr.
 Enzyme assay-The activity of Dihydropteridine Reductase can be measured in the dry blood
spots on the filter paper used for screening purposes. The other enzymes required for the
synthesis of BH4 can also be similarly estimated.

 
 Figure-6- showing Guthrie card
Treatment
The goal of PKU treatment is to maintain the blood level of phenylalanine between 2 and 10
mg/dl. Some phenylalanine is needed for normal growth. This requires a diet that has some
phenylalanine but in much lower amounts than normal.
High protein foods, such as: meat, fish, poultry, eggs, cheese, milk, dried beans, and peas are
avoided. Instead, measured amounts of cereals, starches, fruits, and vegetables, along with a milk
substitute are usually recommended.
In some clinics, a phenylalanine ‘challenge’ may be suggested to evaluate whether or not the child
continues to require a low phenylalanine diet. This test identifies those few persons with a transient
or ‘variant’ form of the disorder.
 No dietary restriction is currently recommended for infants whose phenylalanine levels are
between 2–6mg/dL. Plasma concentrations of phenylalanine in treated patients should be
maintained as close to normal as possible.
Because phenylalanine is not synthesized by the body, “over treatment” may lead to phenylalanine
deficiency manifested by lethargy, failure to thrive, anorexia, anemia, rashes, diarrhea, and even
death; moreover, tyrosine becomes an essential amino acid in this disorder and its adequate intake
must be ensured.
The current recommendation is that all patients be kept on a phenylalanine-restricted diet for life,
in order to promote maximal development and cognitive abilities.
Oral administration of the cofactor (BH4 ) to patients with milder forms
of hyperphenylalaninemia from phenylalanine hydroxylase deficiency may produce significant
reductions.
 
Glutamate- Central role in amino acid metabolism
Q.1- Justify the reasoning that glutamic acid plays a pivotal role in the metabolism of amino acids
Answer- Glutamate occupies a central place in amino acid metabolism. Basically it acts as a
collector of amino group of the amino acids. Free ammonia is toxic to the body especially to brain
cells, it is transported in the bound form to liver where it is finally detoxified forming urea.
Amino acids not needed as building blocks are degraded to specific compounds. The major site of
amino acid degradation in mammals is the liver. The amino group must be removed, in as much as
there are no nitrogenous compounds in energy-transduction pathways. Amino group can be
transferred (Transamination) or it can be removed in the form of ammonia (Deamination). The α-
keto acids that result from amino acids are metabolized so that the carbon skeletons can enter the
metabolic main stream as precursors to glucose or citric acid cycle intermediates.
The formation and fate of glutamate and significance of these processes related to metabolism  of
amino acids can be explained as follows-
Sources of Glutamate include-
1) Transamination of amino acids
2) Hydrolysis of Glutamine
3) Metabolic product of amino acids
Fate of Glutamate
1) Oxidative deamination to from Alpha keto glutarate
2) Amination  to form Glutamine
3) Decarboxylation to form GABA (Gamma amino butyric acid)
4) Formation of N-Acetyl Glutamate
All processes except GABA formation are involved in the catabolism  of amino acids and transport
of amino group or ammonia.
1) Transamination and role of Glutamate
a) General reactions
Aminotransferases catalyze the transfer of an α-amino group from an α-amino acid to an α-keto
acid. These enzymes, also called transaminases, generally funnel α-amino groups from a variety of
amino acids to α-keto-glutarate for conversion into NH4 +(Figure-1)

Figure-1- showing the transfer of alpha amino  group to an-α keto acid catalyzed by amino
transferase
The α -amino group of many amino acids is transferred to α -ketoglutarate to
form glutamate, which is then oxidatively deaminated to yield ammonium ion (NH4) (Figure-2)

Figure-2- showing the  general role of glutamate in the transfer of amino group of amino acid that
can be subsequently  removed as ammonium ion.
All the amino acids except lysine, threonine, proline, and hydroxyproline participate in
transamination. Transamination is readily reversible, and aminotransferases also function in amino
acid biosynthesis.
b) Special reactions
1) Aspartate aminotransferase, one of the most important of these enzymes, catalyzes the transfer
of the amino group of aspartate to α-ketoglutarate.
2) Alanine aminotransferase catalyzes the transfer of the amino group of alanine to α
-ketoglutarate.

2) Deamination of glutamate- The nitrogen atom that is transferred to α-ketoglutarate in the

transamination reaction (forming Glutamate) is converted into free ammonium ion by oxidative
deamination. This reaction is catalyzed by glutamate dehydrogenase. This enzyme is unusual in
being able to utilize either NAD+ or NADP+, at least in some species. The reaction proceeds by
dehydrogenation of the C-N bond, followed by hydrolysis of the resulting Schiff base.

Figure-3- Showing the oxidative deamination of Glutamate to from α- Keto glutarate. Glutamate
carries the amino group of amino acids from peripheral tissue to liver to be released as ammonium
ions .
The equilibrium for this reaction favors glutamate; the reaction is driven by the consumption of
ammonia. Glutamate dehydrogenase is located in mitochondria, as are some of the other enzymes
required for the production of urea. This compartmentalization sequesters free ammonia, which is
toxic.
The sum of the reactions catalyzed by aminotransferases and glutamate dehydrogenase is-

In most terrestrial vertebrates, NH4 + is converted into urea, which is excreted (Figure-4)
 

