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Amino Acid Metabolism

Metabolism of Branched Chain Amino Acids

Valine, isoleucine and leucine are branched essential amino acids.

Catabolism of Branched Chain Amino Acids

The first three metabolic reactions for these branched chain amino acids are similar and are catalyzed by common
enzymes. Therefore, the metabolism of three branched chain amino acids is considered together. These three
reactions are transamination, oxidative decarboxylation and dehydrogenation.

1. Transamination: The initial step in the degradation of the branched chain amino acids is a transamination
reaction to yield corresponding α-keto acids.
2. Oxidative decarboxylation: In the second step, the α-keto acids are oxidatively decarboxylated to the
corresponding acyl-CoA thioesters by branched chain α-keto acid dehydrogenase complex. TPP, FAD, Lipoic
acid, NAD+ and CoA are required as coenzymes in this reaction.
3. Dehydrogenation: The third reaction is a FAD dependent dehydrogenation, a reaction that resembles the first
step of β-oxidation.
4. The subsequent reactions of all the three branched chain amino acids differs and is catabolized as follows:
– Valine is converted to succinyl-CoA accounting for the glucogenic nature of the valine.
– Isoleucine is converted to succinyl-CoA and acetyl-CoA, accounting for the ketogenic and glucogenic nature
of the isoleucine.
– Leucine forms acetoacetate and acetyl-CoA but does not produce succinyl-CoA, which accounts for exclusively
the ketogenic nature of the leucine. Leucine produces hydroxymethyl glutaryl-CoA (HMG-CoA) intermediate
product which is a precursor of cholesterol biosynthesis and ketone body formation.
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Figure 17: Degradation of the branched chain amino acids where, HMG-CoA: Hydroxymethylglutaryl-CoA

METABOLISM OF HYDROXY GROUP CONTAINING AMINO ACIDS

Serine and threonine are the hydroxy group containing amono acids.

Metabolism of Serine

Serine is a non-essential amino acid.

Synthesis of Serine

• Serine is synthesized from glycine by transfer of hydroxymethyl group from N 5N10 -methylene THF.

Catabolism of Serine

• In humans, serine is catabolized via glycine and N5, N10 -methylene tetrahydrofolate. The reaction is catalyzed
by serine hydroxy methyl transferase. Further catabolism of serine merges with that of glycine.
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• In many mammals, serine is degraded by serine dehydratase, an enzyme that requires pyridoxal phosphate
(PLP) and produces NH4 + and pyruvate. This pathway appears to be a minor one in humans.

Figure 18: Degradation of serine

Importance of Serine

• Serine is a constituent of phospholipid, phosphatidylserine, found in brain.

• After decarboxylation serine gives rise to ethanolamine which is the constituent of another phospholipid,
phosphatidylethanolamine (cephalin).

• Serine also takes part in the synthesis of cysteine

Metabolism of Threonine

Threonine is an essential and glucogenic amino acid and its catabolism is by 2 pathways.

Catabolism of Threonine
Threonine is degraded by two pathways:
1. Threonine is cleaved to acetaldehyde and glycine by threonine aldolase. Acetaldehyde is then oxidized to
acetate, which then is converted to acetyl-CoA (Figures 19A and B).
2. Threonine dehydratase produces α-ketobutyrate. Subsequently, α-ketobutyrate is oxidatively decarboxylated
to yield propionyl-CoA, which is then carboxylated to methylmalonyl-CoA, which, in turn, is isomerized to
succinyl-CoA. Succinyl-CoA enters the Kreb’s cycle, (Figures 19A and B) and gives rise to pyruvate. Threonine
is thus glucogenic amino acid.
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Figure 19A and B: Catabolic pathways of threonine

Metabolism of Alanine

Alanine is a nonessential amino acid.

Synthesis and Catabolism of Alanine

It is produced from pyruvate by a transamination reaction catalyzed by alanine transaminase (ALT) and may be
metabolized back to pyruvate by a reversal of the same reaction. Alanine is a major glucogenic amino acid.

