Amino acid metabolism

AMINO ACID METABOLISM
DEVIPRIYA P V
M PHARM

CONTENTS
 General reactions of amino acid metabolism:
Transamination , deamination & decarboxylation
 Urea cycle and its disorders
 Catabolism of phenylalanine and tyrosine and their
metabolic disorders (Phenyketonuria, Albinism,
alkeptonuria, tyrosinemia)
 Synthesis and significance of biological
substances; 5-HT, melatonin, dopamine,
noradrenaline, adrenaline
 Catabolism of heme
 Hyperbilirubinemia and jaundice

Metabolism of amino acid
 The amino group of the amino acids is utilized for
the formation of urea which is an excretory end
product of protein metabolism.
 The carbon skeleton of the amino acids is first
converted to keto acids (by transamination) which
meet one or more of the following fates.
1. Utilized to generate energy.
2. Used for the synthesis of glucose.
3. Diverted for the formation of fat or ketone bodies.
4. lnvolved in the production of non-essential amino
acids.

Transamination
 The transfer of an amino (- NH2) group from an amino
acid to a keto acid.
 It involves the interconversion of a pair of amino acids
and a pair of keto acids, catalysed by a group of
enzymes called transaminases.
 All transaminases require pyridoxal phosphate (PLP), a
coenzyme derived from vitamin B6.
 Aspartate transaminase and Alanine transaminase-make
a significant contribution for transamination.
 Only transfer of amino group occurs (free NH3 is not
liberated).
 Transamination is reversible

 Transamination is very
important for the redistribution
of amino groups and
production of non essential
amino acids, as per the
requirement of the cell.
 Transamination diverts the
excess amino acids towards
energy generation.
 The amino acids undergo
transamination to finally
concentrate nitrogen in
glutamate.
 All amino acids except lysine,
threonine, proline and
hydroxyproline participate in
transamination.
 Transamination is not
restricted to α-amino groups
only.
 Serum transaminases are
important for diagnostic and

Deamination
 The removal of amino group from the amino acids as
NH3 is deamination.
 Deamination may be either oxidative or non-oxidative.
 Oxidative deamination is the liberation of free ammonia
from the amino group of amino acids coupled with
oxidation.
 This takes place mostly in liver and kidney.
 The purpose of oxidative deamination is to provide NH3
for urea synthesis and α-keto acids for a variety of
reactions, including energy generation.

Non-oxidative deamination:
 Some of the amino acids can be deaminated to liberate
NH3 without undergoing oxidation
Amino acid dehydrases:
 Serine, threonine and homoserine are the hydroxy
amino acids undergo non-oxidative deamination.
Amino acid desulfhydrases:
 The sulfur amino acids (cysteine and homocysteine)
undergo deamination coupled with desulfhydration to
give keto acids.
Deamination of histidine :
 The enzyme histidase acts on histidine to liberate NH3

Decarboxylation
 The decarboxylation of amino acids acids or their
derivatives results in the formation of amines.
 This is carried out by a group of enzymes called
decarboxylases.
 Examples:
 Tryptophan 5- Hydroxytryptophan 5-
Hydroxytryptamine.
 Histidine Histamine
PLP
PLP
CO2
CO2

Urea cycle
 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.
 Urea is synthesized in liver and transported to kidneys
for excretion in urine.
Steps involved in urea cycle:
1. Synthesis of carbamoyl phosphate.
2. Formation of citrulline.
3. Synthesis of arginosuccinate.
4. Cleavage of arginosuccinate
5. Formation of urea.

Disorders of urea cycle
 All the disorders invariably lead to a build-up in
blood ammonia (hyperammonemia), leading to
toxicity.
 The clinical symptoms associated with defect in
urea cycle enzymes include vomiting, lethargy,
irritability, ataxia and mental retardation.

Catabolism of Phenylalanine and
Thyrosine
 Under normal conditions, degradation of
phenylalanine mostly occurs through tyrosine.
 Phenylalanine is hydroxylated at para-position by
phenylalanine hydroxylase to produce tyrosine(p-
hydroxy phenylalanine)

DEGRADATION OF TYROSINE:
 The metabolism of phenylalanine and tyrosine is
considered together.
 Tyrosine first undergoes transamination to give p-
hydroxy phenyl pyruvate, catalysed by tyrosine
transaminase.
 p-Hydroxyphenylpyruvate hydroxylase catalyses
oxidative decarboxylation as well as hydroxylation of
the phenyl ring of p-hydroxyphenylpyruvate to produce
homogentisate.
 Homogentisate oxidase cleaves the benzene ring of
homogentisate to form 4-maleylacetoacetate.
 Maleylacetoacetate undergoes isomerization to form
4-fumaryl acetoacetate and this reaction is catalysed
by maleyl acetoacetate isomerase.
 Fumaryl acetoacetase brings the hydrolysis of fumaryl