 
Figure-4-Showing the  process of transdeamination and the role of glutamate
Role of Glutamate and Glutamate dehydrogenase- In majority of the transamination reactions
alpha keto glutarate is the acceptor keto acid forming Glutamate, that is oxidatively deaminated in
the liver by Glutamate dehydrogenase to form alpha keto glutarate and ammonia. Conversion of α-
amino nitrogen to ammonia by the concerted action of glutamate aminotransferase and GDH is
often termed “transdeamination.” Thus Transamination and deamination are coupled processes
though they occur at distant places and in these two processes Glutamate occupies the central
place.
Regulation of Glutamate dehydrogenase– The activity of glutamate dehydrogenase is allosterically
regulated. The enzyme consists of six identical subunits. Guanosine triphosphate (GTP) and
adenosine triphosphate (ATP) are allosteric inhibitors, whereas guanosine diphosphate (GDP) and
adenosine diphosphate (ADP) are allosteric activators. Hence, a lowering of the energy charge
(more of ADP and GDP) accelerates the oxidation of amino acids favoring formation of alpha keto
glutarate that can be channeled towards TCA cycle for complete oxidation to provide energy.
3) Glucose alanine cycle and the role of Glutamate- The transport of amino group of amino acids
also takes place in the form of Alanine.
Nitrogen is transported from muscle to the liver in two principal transport forms. Glutamate is
formed by transamination reactions, but the nitrogen is then transferred to pyruvate to form
alanine, which is released into the blood. The liver takes up the alanine and converts it back into
pyruvate by transamination. The pyruvate can be used for gluconeogenesis and the amino group
eventually appears as urea. This transport is referred to as the alanine cycle. It is reminiscent of the
Cori cycle and again illustrates the ability of the muscle to shift some of its metabolic burden to the
liver (Figure-5)

 Figure-5- The Glucose- Alanine Cycle- Glutamate in muscle is transaminated to alanine, which is
released into the blood stream. In the liver, alanine is taken up and converted into pyruvate for
subsequent metabolism.
) Glutamate and Glutamine relationship
Ammonia Nitrogen can also be transported as glutamine. This is the first line of defense in brain
cells. Glutamine synthetase catalyzes the synthesis of glutamine from glutamate and NH4 + in an
ATP-dependent reaction (Figure-6)

Figure-6- Showing the synthesis of glutamine form glutamate

The nitrogen of glutamine can be converted into urea in the liver.
Hydrolytic release of the amide nitrogen of glutamine as ammonia, catalyzed
by glutaminase (Figure -7 )strongly favors glutamate formation. The concerted action of glutamine
synthase and glutaminase thus catalyzes the interconversion of free ammonium ion and
glutamine.

Figure-7- showing the hydrolysis of glutamine by glutaminase.

Renal glutaminase activity is associated with maintenance of acid base metabolism.
5) Glutamate as a metabolic product– Glutamate is produced  directly from the metabolism of
Proline, Arginine and Histidine, that can be oxidatively deaminated to form Alpha keto glutarate
and ammonia. (Figure-8)
 
Figure-8- Showing the  formation  of glutamate from amino acids  like Arginine, Histidine and
Proline
 6) Glutamate as an activator for urea formation– Glutamate in the form of N-Acetyl Glutamate 
acts as a positive allosteric modifier for Carbamoyl phosphate synthetase-1 , the first  and the rate
limiting enzyme of urea cycle. Carbamoyl phosphate synthase I, is active only in the presence of its
allosteric activator N-acetylglutamate, which enhances the affinity of the synthase for ATP (Figure-
9)
 

 
Figure-9- Showing the role of N-Acetyl Glutamate as a positive modifier for CPS-1
6) Formation of GABA- GABA, an inhibitory neurotransmitter is produced from the decarboxylation
of glutamic acid by glutamate decarboxylase enzyme in the presence of B6-P (Figure-10)
 
Figure-10– showing the synthesis of GABA from glutamate.
Ammonia intoxication  and role of glutamate- Excess of ammonia depletes glutamate and hence
GABA level in brain, To compensate for glutamate, alpha keto glutarate is used , the decrease
concentration of which subsequently depresses TCA and thus deprives brain cells of energy.  Excess
Glutamine is exchanged with Tryptophan , a precursor of Serotonin , resulting in hyper excitation.
The symptoms of ammonia intoxication are all due to energy depletion and a state of
hyperexcitation.
Thus to conclude, Glutamate  represents the major transporter of amino group of amino acids and
has a central role in both  the catabolism of amino acids as well in the synthesis of non-
essential amino acids( through Transamination reactions).
 
 
 
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Posted in Metabolism - Proteins, Subjective Questions
Catecholamines- Synthesis, Degradation and Clinical Significance
Published December 16, 2012 | By Dr. Namrata Chhabra
Q.1- Alpha Methyl dopa is a drug used in the treatment of hypertension. Explain its possible mode
of action.
0r
Describe the steps of catecholamines synthesis  and degradation and highlight the clinical
significance of these reactions.
Answer- Catecholamines are synthesized from Tyrosine.
Cells in the adrenal medulla synthesize and secrete epinephrine and nor epinephrine. In humans 
80% of the catecholamine output is epinephrine.
Synthesis and Secretion of Catecholamines
Synthesis of catecholamines begins with the amino acid tyrosine, which is taken up by chromaffin
cells in the medulla and converted to norepinephrine and epinephrine through the following steps :
1) Tyrosine is hydroxylated to DOPA (Dihydroxy Phenyl Alanine) by Tyrosinase (Figure-1), that
requires BH4 (Tetra hydro biopterine) and NADPH. The reaction is similar to hydroxylation of phenyl
alanine to form Tyrosine. Tyrosinase  meant for catecholamine synthesis is different for the one
required for Melanin synthesis.
2) Dopa decarboxylase, a Pyridoxal phosphate (B6-P)-dependent enzyme, forms dopamine by
decarboxylation of DOPA (Figure-1).
3) Subsequent hydroxylation of Dopamine  by dopamine -β-oxidase then forms norepinephrine
(Figure-1). The enzyme requires molecular oxygen, vitamin C and  Copper ion for its activity.
4) In the adrenal medulla, phenyl ethanolamine-N-methyltransferase utilizes S-adenosylmethionine
to methylate the primary amine of norepinephrine, forming epinephrine (Figure-1).
Figure-1- showing the steps of synthesis of Catecholamines
Norepinephrine and epinephrine are stored in electron-dense granules which also contain ATP and
several neuropeptides. Secretion of these hormones is stimulated by acetylcholine release from
preganglionic sympathetic fibers innervating the medulla. Many types of “stresses” stimulate such
secretion, including exercise, hypoglycemia and trauma. Following secretion into blood, the
catecholamines bind loosely to and are carried in the circulation by albumin and perhaps other
serum proteins.
Adrenergic Receptors and Mechanism of Action
These hormones bind adrenergic receptors on target cells, where they induce essentially the same
effects as direct sympathetic nervous stimulation.  There are multiple receptor types which are
differentially expressed in different tissues and cells. The alpha and beta adrenergic receptors and
their subtypes were originally defined by differential binding of various agonists and antagonists
and, more recently, by analysis of molecular clones.

