BIOCHEMISTRY - Textbook - Ostapchenko L. I. - 2012

Chapter 6. AMINO ACID METABOLISM AND FUNCTIONS. PROTEIN BIOSYNTHESIS

6.4. Catabolism of Amino Acids

6.4.2. Deamination of Amino Acids

AMINO ACID DEAMINATION is the removal of an α-amino group from an amino acid, yielding the corresponding α-keto acid (a nitrogen-free residue) and releasing an ammonia molecule. The subsequent Metabolic pathways of amino acid deamination products are shown in Fig. 6.7.

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Fig. 6.7. Scheme of transformation of amino acid deamination products

Ammonia is toxic to the Central Nervous system; therefore, in The Human Body and mammals, it is converted into urea, a non-toxic, highly soluble compound. Ammonia is eliminated from the body in the form of urea and ammonium salts. The nitrogen-free residue is utilized for the synthesis of Amino Acids via Transamination reactions, in Gluconeogenesis, ketogenesis, and anaplerotic reactions to replenish depleted TCA cycle intermediates, as well as in oxidation reactions to CO₂ and H₂O.

There are several types of amino acid deamination:

✵ oxidative;

✵ indirect (transdeamination);

✵ non-oxidative;

✵ intramolecular.

Oxidative deamination. The deamination of glutamic acid is the most active process occurring in Tissues. The reaction is catalyzed by the enzyme Glutamate dehydrogenase, with NAD⁺ serving as its coenzyme. The reaction proceeds in two steps. First, the enzymatic dehydrogenation of glutamate yields α-iminoglutarate; second, a non-enzymatic hydrolytic Cleavage of the imino group takes place in the form of ammonia, resulting in The formation of α-ketoglutarate:

Oxidative deamination of glutamate is a reversible reaction and, upon an increase in intracellular ammonia concentration, can proceed in the reverse direction as the reductive amination of α-ketoglutarate.

Glutamate dehydrogenase is highly active in the Cell/35.html">Mitochondria of Cells across virtually all Organs, except for Muscles. This enzyme is an oligomer composed of six subunits (molecular weight 312 kDa). Glutamate dehydrogenase plays a crucial role as a regulatory enzyme in Amino acid METABOLISM. Allosteric inhibitors of glutamate dehydrogenase (ATP, GTP, NADH) induce enzyme dissociation and loss of glutamate dehydrogenase activity. High concentrations of ADP activate the enzyme. Thus, a low cellular energy state stimulates The breakdown of Amino Acids and The production of α-ketoglutarate, which enters the TCA cycle as an energy substrate. Glutamate dehydrogenase can be induced by Steroid Hormones (cortisol).

L-Amino Acid Oxidase has been found in The Liver and Kidneys; this enzyme is capable of deaminating certain L-amino acids:

FMN acts as the coenzyme in this reaction. However, THE CONTRIBUTION OF L-amino acid oxidase to deamination is minor because the optimal pH for the enzyme is 10.0. In cells where the ambient pH approaches neutrality, enzyme activity is very low.

D-Amino Acid Oxidase is also found in the kidneys and liver. It is an FAD-dependent enzyme. The pH optimum for this oxidase lies within the neutral range, making it more active than L-amino acid oxidase. The Physiological Role of D-amino acid oxidase is negligible because the concentration of D-isomers in the body is extremely low, as dietary and tissue Proteins in humans and animals contain exclusively natural L-isomers. Presumably, D-amino acid oxidase facilitates their conversion into the corresponding L-isomers (Fig. 6.8).

Fig. 6.8. Biological Role of D-amino acid oxidase

Indirect deamination (transdeamination). Most amino acids cannot undergo direct single-step deamination like Glu. The amino groups of such Amino acids are transferred via transamination to α-ketoglutarate to form glutamic acid, which subsequently undergoes direct oxidative deamination. This two-stage mechanism of amino acid deamination is termed transdeamination, or indirect deamination:

Indirect deamination of amino acids involves two Enzymes: aminotransferase (with the PLP coenzyme) and glutamate dehydrogenase (with the NAD+ coenzyme).

These reactions play a crucial role in amino acid metabolism, as indirect deamination is the primary pathway for deaminating most amino acids. Both stages of indirect deamination are reversible (Fig. 6.9), which allows for both Amino Acid Catabolism (Fig. 6.9, A) and the potential synthesis of virtually any amino acid from its corresponding α-keto acid (Fig. 6.9, B).

Fig. 6.9. Biological role of indirect deamination:

A - amino acid catabolism; B - Amino acid synthesis; AA - amino acids; KA — keto acids

In Muscle tissue, glutamate dehydrogenase activity is low; therefore, under intensive physical exertion, these cells utilize an alternative pathway of indirect deamination involving the IMP-AMP cycle. The process begins with The transfer of an amino group from amino acids to aspartate, then to inosine monophosphate (IMP), and finally culminates in the deamination of AMP. The scheme below illustrates The sequence of reactions in indirect Non-Oxidative Deamination:

The process comprises four distinct stages:

✵ transamination with α-ketoglutarate, yielding glutamate;

✵ transamination of glutamate with oxaloacetate (catalyzed by AST), yielding aspartate;

✵ transfer of the amino group from aspartate to IMP (inosine monophosphate), yielding AMP and fumarate;

✵ hydrolytic deamination of AMP.

The scheme demonstrates the exact mechanism of amino acid transfer from aspartate and the subsequent synthesis of AMP:

The deamination of adenylic acid is catalyzed by the enzyme AMP deaminase:

This deamination pathway predominates in skeletal muscles during intense exercise, which leads to the accumulation of lactic acid. The released ammonia helps prevent intracellular acidification caused by lactate production.

Non-oxidative deamination. Human liver tissue contains specific enzymes that catalyze the non-oxidative deamination of the amino acids Serine, Threonine, and Histidine.

The non-oxidative deamination of serine is catalyzed by serine dehydratase (SD):

The reaction begins with the elimination of a Water molecule and the formation of a methylene group, followed by a non-enzymatic molecular rearrangement that yields an imino group loosely bound to the α-carbon atom. Subsequent non-Enzymatic Hydrolysis releases an ammonia molecule and produces Pyruvate.

The non-oxidative deamination of threonine is catalyzed by Threonine dehydratase (TD). The reaction mechanism is analogous to that of serine deamination:

These enzymes are Pyridoxal phosphate-dependent.

The non-oxidative deamination of histidine, mediated by histidase (histidine ammonia-lyase), is an intramolecular process because the ammonia molecules are derived from The amino acid's own atoms without the involvement of a water molecule. This reaction occurs exclusively in the liver and Skin: