Biological Chemistry - Berezov T. T., Korovkin B. F. 1998

Metabolism of Simple Proteins
Intermediate Metabolism of Amino Acids in Tissues
Decarboxylation of Amino Acids

The process of splitting off the carboxyl group of Amino Acids in the form of СО₂ is termed decarboxylation. Despite the limited range of Amino Acids and their derivatives that undergo decarboxylation in animal Tissues, the resulting reaction products—biogenic amines—exert powerful pharmacological effects on numerous physiological Functions in humans and animals. Decarboxylation of the following amino acids and their derivatives has been established in animal tissues: Tyrosine, Tryptophan, 5-hydroxytryptophan, valine, Serine, Histidine, glutamic and y-hydroxyglutamic acids, 3,4-dihydroxyphenylalanine, Cysteine, Arginine, Ornithine, S-adenosylmethionine, and a-aminomalonic acid. In addition, the decarboxylation of A number of Other Amino Acids has been discovered in microorganisms and plants.

Four types of AMINO ACID DECARBOXYLATION have been discovered in living organisms:

1. a-Decarboxylation, characteristic of animal tissues, in which the carboxyl group adjacent to the a-carbon atom is split off from The amino acid. The reaction products are СО₂ and biogenic amines:

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2. ω-Decarboxylation, characteristic of microorganisms. For example, a-Alanine is formed from aspartic acid via this pathway:

3. Decarboxylation coupled with Transamination:

This reaction yields an aldehyde and a new amino acid corresponding to the initial keto acid.

4. Decarboxylation coupled with the Condensation of two molecules:

This reaction in animal tissues takes place during the synthesis of b-aminolevulinic acid from Glycine and succinyl-CoA (see Chapter 13), during the synthesis of Sphingolipids, and in plants during the synthesis of biotin.

Unlike other intermediary Amino acid METABOLISM processes, decarboxylation reactions are irreversible. They are catalyzed by specific Enzymes—amino acid Decarboxylases—which differ from a-keto acid decarboxylases (see Chapter 10) in both their protein component and The Nature of their coenzyme. Amino acid decarboxylases consist of a protein moiety, which ensures reaction Specificity, and a prosthetic group represented by Pyridoxal phosphate (PLP), just like transaminases.

Thus, the exact same coenzyme participates in two completely different processes of amino acid metabolism. Exceptions include two decarboxylases: histidine decarboxylase from Micrococcus and Lactobacillus, and adenosylmethionine decarboxylase from E. coli, which contain a pyruvic acid residue instead of PLP*.

In accordance with the general theory of pyridoxal catalysis (see Fig. 12.3), The Mechanism of amino acid decarboxylation reduces to The formation of a PLP-substrate complex represented, as in transamination reactions, by a Schiff base formed by PLP and the amino acid:

The formation of such a complex, combined with a certain degree of electron withdrawal by the protein moiety of the enzyme molecule, is accompanied by the labilization of one of the three bonds at the a-carbon atom, enabling the amino acid to participate in transamination (a), decarboxylation (b), and aldol Cleavage (c) reactions.

Below are specific Examples of amino acid decarboxylation, particularly those whose reaction products exert strong pharmacological effects. One of the well-studied enzymes is aromatic amino acid decarboxylase. It lacks strict substrate specificity and catalyzes the decarboxylation of L-isomers of tryptophan, 5-hydroxytryptophan, and 3,4-dihydroxyphenylalanine (DOPA); the reaction products, besides СО₂, are tryptamine, serotonin, and dihydroxyphenylethylamine (dopamine), respectively.

* It is hypothesized that certain decarboxylases in animal tissues—for instance, those decarboxylating S-adenosylmethionine, phosphatidylserine, and aspartate—also contain Pyruvate.

Aromatic amino acid decarboxylase has been obtained in pure form (molecular mass 112,000), with PLP as its coenzyme. It is found in large amounts in the Adrenal Glands and the Central Nervous system, playing a vital role in regulating biogenic amine levels. Serotonin, formed from 5-hydroxytryptophan, has proven to be a highly active biogenic amine with vasoconstrictive action. Serotonin regulates Blood pressure, body Temperature, Respiration, renal filtration, and acts as a neurotransmitter in the central nervous system. Some authors implicate serotonin in The Development of allergies, dumping syndrome, gestational toxicosis, carcinoid syndrome, and hemorrhagic diatheses.

The product of the decarboxylation reaction, dopamine, is a precursor of catecholamines (norepinephrine and epinephrine). The source of DOPA in the body is tyrosine, which is converted into 3,4-dihydroxyphenylalanine by a specific hydroxylase (see Chapter 8). Tyrosine 3-monooxygenase has been discovered in the adrenal glands, Brain tissue, and the Peripheral Nervous System. The prosthetic group of tyrosine monooxygenase, like that of dopamine monooxygenase (the latter catalyzes The conversion of dopamine to norepinephrine), is tetrahydrobiopterin, which has the following Structure:

The Physiological Role of tyrosine 3-monooxygenase is exceptionally great, since the reaction catalyzed by this enzyme determines The rate of Biosynthesis of Catecholamines, which regulate cardiovascular activity. In medical practice, inhibitors of aromatic amino acid decarboxylase—specifically a-methyldopa (aldomet), which causes a drop in blood pressure—are widely used.