Receptor Effectively Binds Effect of Ligand Binding

Alpha1 Epinephrine, Norepinphrine Increased free calcium

Alpha2 Epinephrine, Norepinphrine Decreased cyclic AMP

Beta1 Epinephrine, Norepinphrine Increased cyclic AMP

Beta2 Epinephrine Increased cyclic AMP

 
Physiologic Effects of Medullary Hormones
In general, circulating epinephrine and norepinephrine released from the adrenal medulla have the
same effects on target organs as direct stimulation by sympathetic nerves, although their effect is
longer lasting. Additionally, of course, circulating hormones can cause effects in cells and tissues
that are not directly innervated. The physiologic consequences of medullary catecholamine release
are justifiably framed as responses which aid in dealing with stress. A listing of some major effects
mediated by epinephrine and norepinephrine are:
 Increased rate and force of contraction of the heart muscle: this is predominantly an effect
of epinephrine acting through beta receptors.
 Constriction of blood vessels: norepinephrine, in particular, causes widespread
vasoconstriction, resulting in increased resistance and hence arterial blood pressure.
 Dilation of bronchioles: assists in pulmonary ventilation.
 Stimulation of lipolysis in fat cells: this provides fatty acids for energy production in many
tissues and aids in conservation of dwindling reserves of blood glucose.
 Increased metabolic rate: oxygen consumption and heat production increase throughout
the body in response to epinephrine. Medullary hormones also promote breakdown of
glycogen in skeletal muscle to provide glucose for energy production.
  Dilation of the pupils: particularly important under conditions of low ambient light.
 Inhibition of certain “non-essential” processes: an example is inhibition of gastrointestinal
secretion and motor activity.
Common stimuli for secretion of adrenomedullary hormones include exercise, hypoglycemia,
hemorrhage and emotional distress. The alpha and Beta blockers are used as drugs to inhibit the
action of catecholamines.
Catecholamine degradation
Catecholamines are degraded in the liver by two enzymes, COMT( Catechol-O-Methyl-Transferase)
and MAO(Mono amine Oxidase). By the action of COMT, epinephrine and Nor epinephrine are
converted to metanephrine and nor metanephrine respectively. Both these products are further
acted upon by MAO to form VMA (Vanillyl Mandelic acid) and MOPG (3-Methoxy 4-
hydroxyphenylglycol). These products are further excreted in urine. Epinephrine and nor epinephrine
can be acted upon directly also by MAO to form DOPG and DOMA (Figure-2).The Excretory products
are increased in Pheochromocytoma and that forms the basis for the diagnostic test.
Figure-2- showing the steps of degradation of Catecholamines
Clinical Significance-
Methyldopa (L-α-Methyl-3,4-dihydroxyphenylalanine; Aldomet, Aldoril, Dopamet, Dopegyt, etc.) is
a drug used as a sympatholytic or antihypertensive agent . It is less commonly used now following
the introduction of alternative safer classes of agents. However, it continues to have a role in
otherwise difficult to treat hypertension and gestational hypertension (also known as pregnancy-
induced hypertension (PIH)) and pre eclampsia.
Mechanism of action- Methyldopa has a dual mechanism of action:
 It is a competitive inhibitor of the enzyme DOPA decarboxylase, also known as aromatic L-
amino acid decarboxylase, which converts L-DOPA into dopamine. This inhibition results in
reduced dopaminergic and adrenergic neurotransmission in the peripheral nervous system.
This effect may lower blood pressure and cause central nervous system effects such
as depression, anxiety, apathy, and parkinsonism.
 It is converted to α-methylnorepinephrine by dopamine beta-hydroxylase (DBH). α-
methylnorepinephrine is an agonist of presynaptic central nervous system α2-
adrenergic receptors. Activation of these receptors in the brainstem appears to
inhibit sympathetic nervous system output and lower blood pressure.

Figure-3  showing the  mechanism of action of alpha methyl DOPA. 

2) L-DOPA-L-DOPA crosses the protective blood–brain barrier, whereas dopamine itself cannot.
Thus, L-DOPA is used to increase dopamine concentrations in the treatment of Parkinson’s
disease and dopamine-responsive dystonia.
Once L-DOPA has entered the central nervous system, it is converted into dopamine by the enzyme 
DOPA decarboxylase (DDC). Pyridoxal phosphate (vitamin B6) is a required cofactor in this reaction,
and may occasionally be administered along with L-DOPA, usually in the form of pyridoxine.
3) Dopamine drips are intravenous deliveries of dopamine, that can be necessary for a
hemodynamically unstable patient, at risk of shock caused by low blood pressure. These can
include patients with a recent history of open heart surgery, heart attacks, or renal failure.
4) Pheochromocytoma- Pheochromocytomas and paragangliomas are catecholamine-producing
tumors derived from the sympathetic or parasympathetic nervous system. Elevated plasma and
urinary levels of catecholamines and the methylated metabolites, metanephrines, are the
cornerstone for the diagnosis.
 