Disorders of Thyrosine (phenyl alanine)
metabolism
Phenylketonuria( PKU):
 Due to the deficiency of the hepatic enzyme,
phenylalanine hydroxylase, caused by an autosomal
recessive gene.
 This enzyme deficiency impairs the synthesis of
tetrahydro biopterin required for the action of
phenylalanine hydroxylase
 Phenylketonuria causes the accumulation of
phenylalanine in tissues and blood, and results in its
increased excretion in urine.
 Effects on central nervous system : Mental retardation,
failure to walk or talk, failure of growth, seizures and
tremor.
 Effect on pigmentation: hypopigmentation that causes
light skin colour, fair hair, blue eyes etc (ie, inhibit
melanin formation)

 PKU is mostly detected by screening the newborn
babies for the increased plasma levels of
phenylalanine( PKU, 20-65 mg/dl; normal 1-2mg/dl) -
Guthrie test.
 plasma phenylalanine concentration can be
maintained within the normal range by selecting
foods with low phenylalanine content and/or feeding
synthetic amino acid preparations, low in
phenylalanine.
 In some seriously affected PKU patients, treatment
includes administration of 5-hydroxytryptophan and
dopa

Albinism:
 Occurs due to the lack of synthesis of the pigment
melanin.
 lt is an autosomal recessive disorder
Causes for Albinism:
1. Deficiency or lack of the enzyme tyrosinase (enzyme
most responsible for the synthesis of melanin).
2. Decrease in melanosomes of melanocytes.
3. lmpairment in melanin polymerization.
4. Lack of protein matrix in melanosomes.
5. Limitation of substrate(tyrosine) availability.
6. Presence of inhibitors of tyrosinase.
 Lack of melanin in albinos makes them sensitive to
sunlight.
 Increased susceptibility to skin cancer (carcinoma) is
observed.
 Photophobia (intolerance to light) is associated with lack of

Alkaptonuria:
 Defect in enzyme homogentisate oxidase.
 Homogentisate accumulates in tissues and blood, and
is excreted into urine.
 Homogentisate gets oxidized to the corresponding
quinones, which polymerize to give black or brown
colour (due to the presence of pigment alkapton).
 For this reason, the urine of alkaptonuric patients
resembles coke in colour.
 Alkapton deposition occurs in connective tissue, bones
and various organs (nose, ear etc.) resulting in a
condition known as ochronosis.
 consumption of protein diet with relatively low phenyl
alanine content is recommended as treatment.

Tyrosinosis or Tyrosinemia Type I
 This is due to the deficiency of the enzymes fumaryl aceto
acetate hydroxylase and/or maleyl acetoacetate isomerase.
 lt causes liver failure, rickets, renal tubular dysfunction and
polyneuropathy.
 In acute tyrosinosis, the infant exhibits diarrhea, vomiting,
and 'cabbage-like' odor.
 Death may even occur due to liver failure within one year.
 For the treatment, diets low in tyrosine, phenylalanine and
methionine are recommended.
Tyrosinemia type ll (Richner- Hanhart syndrome)
 This is due to a defect in the enzyme tyrosine transaminase.
 Blockade in the routine degradative pathway of tyrosine.
 Accumulation and excretion of tyrosine and its metabolites(p-
hydroxy phenyl pyruvate, p-hydroxyphenyl acetate, N-
acetyltyrosine and tyramine ) are observed.
 The absence of the enzyme p-hydroxyphenylpyruvate
dioxygenase causes neonatal tyrosinemia.

