Amino Acid Metabolism

By-Virendra Singh
 Overview Of Amino Acid Metabolism
ENVIRONMENT ORGANISM

Bio-
synthesis
Ingested Protein
protein

1 2 3
a
AMINO
ACIDS
b
c c
Purines
Degradation Pyrimidines
(required) 2 Porphyrins
Carbon
Nitrogen skeletons

(ketogenic) (glucogenic)
Used for
Urea energy
acetoacetate pyruvate
acetyl CoA α-ketoglutarate
succinyl-CoA
fumarate
oxaloacetate
Amino Acid Synthesis
Acetyl CoA

Acetyl CoA
Overview of amino acid anabolism

• The glutamate family

• includes glutamate, glutamine, proline, and arginine and derive their carbon skeletons
from a-ketoglutarate.
• The members of the serine family —
• serine, glycine, and cysteine—derive their carbon skeletons from glycerate-3-phosphate.
• The aspartate family
• includes aspartate, asparagine, lysine, methionine, and threonine and derive their
carbon skeletons from oxaloacetate.
• The pyruvate family
• consists of alanine, valine, leucine, and isoleucine and derive their carbon skeletons
from pyruvate.
• The members of the aromatic family —
• phenylalanine, tyrosine, and tryptophan — derive their carbon skeletons from
phosphoenol pyruvate and erythrose 4phosphate.
• The member histidine family-
• histidine-derive their carbon skeletons from ribose 5•phosphate.
Amino Acid Synthesis Transamination
Transamination
Molecule derived From
amino Acid
Amino Acid Synthesis
Biosynthesis of cysteine from homocysteine and serine
• In mammals.
• The homocysteine is formed from methionine.
Amino Acids from Oxaloacetate and Pyruvate
Amino Acids from Oxaloacetate and Pyruvate
Amino Acids from Oxaloacetate and Pyruvate
Hydroxyethyl.TPP
Synthesis of Tryptophan, Phenylalanine, and Tyrosine
Chorismate Is a Key Intermediate
Synthesis of Tryptophan, Phenylalanine, and Tyrosine
Fate of amino acid
Amino Acid Catabolism
Amino Acid Catabolism

17
Glucogenic / ketogenic amino acids

18
Enzyme-catalyzed transaminations

• Transamination reactions require pyridoxal

phosphate.

• One-carbon transfers are common in amino

acid catabolism.

• Cofactors involved in one-carbon transfers:

• biotin,
19

• tetrahydrofolate,

• S-adenosylmethionine.
 Deamination

• Oxidative deamination of glutamate releases ammonia for disposal.

• Transamination, of course, does not result in any net deamination.

• Glutamate, however, can be oxidatively deaminated by glutamate dehydrogenase (GDH),

yielding ammonia and regenerating a-ketoglutarate for use in additional trans- amination
reactions.

• Glutamate dehydrogenase,
• a mitochondrial enzyme, is the
• only known enzyme that can accept either NAD+ or NADP+ as its redox
coenzyme.
• The enzyme is allosterically inhibited by GTP and NADH
• activated by ADP and NAD+.
Some enzyme cofactors important in one-carbon transfer reactions

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Some enzyme cofactors important in one-carbon transfer reactions

• Biotin transfers CO2 (most oxidized state of carbon).

• Tetrahydrofolate transfers one-carbon groups in intermediate oxidation states.

• S-adenosylmethionine transfers methyl groups (most reduced state of carbon).

• Tetrahydrofolate

• Folate is converted to tetrahydrofolate by dihydrofolate reductase.

• One-carbon groups bind to N-5 or N-10 in tetrahydrofolate.

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• The conversion of N5,N10-methylenetetrahydrofolate to N5-methyltetrahydrofolate is

irreversible.

• N10-formyltetrahydrofolate is used in purine synthesis and formylmethionine formation.

Synthesis of methionine and S-adenosylmethionine

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Alanine, Cysteine, Glycine, Serine, and Threonine Are Degraded to Pyruvate
Alanine, Cysteine, Glycine, Serine, and Threonine Are Degraded to Pyruvate
Alanine, Cysteine, Glycine, Serine, and Threonine Are Degraded to Pyruvate
Asparagine and Aspartate Are Degraded to Oxaloacetate
Interestingly, L-
asparaginase is an
effective
chemotherapeutic agent
in the treatment of
cancers that must obtain
asparagine from the
blood, particularly acute
lymphoblastic
leukemia.
Arginine, Glutamate, Glutamine, Histidine, and Proline Are Degraded to 𝛂-Ketoglutarate
Arginine, Glutamate, Glutamine, Histidine, and Proline Are Degraded to 𝛂-Ketoglutarate
Arginine, Glutamate, Glutamine, Histidine, and Proline Are Degraded to 𝛂-Ketoglutarate
The pathway of tryptophan degradation

(1)tryptophan-2,3-dioxygenase,
(2) formamidase,
(3) kynurenine-3-monooxygenase, and
(4) kynureninase
(a PLP-dependent enzyme)
The pathway of Phenylalanine degradation
The pathway of Phenylalanine degradation
The pathway of amino acid degradation
The pathway of branched amino acid degradation
The pathway of amino acid degradation
 Urea Cycle

• Most animals convert excess nitrogen to urea,

prior to excreting it.