Transamination and Transaminases

Q.- Give a brief description of the process of Transamination, highlight the role of B6 phosphate in
this process.
Answer- Transamination interconverts pairs of α -amino acids and α -keto acids. During
Transamination, the amino group of an amino acid (amino acid R 1) is transferred to a keto acid
(keto acid R 2), this produces a  new keto acid while from the original keto acid, a new amino acid
is formed (Figure-1)

Figure-1- showing the transfer of amino group from a donor amino acid to a keto acid for the
formation of a new amino acid and a new keto acid
The general process of transamination is reversible and is catalyzed by a transaminase, also called
amino transferase that require B6-Phosphate as  a coenzyme.
Most of the amino acids act as substrate for the transaminases but the amino acids like lysine,
threonine, proline, and hydroxyproline do not participate in transamination reactions.
Transamination is not restricted to α -amino groups. The δ-amino group of ornithine and the  ε-
amino group of lysine—readily undergoes transamination.
Role of B6 Phosphate as a coenzyme
The coenzyme pyridoxal phosphate (PLP) is present at the catalytic site of aminotransferases and
of many other enzymes that act on amino acids. PLP, is  a derivative of vitamin B6 (Figure-2).
Figure-2- Showing the structure of B6-Phosphate
1) B6-P forms an enzyme-bound Schiff base intermediate that can rearrange in various ways-

Figure-3-In the “resting” state, the aldehyde group of pyridoxal phosphate is in a Schiff base
linkage to the ε-amino group of an enzyme lysine side-chain.
2) During transamination, bound PLP serves as a carrier of amino groups (Figure-5 and 6)
3) Rearrangement forms an α -keto acid and enzyme-bound Pyridoxamine phosphate(Figure-4, 5
and 6), which forms a Schiff base with a second keto acid (Figure-5).
Figure-4-The α-amino group of a substrate amino acid displaces the enzyme lysine, to form a Schiff
base linkage to PLP. 

Figure-5- A different a-keto acid reacts with PMP (Pyridoxamine phosphate) and the
process reverses, to complete the reaction.
 

Figure-6 -Overall reaction showing the role of B6-Phosphate,  the transfer of  α-amino group from 
donor amino acid to Pyridoxal phosphate forms Pyridoxamine phosphate, and a keto acid. The α-
amino group is finally passed on to an acceptor  an α-keto acid to form a new amino acid.
Significance of Transamination – Transamination is used both for the catabolic as well as anabolic
processes. The resultant α-Keto acid can be completely oxidized to provide energy, glucose, fats or
ketone bodies depending upon the cellular requirement. Since it is a reversible process, it  is also
used or the synthesis of non-essential amino acids. Some points of significance are as follows-
 Once the keto acids have been formed from the appropriate amino acids by
transamination, they may be used for several purposes. The most obvious is the complete
metabolism into carbon dioxide and water by the citric acid cycle.
 However, if there are excess proteins in the diet those amino acids  that are converted into
pyruvic acid and acetyl CoA can be converted into lipids by the lipogenesis process. If
carbohydrates are lacking in the diet or if glucose cannot get into the cells (as in diabetes),
then those amino acids converted into pyruvic acid and oxaloacetic acids can be converted
into glucose or glycogen.
  The most usual and major keto acid involved with transamination reactions is alpha-
ketoglutaric acid, an intermediate in the citric acid cycle.
 All of the amino acids can be converted through a variety of reactions and transamination
into a keto acid which is a part of or feeds into the citric acid cycle. 
 In addition to the catabolic function of transamination reactions, these reactions can also
be used to synthesize amino acids needed or not present in the diet. An amino acid may be
synthesized if there is an available “root” keto acid with a synthetic connection to the final
amino acid. Since an appropriate “root” keto acid does not exist for eight amino acids, (lys,
leu, ile, met, thr, try, val, phe), they are essential and must be included in the diet because
they cannot be synthesized. Transaminases equilibrate amino groups among available  α-
keto acids. This permits synthesis of non-essential amino acids, using amino groups derived
from other amino acids and carbon skeletons synthesized in the cell. Thus a balance of
different amino acids is maintained, as proteins of varied amino acid contents are
synthesized. 
 Glutamic acid usually serves as the source of the amino group in the transamination
synthesis of new amino acids. The reverse of the reactions are the most obvious methods
for producing the amino acids alanine and aspartic acid.
 In addition to equilibrating amino groups among available  α-keto acids,
transaminases funnel amino groups from excess dietary amino acids to those amino acids
(e.g., glutamate) that can be deaminated. Carbon skeletons of deaminated amino acids can
be catabolized for energy or used to synthesize glucose or fatty acids for energy storage.

Figure-7 – Glutamate is the ultimate collector of amino groups of amino acids, In the liver it is
rapidly deaminated, ammonia thus released is detoxified by forming urea
Q.- Discuss the clinical significance of transaminases.
Answer– The enzymes catalyzing transamination process exist for all amino acids except threonine
and lysine. The most common compounds involved as a donor/acceptor pair in transamination
reactions are glutamate and  α-ketoglutarate ( α-KG), which participate in reactions with many
different aminotransferases. Serum aminotransferases such as serum glutamate-oxaloacetate-
aminotransferase (SGOT) (also called aspartate aminotransferase, AST) and serum glutamate-
pyruvate aminotransferase (SGPT) (also called alanine transaminase, ALT) have been used as
clinical markers of tissue damage, with increasing serum levels indicating an increased extent of
damage. 
1) AST is found in the liver, cardiac muscle, skeletal muscle, kidneys, brain, pancreas, lungs,
leukocytes, and erythrocytes in decreasing order of concentration.
Reaction catalyzed can be represented as follows-
 

Figure-8- Showing the reaction catalyzed by AST (Aspartate amino transferase)

Normal serum activity is  0-41 IU/L. The concentration of the enzyme is very high in myocardium.
The enzyme is both cytoplasmic as well as mitochondrial in nature.
2) ALT is found primarily in the liver.
Reaction catalyzed can be represented as follows-

Figure-9 – Showing the reaction catalyzed by ALT(Alanine amino transferase)