Serotonin / 5-hydroxytryptamine
(5HT)
Melatonin
 5HT is a neurotransmitter,
synthesized from tryptophan
Functions:
1. Serotonin is a powerful vaso-
constrictor and results in smooth
muscle contraction in
bronchioles and arterioles.
2. lt is involved in the regulation of
cerebral activity (excitation).
3. Serotonin controls the
behavioural patterns, sleep,
blood pressure and body
temperature.
4. Serotonin evokes the release of
peptide hormones from gastro
intestinal tract.
5. lt is also necessary for the
motility of GIT (peristalsis)
 Melatonin is a hormone, mostly
synthesized by the pineal gland.
 The synthesis and secretion of
melatonin from pineal gland is
controlled by light.
Functions:
1. Melatonin is involved in circadian
rhythms or diurnal variations (24 hr
cyclic process) of the body. It playsa
significant role in sleep and wake
process.
2. It inhibits the production of
melanocyte stimulating hormone
(MSH) and adrenocorticotropic
hormone (ACTH).
3. lt has some inhibitory effect on
ovarian functions.
Synthesis and Significance of 5-HT, Melatonin

Synthesis of Catecholamines
(Dopamine, Noradrenaline , Adrenaline)
 Catechol refers to the dihydroxylated phenyl ring
 Amine derivatives of catechol are called catecholamines.
 Tyrosine is the precursor for the synthesis of
catecholamines , namely dopamine, norepinephrine
(noradrenaline) and epinephrine (adrenaline).
 The conversion of tyrosine to catecholamines occurs in
adrenal medulla and central nervous system.
Functions of catecholamines :
 Norepinephrine and epinephrine regulate carbohydrate and
lipid metabolisms.
 They stimulate the degradation of triacylglycerol and
glycogen.
 They cause an increase in the blood pressure.
 Dopamine and norepinephrine serve as neurotransmitters in
the brain and autonomous nervous system.

Synthesis of catecholamines:
 Tyrosine is hydroxylated to
3,4-dihydroxyphenylalaine
(DOPA) by tyrosine
hydroxylase.
 This reaction requires tetra
hydro biopterin as coenzyme.
 DOPA undergoes PLP-
dependend decarboxylation to
give dopamine which, in turn,
is hydroxylated to produce
norepinephrine.
 Methylation of norepinephrine
by S-adenosyl methionine
gives epinephrine.
 The difference between
epinephrine and
norepinephrine is only a
methyl group (norepinephrine
has no methyl group).

Catabolism of Heme
 Heme is the non-protein part of Hemoglobin.
 Heme is the most important porphyrin containing compound.
 Porphyrins are cyclic compounds composed of 4 pyrrole rings held
together by methenyl(=CH) bridges.
 lt is synthesized in the liver and bone marrow.

 Heme oxygenase utilizes NADPH and
02 and cleaves the methenyl bridges
between the two pyrrole rings (A and
B) to form biliverdin.
 Simultaneously, ferrous iron (Fe2+) is
oxidized to ferric form (Fe3+) and
released.
 The products of heme oxygenase
reaction are biliverdin (a green
pigment), Fe3+and carbon monoxide
(CO).
 Biliverdin's methenyl bridges
(between the pyrrole rings C and D)
are reduced to form bilirubin (yellow
pigment).
 This reaction is catalysed by biliverdin
reductase.
 Transport of bilirubin to liver : Bilirubin
is lipophilic and therefore insoluble in
aqueous solution. So it is non
covalently bound to albumin and is
transported.

Hyperbilirubinemia and
Jaundice
 Hyperbilirubinemia represent the increased concentration
of serum bilirubin.
 Jaundice is a clinical condition characterized by yellow
colour of the white of the eyes (sclerae) and skin.
 This is due to the elevated serum bilirubin level, usually
beyond 2 mg/dl (normal < 1 mg/dl).
 Hemolytic jaundice : is associated with increased
hemolysis of erythrocytes
 In hemolytic jaundice, more bilirubin is excreted into the
bile.
 Hemolytic jaundice is characterized by:
1. Elevation in the serum unconjugated bilirubin.
2. Increased excretion of urobilinogen in urine.
3. Dark brown colour of feces

 Hepatic (hepatocellular) jaundice is caused by dysfunction of the
Iiver due to damage to the parenchymal cells.
 Hepatic jaundice is characterized by
1. Increased levels of conjugated and unconjugated bilirubin in the
serum.
2. Dark coloured urine.
3. lncreased activities of alanine transaminase (SGPT) and
aspartate transaminase (SCOT) released into circulation due to
damage to hepatocytes.
4. The patients pass pale, clay coloured stools.
5. Nausea and anorexia (loss of appetite)
 Obstructive (regurgitation) jaundice is due to an obstruction in the
bile duct that prevents the passage of bile into the intestine.
 Obstructive jaundice is characterized by:
1. Increased concentration of conjugated bilirubin in serum.
2. Serum alkaline phosphatase is elevated
3. Dark coloured urine.
4. Feces contain excess fat
5. nausea and gastrointestinal pain

Amino acid metabolism

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