• Urea is less toxic than ammonia.

• The Urea Cycle occurs mainly in liver.

• The 2 nitrogen atoms of urea enter the Urea

Cycle as NH3 (produced mainly via Glutamate
Dehydrogenase) and as the amino N of
aspartate.

• The NH3 and HCO3- (carbonyl C) that will be part

of urea are incorporated first into carbamoyl
phosphate.
Amino group catabolism
 Glutamate Releases Its Amino Group as Ammonia in the Liver

• Urea cycle begins with free ammonia.

• NH4+ collected in glutamate or glutamine.

• Glutamate undergoes oxidative deamination.

• Catalyzed by L-glutamate dehydrogenase enzyme.

• Enzyme uses NAD+ or NADP+ cofactors.

• Transdeamination combines aminotransferase, dehydrogenase.

• α-ketoglutarate used in citric acid cycle.

• Enzyme regulated by ADP (activator), GTP (inhibitor).

• Mutations cause hyperinsulinism-hyperammonemia syndrome.

• Condition causes hypoglycemia and high ammonia levels.

Glutamate Releases Its Amino Group as Ammonia in the Liver
 Glutamine Transports Ammonia in the Bloodstream

• Glutamine transports ammonia in the bloodstream.

• Ammonia is toxic, tightly regulated in tissues.

• Glutamine synthetase converts glutamate to glutamine.

• Glutamine formed from glutamate and ammonia.

• ATP required for glutamine synthetase reaction.

• Glutamine transports excess ammonia to liver.

• Glutaminase releases ammonia from glutamine.

• Ammonia processed in liver via urea synthesis.

• In acidosis, kidneys increase glutamine breakdown.

• Bicarbonate from α-ketoglutarate buffers blood.

Glutamine Transports Ammonia in the Bloodstream
 Glucose-alanine cycle
• Alanine transports ammonia from muscles to liver.

• Muscles produce pyruvate, lactate, and ammonia during anaerobic activity.

• Alanine aminotransferase converts pyruvate to alanine via transamination.

• Alanine transports ammonia to the liver in a nontoxic form.

• The process is part of the glucose-alanine cycle.

• In the liver, alanine is converted back to pyruvate and glutamate.

• Glutamate releases ammonia via glutamate dehydrogenase.

• Aspartate also donates nitrogen for urea synthesis.

• The cycle saves muscle ATP for muscle contraction.

• Works in concert with the Cori cycle to balance energy use.

Glucose-alanine cycle
Urea Cycle

Thus, urea's two nitrogen

atoms are contributed by
ammonia and aspartate,
whereas its carbon atom
comes from HCO3-
Urea Cycle
Urea Cycle
Urea Cycle
Links between the urea cycle and citric acid cycle
Amino acid Metabolism disorder

Medical Condition Defective Process Defective Enzyme Symptoms and Effects

Melanin synthesis from Lack of pigmentation;

Albinism Tyrosinase
tyrosine white hair, pink skin

Alkaptonuria Tyrosine degradation Homogentisate oxidase Dark pigment in urine

Faulty bone
Homocystinuria Methionine degradation Cystathionine beta-synthase development; mental
retardation

Vomiting; convulsions;
Maple Syrup Urine Isoleucine, leucine, and Branched-chain alpha-keto
mental retardation; early
Disease valine degradation acid dehydrogenase complex
death

Conversion of Neonatal vomiting;

Phenylketonuria Phenylalanine hydroxylase
phenylalanine to tyrosine mental retardation
Amino acid Metabolism disorder
Molecule derived From amino Acid
Biomolecule Precursor Amino Acids
Auxin (Indole 3-acetic acid) Tryptophan
Catecholamines (dopamine, Norepinephrine
Tyrosine
and Epinephrine)
GABA (γ-amino butyrate) Glutamate

Serotonin Tryptophan

Histamine Histidine

Polyamines (e.g., spermine, spermidine) Ornithine, Methionine

Nitric oxide Arginine

Creatine Arginine, Glycine

Lignin Phenylalanine and Tyrosine

Porphyrin Glycine, Glutamate

Glutathione Glycine, Glutamate, Cysteine

Biosynthesis of two plant substances from amino acids.
Molecule derived From amino Acid
Biosynthesis of two plant substances from amino acids.
Molecule derived From amino Acid
Biosynthesis of nitric oxide
Other Products of Amino Acid Metabolism
• Heme is synthesized from glycine and succinyl-CoA and is degraded to a variety of colored
compounds for excretion.
• The synthesis of bioactive amines begins with amino acid decarboxylation.
• Arginine gives rise to the hormonally active gas nitric oxlide.
Heme
Molecule derived From amino Acid
Biosynthesis of heme from δ-aminolevulinate

porphobilinogen uroporphyrinogen
synthase synthase uroporphyrinogen III
cosynthase

uroporphyrinogen
decarboxylase

ferrochelatase

protoporphyrinogen coproporphyrinogen
oxidase oxidase
Bilirubin and its breakdown products
Bilirubin and its breakdown products