The normal serum activity ranges between 0-45 IU/L.
Diagnostic significance of amino transferases-
I) Liver Diseases- The aminotransferases are normally present in the serum in low concentrations.
These enzymes are released into the blood in greater amounts when there is damage to the liver
cell membrane resulting in increased permeability.These are sensitive indicators of liver cell injury
and are most helpful in recognizing acute hepatocellular diseases such as hepatitis. Any type of
liver cell injury can cause modest elevations in the serum aminotransferases.
 Levels of up to 300 U/L are nonspecific and may be found in any type of liver disorder.
  Striking elevations—i.e., aminotransferases > 1000 U/L—occur almost exclusively in
disorders associated with extensive hepatocellular injury such as (1) viral hepatitis, (2)
ischemic liver injury (prolonged hypotension or acute heart failure), or (3) toxin- or drug-
induced liver injury.
 In most acute hepatocellular disorders, the ALT is higher than or equal to the AST.
 An AST: ALT ratio > 2:1 is suggestive while a ratio > 3:1 is highly suggestive of alcoholic
liver disease.
 The AST in alcoholic liver disease is rarely >300 U/L and the ALT is often normal. A low
level of ALT in the serum is due to an alcohol-induced deficiency of Pyridoxal phosphate.
 In obstructive jaundice the aminotransferases are usually not greatly elevated. One notable
exception occurs during the acute phase of biliary obstruction caused by the passage of a
gallstone into the common bile duct. In this setting, the aminotransferases can briefly be in
the 1000–2000 U/L range. However, aminotransferase levels decrease quickly, and the
liver function tests rapidly evolve into one typical of cholestasis.
2) Acute myocardial infarction- In acute MI the serum activity rises sharply within the first 12 hours,
with a peak level of 24 hours or over and returns to normal within 3 to 5 days.
 Levels > 350 IU/L are usually fatal and signify massive infarction
 Levels < 50 IU/L are associated with low mortality
 The rise depends upon the size of infarction
 There is no rise of ALT in acute MI
 Reinfarction results in secondary rise of AST
3) Extra cardiac and extra hepatic conditions-
 Elevation of AST can also be seen in Muscle disorders like muscular dystrophies- myositis
etc.
 Increase activity  of AST is also observed in acute pancreatitis, leukemias and acute
hemolytic anemias
 In normal health slight rise of AST level can be observed after prolonged exercise
4) Glucose Alanine cycle- Alanine transaminase has an important function in the delivery of
skeletal muscle carbon and nitrogen (in the form of alanine) to the liver. In skeletal muscle,
pyruvate is transaminated to alanine, thus affording an additional route of nitrogen transport from
muscle to liver. In the liver alanine transaminase transfers the ammonia to  α-KG and regenerates
pyruvate. The pyruvate can then be diverted into gluconeogenesis. This process is referred to as
the glucose-alanine cycle.
Figure-10- Glucose Alanine cycle functions to transport amino group of amino acids in the form of
alanine from skeletal muscle to liver
Protein metabolism (Subjective Questions)-Set-1
Q.1- What is the biological advantage of secretion of proteolytic enzymes  in the zymogen form ?
Answer- Certain proteins are synthesized and secreted as inactive precursor proteins known as
proproteins. The proproteins of enzymes are termed pro enzymes or zymogens. Selective
proteolysis convert a proprotein by one or more successive proteolytic “clips” to a form that exhibits
the characteristic activity of the mature protein, eg, its enzymatic activity. (Figure-1)

Figure-1- showing the selective cleavage of a zymogen to form an active enzyme

Examples of other Proproteins or Zymogens
Proteins synthesized as proproteins include the hormone insulin (proprotein = Proinsulin), the
digestive enzymes pepsin, trypsin, and chymotrypsin (proproteins = pepsinogen, trypsinogen, and
chymotrypsinogen, respectively), several factors of the blood clotting and blood clot dissolution
cascades and the connective tissue protein collagen (proprotein = procollagen).
Biological advantage of having  proteolytic zymogens
The synthesis and secretion of proteases as catalytically inactive proenzymes protects the tissue of
origin (e.g., the pancreas) from auto digestion, such as can occur in  Acute pancreatitis.
Physiologic processes such as digestion are intermittent but fairly regular and predictable. Enzymes
needed intermittently but rapidly often are secreted in an initially inactive form since the secretion
process or new synthesis of the required proteins might be insufficiently rapid for response to a
pressing pathophysiologic demand . Proenzymes facilitate rapid mobilization of an activity in
response to physiologic demand.
Q.2- Give a brief account of the mechanism of absorption of products of digestion of protein,
highlighting the role of Glutathione in this process.
Answer- Digestive products of protein can be absorbed as amino acids, dipeptides, and
tripeptides (in contrast to carbohydrates, which can only be absorbed as monosaccharides). The
absorption of amino acids takes place mainly in the small intestine. There are two mechanisms for
amino acid absorption-
A) Carrier protein transport system (Figure-2)
 It is the main mechanism for amino acid absorption
 It is an active and energy requiring process.
 The needed energy is provided by ATP
 There are approximately 7 carrier proteins, each specific for a group of amino acids
 These carrier proteins are Sodium dependent symport systems
 Each transporter has two binding sites, one for sodium and the other for an amino acid.
 Absorption of dipeptides and tripeptides is faster than absorption of free amino acids.
 Na+dependent cotransport of dipeptides and tripeptides also occurs in the luminal
membrane.
 After the dipeptides and tripeptides are transported into the intestinal
cells, cytoplasmic peptidases hydrolyze them to amino acids.
 After absorption the amino acids are transported to the portal circulation by
facilitated diffusion. Na + is expelled out of the cell in exchange for K +through the Na+ -
K+ ATPase pump (Figure-2).
 Figure-2-Mechanism of absorption of amino acids, dipeptides, and tripeptides by intestinal
epithelial cells. Each is absorbed by Na+-dependent co transport.
Clinical significance
1) Cystinuria- Common transporter for cystine, ornithine, arginine and lysine(COAL) is present in gut
and renal tubules. Deficiency of transporter results in loss of these  amino acids in the feces and
urine.
2) Hart- Nup Disease-The  transporter for tryptophan  and neutral amino acid is deficient. There is
reduced  absorption of tryptophan , tryptophan deficiency produce neurological and skin
manifestation (pellagra-like rashes).Neurological symptoms are due to the fact that tryptophan is a
precursor for serotonin and melatonin, while skin rashes are due to deficiency of niacin,  since
niacin can be synthesized from tryptophan.
3) Food allergies– Relatively large peptides may be absorbed intact, either by uptake into mucosal
epithelial cells (transcellular) or by passing between epithelial cells (paracellular). Many such
peptides are large enough to stimulate antibody formation—this is the basis of allergic reactions to
foods.
B) Glutathione transport system (Υ- Glutamyl cycle)- Glutathione is used to transport  neutral amino
acids in intestine, brain and kidney tubules.
Glutathione. This tripeptide consists of a cysteine residue flanked by a glycine residue and a
glutamate residue that is linked to cysteine by an isopeptide bond between glutamate’s side-chain
carboxylate group and cysteine’s amino group.(Figure-3)
 