Figure 20: Synthesis and catabolism of alanine

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METABOLISM OF ACIDIC AMINO ACIDS

Metabolism of Glutamic Acid
Glutamic acid is a nonessential, glucogenic amino acid.
Synthesis of Glutamic Acid
It is synthesized from α-ketoglutarate an intermediate of citric acid cycle by:
• Transamination (Figure 21A)
• By reductive amination of a ketoglutarate by NH4 +, catalyzed by glutamate dehydrogenase (Figure 21B).

Catabolism of Glutamic Acid

When glutamate is degraded, it is converted back to α-ketoglutarate either by transamination or by glutamate
dehydrogenase reaction (Figures 21A and B).

Importance of Glutamic Acid

• A number of other amino acids like glutamine, proline and arginine are derived from glutamate.
• Glutamate involved in the synthesis of glutathione, (γ-glutamyl-cysteinyl glycine) which is involved in the
reduction of H2O2 to H2O and transport of amino acids into cells of kidney and intestine.
• Glutamate is decarboxylated at C-1 to form amine gamma aminobutyric acid (GABA), which serves as a
neurotransmitter.

Metabolism of Glutamine
Glutamine is an amide of glutamate.
Synthesis of Glutamine
It is produced from glutamate by glutamine synthetase, which adds NH4 + to the carboxyl group of the side
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chain, forming an amide (Figure 22).

Degradation of Glutamine
Glutamine is reconverted to glutamate by a different enzyme, glutaminase, which is particularly important
in the kidney.
Importance of Glutamine
• Glutamine is the major transport form of ammonia.
• Glutamine is the principal source of ammonia in the kidney, the ammonia it produces enters the urine and
decreases its acidity (NH3 + H+ →NH4 +) and in this way it plays an important role in the maintenance of acid-
base balance.

Figure 22: Synthesis and degradation of glutamine

• Glutamine participates in a number of biosynthetic reactions, usually by supplying amino or

ammonia nitrogen, e.g. in the formation of arginine, carbamoyl phosphate, purines, etc.

Metabolism of Aspartic Acid

Aspartic acid is a nonessential, glucogenic amino acid.
Synthesis of Aspartic Acid
Aspartate is synthesized from Kreb’s citric acid cycle intermediate, oxaloacetate by transamination reaction
(Figure 21A).
Degradation of Aspartic Acid
Because the transamination reaction is readily reversible, aspartate can be converted to oxaloacetate, an
intermediate of citric acid cycle (Figure 21A).
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Functions of Aspartic Acid

• In the urea cycle, aspartate reacts with citrulline to form arginosuccinate, which is cleaved, forming an
essential amino acid arginine and fumarate.
• Aspartate reacts with inosine monophosphate (IMP) to form AMP.

Metabolism of Aspargine
Aspargine is an amide of aspartate.
Synthesis of Aspargine
• Aspargine is formed from aspartate by a reaction in which glutamine provides the nitrogen for formation of
the amide group (Figure 23).
Degradation of Aspargine
• Hydrolytic release of the amide nitrogen of aspargine as ammonia and aspartate is catalyzed by asparginase
(Figure 23).

Figure 23: Synthesis and degradation of aspartate and aspargine

Clinical Importance of Asparginase

• Certain types of tumor cells, particularly leukemic cells, require aspargine. Therefore, asparginase has been used
as an antitumor agent.
• It acts by converting aspargine to aspartate, decreasing the amount of aspargine available for tumor cell growth.
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METABOLISM OF IMINO ACID

Metabolism of Proline
Proline is a non-essential, glucogenic amino acid.

Synthesis of Proline
• Proline is formed from glutamate by reversal of the reactions of proline catabolism (Figure 24).
• Glutamate is first phosphorylated and then converted to glutamate -semialdehyde by reduction.
• This semialdehyde spontaneously cyclizes and reduction of this cyclic compound yields proline.
Degradation of Proline
• Proline rather than undergoing direct transamination is oxidized to dehydroproline, which adds water, forming
glutamate γ-semialdehyde.
• This is further oxidized to glutamate and transaminated to α-ketoglutarate (Figure 25).
Importance of Proline
• Proline serves as a precursor of hydroxyproline. Hydroxyproline is an important constituent of collagen which
stabilizes the collagen triple helix.