In animal tissues, the decarboxylation of histidine proceeds at a high rate under the action of a specific decarboxylase.

Histamine exerts a wide spectrum of biological effects. In terms of its MECHANISM OF ACTION on Blood Vessels, it differs sharply from other biogenic amines due to its potent vasodilating properties. Large amounts of histamine are produced in areas of inflammation, which serves a distinct biological purpose. By inducing vasodilation at the site of inflammation, histamine accelerates the influx of leukocytes, thereby helping to activate the body's defense mechanisms. In addition, histamine is involved in stimulating gastric Hydrochloric acid secretion, a property widely utilized in clinical practice to evaluate gastric secretory function (the histamine test). It is also directly implicated in phenomena of sensitization and desensitization. For patients with hypersensitivity to histamine, clinicians administer antihistamines (such as sanorin or diphenhydramine) that act on vascular receptors. Furthermore, histamine is believed to act as a pain mediator. Pain is a complex process whose exact details remain to be fully elucidated, but the involvement of histamine in this mechanism is beyond doubt.

Another product of L-glutamic acid alpha-decarboxylation widely used in clinical practice is gamma-aminobutyric acid (GABA). The enzyme catalyzing this reaction, glutamate decarboxylase, exhibits high specificity.

Interest in GABA stems from its inhibitory effect on the central nervous system. The highest concentrations of GABA and glutamate decarboxylase are found in the Gray matter of the Cerebral Cortex, whereas the cerebral White matter and the peripheral nervous system contain virtually none. Administration of GABA induces a diffuse inhibitory process in the cortex (central inhibition) and leads to the loss of conditioned Reflexes in animals. GABA is used clinically as a therapeutic agent for certain central nervous system disorders associated with excessive excitation of the cerebral cortex. For instance, the administration of glutamic acid has been shown to produce a favorable therapeutic effect in Epilepsy, sharply reducing the frequency of epileptic seizures. As it turned out, this therapeutic effect is attributable not to glutamic acid itself, but to its decarboxylation product—GABA.

In animal tissues, two cysteine derivatives—cysteinesulfinic and cysteic acids—are also rapidly decarboxylated. These specific enzymatic reactions yield taurine, which the body utilizes to synthesize conjugated Bile acids (see Chapter 11).

Mention should also be made of two recently discovered animal tissue enzymes that catalyze the decarboxylation of ornithine and S-adenosylmethionine: ornithine decarboxylase and S-adenosylmethionine decarboxylase.

The Significance of these reactions for animal tissues is immense, as their products are essential for the synthesis of Polyamines, namely spermidine and spermine.

Polyamines, which also include the diamine putrescine, play a crucial role in Cell growth and differentiation, as well as in The regulation of DNA, RNA, and Protein Synthesis by stimulating Transcription and Translation (see below), although the exact mechanism of their involvement in these processes remains partially unclear.

Thus, biogenic amines are potent pharmacologically active substances that exert diverse effects on the physiological Functions of the body. Several biogenic amines have found widespread application as pharmaceutical drugs.

Catabolism of biogenic amines. The accumulation of biogenic amines can adversely affect physiological status and cause a range of significant functional disorders in the body. However, individual Organs and tissues, as well as the Organism as a whole, possess specialized mechanisms for inactivating biogenic amines. Generally, these mechanisms involve the Oxidative Deamination of these amines to yield the corresponding aldehydes and release ammonia:

The enzymes catalyzing these reactions are known as monoamine and diamine oxidases. The mechanism of monoamine oxidative deamination has been studied in greatest detail. This enzymatic process is irreversible and proceeds in two stages:

R-CH₂-NH₂ + Е-ФАД + H₂O -> R-CHO + NH₃ + Е-ФАДН₂       (1)

Е-ФАДН₂ + O₂ -> Е-ФАД + H₂O₂       (2)

The first (anaerobic) stage (1) is characterized by the formation of an aldehyde, ammonia, and the reduced enzyme. In the aerobic phase, the latter is reoxidized by molecular oxygen. The resulting hydrogen peroxide is subsequently broken down into Water and oxygen. Monoamine oxidase (MAO), a FAD-containing enzyme located predominantly in Mitochondria, plays a critically important role in the body by regulating the rates of BIOSYNTHESIS AND DEGRADATION of biogenic amines. Certain monoamine oxidase inhibitors (such as iproniazid, harmine, and pargyline) are used in the Treatment of Hypertension, depressive states, Schizophrenia, and other conditions.