Figure-3- showing the structure of glutathione (Gamma glutamyl cysteinyl glycine)
Role of glutathione in the absorption of amino acids (Figure-4)
 Glutathione reacts with amino acid to form gamma glutamyl amino acid.This is catalyzed
by Gamma glutamyl Transferase (GGT) in the presence of Na + (figure-2) to form Υ-
Glutamyl amino acid and cysteinyl glycine.
 The Υ-Glutamyl amino acid is then cleaved to give free amino acid and 5-oxo proline.
  Amino acid during this process is transported inside the cell.
 It is an energy requiring process, which is supplied by the hydrolysis of peptide bond of
Glutathione.
 5-oxo proline in the presence of the enzyme 5-oxo prolinase and ATP forms Glutamic acid
 Cysteinyl glycine formed in the first step is cleaved to form cysteine and glycine.
 Glutamic acid combines with cysteine first to form glutamyl cysteine and then combines
with glycine to form glutathione.
 Glutathione is regenerated again  and that completes the Υ- Glutamyl cycle.
 The transport of one amino acid and regeneration of Glutathione requires 3  molecules of
ATP.
 
Figure-4- showing the role of glutathione in the absorption of amino acids
Clinical  Significance- The deficiency of 5 oxoprolinase causes oxoprolinuria
Q.3- What is nitrogen balance ? Explain its significance and enlist the conditions causing deviations
in the nitrogen balance.
Answer- The state of protein nutrition can be determined by measuring the dietary intake and
output of nitrogenous compounds from the body. Although nucleic acids also contain nitrogen,
protein is the major dietary source of nitrogen and measurement of total nitrogen intake gives a
good estimate of protein intake (mg N x 6.25 = mg protein, as N is 16% of most proteins). The
output of N from the body is mainly in urea and smaller quantities of other compounds in urine,
undigested protein in feces; significant amounts may also be lost in sweat and shed skin. The
difference between intake and output of nitrogenous compounds is known as nitrogen balance
(Figure-5)
Figure-5- Showing nitrogen balance. The intake of nitrogen is in the form of dietary proteins while
the output is through urine and feces in the form of undigested proteins, urea, uric acid, creatinine,
ammonia and amino acids.
States of nitrogen balance
Three states can be defined-
1)  Nitrogen equilibrium– In a healthy adult, nitrogen balance is in equilibrium, when intake equals
output, and there is no change in the total body content of protein.
Intake = output : N equilibrium
2) Positive nitrogen balance– when the excretion of nitrogenous compounds is less than the dietary
intake and there is net retention of nitrogen in the body as protein.
Intake > output: positive N balance
Examples- In a growing child, a pregnant woman, or a person in recovery from illness there is
positive nitrogen balance.
3) Negative nitrogen balance– There is net loss of protein nitrogen from the body
In response to trauma or infection, or if the intake of protein is inadequate to meet requirements
there is negative nitrogen balance.
Intake < output: negative N balance
Significance of nitrogen balance
1) Growth-The continual catabolism of tissue proteins creates the requirement for dietary protein,
even in an adult who is not growing; although some of the amino acids released can be reutilized,
much are used for gluconeogenesis in the fasting state.The average daily requirement is 0.6 g of
protein/kg body weight (0.75 allowing for individual variation), or approximately 50 g/day. Average
intakes of protein in developed countries are of the order of 80–100 g/day, ie, 14–15% of energy
intake. Because growing children are increasing the protein in the body, they have a proportionally
greater requirement than adults and should be in positive nitrogen balance.. In some countries,
protein intake may be inadequate to meet these requirements, resulting in stunting of growth.
2) Illness and convalescence– Negative nitrogen balance is seen immediately after acute illnesses
like surgery, trauma and burns.
One of the metabolic reactions to a major trauma, such as a burn, a broken limb, or surgery, is an
increase in the net catabolism of tissue proteins. As much as 6–7% of the total body protein may
be lost over 10 days.
Chronic illnesses like malignancy, uncontrolled diabetes mellitus and other debilitating
diseases also show negative nitrogen balance
Prolonged bed rest results in considerable loss of protein because of atrophy of muscles. Protein is
catabolized as normal, but without the stimulus of exercise, it is not completely replaced.
Lost protein is replaced during convalescence, when there is positive nitrogen balance. A normal
diet is adequate to permit this replacement.
3) Hormones- Insulin , growth hormone and androgens promote positive nitrogen balance while
corticosteroids induce negative nitrogen balance.