Figure 24 : Synthesis of proline from glutamate

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Figure 25: Degradation of L-proline and L-arginine to α-ketoglutarate

Collagen contains about one-third glycine and one third proline plus hydroxyproline.
• Proline and ornithine are readily interconverted in the body. Thus, proline may yield ornithine for urea synthesis
or ornithine may be broken down via proline (Figure 24).

METABOLISM OF BASIC AMINO ACIDS

Metabolism of Arginine
• Arginine is considered to be a semi-essential amino acid. It can be synthesized in the body but not in quantities
sufficient to permit normal growth. It is thus an amino acid, which is essential for growth but not for maintenance.
Synthesis of Arginine
• Arginine is synthesized from glutamate (Figure 26).
• Glutamate is reduced to glutamate-γ-semialdehyde, which is then transaminated to yield ornithine, an
intermediate of urea cycle.
• The reactions of the urea cycle convert ornithine to arginine.
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Degradation of Arginine
• Arginine is cleaved by arginase to form urea and ornithine.

Figure 26: Synthesis and degradation of arginine

• If ornithine is present in amounts in excess of those required for the urea cycle, it is transaminated to
glutamate semialdehyde which is reduced to glutamate (Figure 26).
Importance of Arginine
• Arginine takes part in the formation of urea.
• Arginine is involved in the synthesis of creatine, an important constituent of muscle. In the formation of creatine,
the guanidinium group of arginine is transferred to glycine.
• Nitric oxide is synthesized from arginine (Figure 27). Nitric oxide is a biological messenger in a variety of
physiological responses including vasodilation, neurotransmission and the ability to kill tumor cells and parasites.
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Figure 27: Synthesis of nitric oxide where, NOS: Nitric oxide synthase, NO: Nitric Oxide

Metabolism of Histidine
Histidine like arginine is a nutritionally semi-essential amino acid and is glucogenic.
Degradation of Histidine
Degradation of histidine occurs mainly in the liver. The major pathway and principal intermediates are shown
in Figure 28.
• In a series of steps, histidine is converted to formiminoglutamate (FIGLU).
• The subsequent reactions transfer one carbon group, i.e. formimino group of FIGLU to the tetrahydrofolate
(THF) to form N5-formimino THF leaving L-glutamate.
• N5-formimino THF may be used in one carbon metabolism (Figure 16).

Figure 28 : Degradation of histidine

Clinical Significance of FIGLU

• In folic acid deficiency transfer of formimino group of FIGLU to THF reaction is partially or totally blocked,
and FIGLU is excreted in the urine.
• Excretion of FIGLU, therefore, provides a diagnostic test for folic acid deficiency.

Importance of Histidine
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Histidine has several other important functions in addition to the general role of amino acids in tissue protein
formation as follows:
• Upon decarboxylation, it forms histamine, which reduces blood pressure, is a vasodilator and increases the
secretion of gastric juice. Allergicreactions stimulate an excessive liberation of histamine.
• Histidine is involved in the formation of biologically important peptides like carnosine and anserine present
in muscle, ergothioneine present in erythrocytes, liver and brain.

Metabolism of Lysine
• Lysine is a nutritionally essential amino acid.
• Lysine is both glucogenic and ketogenic amino acid.
• It contains two amino groups, neither of which can undergo direct transamination.
Catabolism of Lysine
Lysine is degraded by a complex pathway in which saccharopine, -ketoadipate and crotonyl-CoA are
intermediates (Figure 29). Ultimately, lysine generates acetyl-CoA.
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Figure 29: Degradation of L-lysine

Importance of Lysine
Lysine is involved in the synthesis of carnitine, that serves to shuttle fatty acyl groups across mitochondrial
membrane.
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