Multiple Choice Questions (Solved)- Amino acid Metabolism – Set-2

Q.1- A 10 -year-old boy develops convulsions. After running an Electroencephalogram(EEG), a
neurologist determines that the child has epilepsy. He is started on benzodiazepine which
promotes the activity of GABA. GABA is derived from Glutamate by which of the following
reactions ?
a) Transamination
b) Decarboxylation
c) Deamination
d) Hydroxylation
e) Dehydrogenation
Q.2- A couple of African- American descent gives birth to a boy  after an otherwise uneventful
pregnancy. The child is exceptionally fair skinned and has almost white hair. Further examination
reveals red pupils.  A postnatal screen is likely to confirm the deficiency of which of the following
enzymes ?
a) Glutathione reductase
b) Glutathione peroxidase
c) Tyrosinase
d) Methionine synthase
e) Cystathionine beta synthase
Q.3- A 16- year -old girl is found by her parents unconscious on the bathroom floor with an empty
bottle of acetaminophen in the toilet. She is rushed to the hospital where she is given several doses
of N-acetyl Cysteine. Acetaminophen overdose is potentially life threatening because it depletes the
cellular stores of Glutathione. Which of the following amino acid is another component of
Glutathione besides Cysteine and Glutamic acid ?
a) Methionine
b) Arginine
c) Lysine
d) Ornithine
e) Glycine
Q.4-  A 56- year-old man with  long-standing poorly controlled diabetes mellitus visits his primary
care physician for a follow-up after a recent hospitalization. The patient experienced an episode of
acute renal failure while in hospital and his serum creatinine rose to 2.4 mg/dl ( Normal, 0.7- 1.5
mg/dl). Creatinine, a marker of kidney function, is derived from which of the following precursors ?
a) Arginine, Lysine and Glutamine
b) Glutamic acid, Cysteine and Glycine
c) Methionine, Serine and Glycine
d) Methionine, Arginine and Glycine
e) Cysteine, Glycine and Arginine.
Q.5- S- Adenosyl  Methionine (Active Methionine) is required for the synthesis  of which of the
following compounds ?
a) Thyroid hormone
b) Melanin
c) Epinephrine
d) Serotonin
e) Bile salts.
Q.6- Which of the following compounds is formed from  hydroxylation requiring vitamin C and
subsequent methylation ?
a) Histamine
b) Dopamine
c) Epinephrine
d) Creatine
e) Melanin
Q.7- A 40-year old woman complains of deceased energy, significant weight gain and cold
intolerance. She is seen by her family physician, who has diagnosed her to be having
hypothyroidism (Low  level of thyroid hormone). Which of the following is a precursor for thyroid
hormone ?
a)  DOPA
b) Glutamine
c)  Tyrosine
d) Tryptophan
e) Threonine.
Q.8- A 63 -year old woman reports a long history of joint pains. Her fingers are severely deformed
secondary to rheumatoid arthritis. Upon visiting a rheumatologist, she is started on methotrexate.
This drug inhibits which of the following conversions ?
a) Dopamine to norepinephrine conversion
b) Tyrosine to Dopa
c) Dihydrofolate to Tetra hydro folate
d) Phenyl Alanine to Tyrosine
e) N-Acetyl serotonin to melatonin
Q.9-  A 59-year-old woman develops a shuffling gait and a pin- rolling tremor. She is referred to a
neurologist for evaluation. After a thorough workup, a diagnosis of Parkinson disease is made and
the patient is placed on Mono amine oxidase inhibitor. The drug in this case, is given to decrease
the degradation of which of the followings ?
a) Serotonin
b) Dopamine
c) Nicotinamide
d) Melatonin
e) Nitric oxide
Q.10- During a medical rotation, a medical student volunteered for a respiratory physiology
examination that determines basal metabolic rate and the respiratory quotient. She followed the
protocol for a resting individual in the post absorptive state. Which of the following amino acids
would be found in the highest concentration in the serum ?
a) Alanine and Glutamine
b) Arginine and Ornithine
c) Glutamate and Aspartate
d)  Branched chain amino acids
e) Hydrophobic amino acids
Q.11- A 27- year-old semiprofessional  tennis player seeks advice from a hospital -based nutritionist
concerning his diet supplements. His coach had given him amino acid supplements consisting of
phenyl alanine and tyrosine. The rationale was that these precursors to several neurotransmitters
will “help his brain focus” on his game. In reality, the excess amino acids are used for energy, with a
poor and eclectic diet. Phenyl Alanine upon metabolism, enter TCA cycle as which of the following ?
a) Oxalo acetate
b) Citrate
c) Succinyl co A
d) Fumarate
e) α- Keto glutarate
Q.12- In a 39-year-old woman who just gave birth, chorionic villus sampling was performed, and a
battery of genetic panels was assessed on the new-born. One marker indicated a defective
Cystathionine -β- Synthase. Which of the following compounds you most likely expect to be
elevated  in the blood of the infant at birth if the mother was not treated properly ?
a) Valine
b) Homocysteine
c) Threonine
d) Glutamine
e) Cysteine
Q.13- A 55-year-old man suffers from cirrhosis of liver. Toxins such as ammonia are not properly
metabolized by the liver and can damage brain. Which of the following compounds is expected to
be in highest concentration in brain  as a result of detoxification of ammonia?
a) Alpha keto glutarate
b) Glutamate
c)  Glutamine
d) GABA
e) Asparagine
Q.14- Which of the following enzymes requires adenosine triphosphate (ATP) to mediate its
reactions ?
a) Argino Succinate lyase
b) Argino Succinate synthetase
c) Arginase
d) Glutaminase
e) Ornithine transcarbamoylase
Q.15- Which of the following amino acids is not converted to Acetyl co A upon metabolism ?
a) Tyrosine
b) Leucine
c) Tryptophan
d) Lysine
e) Valine
 
 
Key to Answers-
1)-b,      2)-c,      3)-e,      4)- d,     5)- c,      6)-c,       7)-c,       8)-c,       9)-b,      10)-a,    11)- d,   12-b,    
13)-C
14)-b,    15)-e
Multiple Choice Questions- Amino acid metabolism (Solved)-Set-1

Q.1- Which of the following is a common compound shared by the TCA cycle and the Urea cycle?
a) α- Keto glutarate
b) Succinyl co A
c) Oxalo acetate
d) Fumarate
Q.2-Which of the followings is a common nitrogen acceptor for all reactions involving
transaminases?
a) α- Keto glutarate
b) Pyruvate
c) Oxaloacetate
d) Acetoacetate
Q.3- In a 55- year-old man, who has been diagnosed with cirrhosis of liver, Ammonia is not getting
detoxified and can damage brain. Which of the following amino acids can covalently bind
ammonia, transport and store in a non toxic form?
a) Aspartate
b) Glutamate
c) Serine
d) Cysteine
Q.4- In a new born presenting with refusal to feeds and irritability, a deficiency of Cystathionine –β–
synthase has been diagnosed, which of the following compounds is expected to be elevated in
blood?
a) Serine
b) Glutamate
c) Homocysteine
d) Valine
Q.5 -A 3- month-old child is being evaluated for vomiting and an episode of convulsions, Laboratory
results show hyperammonemia and Orotic aciduria. Which of the following enzyme defect is likely
to be there?
a) Glutaminase
b) Arginase
c) Argino succinic acid synthase
d) Ornithine Transcarbamoylase
Q.6- Which out of the following amino acids is not converted to Succinyl co A?
a) Methionine
b) Valine
c) Isoleucine
d) Histidine
Q.7-All of the following compounds are synthesized by transmethylation reactions, except-
a) Choline
b) Epinephrine
c) Creatine
d) Ethanolamine
Q.8- A patient diagnosed with Hart Nup disease, (due to deficiency of transporter required for the
absorption of amino acid tryptophan), has been brought with skin rashes and suicidal tendencies.
Tryptophan is a precursor for many compounds, the deficiencies of which can cause the said
symptoms. Which out of the following compounds is not synthesized by tryptophan?
a) Serotonin
b) Epinephrine
c) Melatonin
d) Niacin
Q.9- Histamine, a chemical mediator of allergies and anaphylaxis, is synthesized from amino acid
Histidine by which of the following processes?
a) Deamination
b) Decarboxylation
c) Transamination
d) Dehydrogenation
Q.10- The synthesis of all of the following compounds except one is deficient in a patient suffering
from Phenylketonuria-
a) Melanin
b) Melatonin
c) Catecholamines
d) Thyroid hormone
Q.11- The diet of a child suffering from Maple syrup urine disease (an amino acid disorder), should
be low, in which out of the following amino acids content?
a) Branched chain amino acids
b) Phenylalanine Alanine
c) Methionine
d) Tryptophan
Q.12- Which out of the following amino acids in not required for creatine synthesis?
a) Methionine
b) Serine
c) Glycine
d) Arginine
Q.13- All of the following substances are synthesized from Cysteine, except-
a) Taurine
b) Mercaptoethanolamine
c) Melanin
d) Pyruvate
Q.14- Urea is synthesized in –
a) Cytoplasm
b) Mitochondria
c) Both cytoplasm and mitochondria
d) In lysosomes
Q.15-Blood urea decreases in all of the following conditions, except-
a) Liver cirrhosis
b) Pregnancy
c) Renal failure
d) Urea cycle disorders
Q.16- All of the following amino acids are donors of one carbon compounds except-
a) Histidine
b) Tyrosine
c) Tryptophan
d) Serine
Q.17- The two nitrogen of urea are derived from-
a) Aspartate and Ammonia
b) Glutamate and ammonia
c) Argino succinate and ammonia
d) Alanine and ammonia
Q.18- Which out of the following amino acids is not required for the synthesis of Glutathione?
a) Serine
b) Cysteine
c) Glutamic acid
d) Glycine
Q.19- The first line of defence in brain in conditions of hyperammonemia is-
a) Urea formation
b) Glutamine synthesis
c) Glutamate synthesis
d) Asparagine formation
Q.20- Which coenzyme out of the followings is required for the oxidative deamination of most of
amino acids?
a) Folic acid
b) Pyridoxal- P
c) FMN
d) FAD
Q.21-Chose the incorrect statement about amino acid Glycine-
a) One carbon donor
b) Required for the synthesis of haem
c) Forms oxalates upon catabolism
d) Both glucogenic as well as ketogenic
Q.22- Which out of the followings is required as a coenzyme for the transamination reactions?
a) Coenzyme A
b) Pyridoxal-P
c) Folic acid
d) Cobalamine
Q.23- A patient diagnosed with Homocystinuria should be supplemented with all of the following
vitamins except-
a) Vitamin C
b) Folic acid
c) Vitamin B12
d) Pyridoxal- P
Q.24- In a patient suffering from Cystinuria, which out of the following amino acids is not seen in
urine of affected patients?
a) Arginine
b) Methionine
c) Lysine
d) Ornithine
Q.25- Positive nitrogen balance is seen in all of the following conditions except-
a) Pregnancy
b) Growth
c) Fever
d) Convalescence
Q.26- The L-amino acids are absorbed from intestine by-
a) Active transport
b) Passive diffusion
c) Pinocytosis
d) Facilitated diffusion
Q.27- A child presented with increased frequency of urination, photophobia and impairment of
vision. Which out of the following defects could be responsible for the said symptoms?
a) Tyrosinosis
b) Cystinosis
c) Alkaptonuria
d) Albinism
Q.28- Which out of the following statements about Glutamate dehydrogenase is correct?
a) Required for transamination reactions
b) Universally present in all the cells of the body
c) Can utilize either of NAD+ /NADP+
d) Catalyzes conversion of glutamate to glutamine
Q.-29-A child was brought to paediatric OPD with complaint of passage of black colored urine. A
disorder of Phenylalanine metabolism was diagnosed. A low phenylalanine diet and a
supplementation of vitamin C were recommended. Which enzyme defect is expected in this child?
a) Phenyl alanine hydroxylase
b) Tyrosine transaminase
c) Homogentisic acid oxidase
d) Hydrolase
Q.30- Dopamine is synthesized from which of the following amino acids?
a) Tyrosine
b) Tryptophan
c) Histidine
d) Methionine
Q.31- In mammalian tissue serine can be a biosynthetic precursor for which amino acid?
a) Methionine
b) Glycine
c) Arginine
d) Lysine
Q.32- Hydroxylation of Phenyl Alanine to Tyrosine requires all except
a) Glutathione
b) Tetra hydrobiopterin
c) Molecular oxygen
d) NADPH
Q.33- The amino acid that undergoes oxidative deamination at a highest rate is-
a) Glutamine
b) Glutamate
c) Aspartate
d) Alanine
Q.34- All of the following statements regarding serotonin are true except-
a) Causes vasodilatation
b) Causes broncho constriction
c) Metabolized to 5-hydroxy Indole acetic acid
d) Causes diarrhoea
Q.35- Choose the incorrect statement about cysteine-
a) Carbon skeleton is provided by serine
b) Sulfur group is provided by Methionine
c) Forms Hippuric acid for detoxification of xenobiotics
d) Required for Bile salt formation
 
 Answers-
1) – d, 2) – a, 3) – b, 4) -c, 5) – d, 6) – d, 7) – d, 8) – b, 9) – b, 10) – b, 11) – a), 12) – b, 13) – c, 14)
– c, 15) – c,16) – b, 17) – a, 18) – a,
19) – b, 20) – c, 21) – d, 22) – b,23) -a, 24)- b, 25) – c, 26) – a, 27) – b, 28) – c, 29) – c, 30) –
a, 31) – b,32) – a, 33) – b, 34) – a,35) – c.