BIOCHEMISTRY - Textbook - Ostapchenko L. I. - 2012

Chapter 6. AMINO ACID METABOLISM AND FUNCTIONS. PROTEIN BIOSYNTHESIS

6.9. Nitrogen-Containing Compounds: Amino Acid Derivatives

6.9.1. Decarboxylation of Amino Acids and Their Derivatives

Certain Amino Acids and their derivatives can undergo decarboxylation—the removal of the α-carboxyl group. In mammalian tissues, a wide range of amino acids or their derivatives can undergo this process: Thr, Tyr, Val, His, Glu, Cys, Arg, Ornithine, SAM, L-DOPA, 5-hydroxytryptophan, and others. The reaction products are CO₂ and amines that exhibit pronounced biological effects on the Organism (biogenic amines):

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Decarboxylation reactions are irreversible and are catalyzed by decarboxylase Enzymes. In animal Cells, the prosthetic group of Decarboxylases is Pyridoxal phosphate. Some microbial decarboxylases may contain a Pyruvate residue instead of PLP, such as Histidine decarboxylase in Micrococcus and Lactobacillus, SAM decarboxylase in E. coli, etc. The reaction mechanism resembles the pyridoxal phosphate-dependent Transamination reaction and also proceeds via The formation of a Schiff base intermediate between PLP and The amino acid in The First stage.

Amines formed As a result of AMINO ACID DECARBOXYLATION are frequently BIOLOGICALLY ACTIVE SUBSTANCES. They function as Neurotransmitters (serotonin, dopamine, GABA, etc.), Hormones (norepinephrine, epinephrine), and local regulatory factors (histamine, carnosine, spermine, etc.).

Serotonin is a neurotransmitter of Neural Pathways. It is synthesized in the Adrenal Glands and the Central Nervous system from the amino acid 5-hydroxytryptophan through the action of aromatic amino acid decarboxylase. This enzyme has a broad Specificity and is also capable of decarboxylating Tryptophan and L-DOPA (derived from Tyrosine). 5-Hydroxytryptophan is synthesized from tryptophan by tryptophan hydroxylase, which utilizes tetrahydrobiopterin (H4B) as a coenzyme (this enzyme is specific to aromatic Amino Acids and also hydroxylates phenylalanine):

Serotonin can be converted into the hormone melatonin, which regulates circadian and seasonal metabolic rhythms and participates in The regulation of reproductive function.

Serotonin is a broad-spectrum biologically active substance. It stimulates smooth Muscle contraction, exerts a vasoconstrictive effect, regulates Blood pressure, body Temperature, and Respiration, and acts as an antidepressant. According to some data, it may also be involved in allergic reactions, as it is synthesized in small quantities by mast cells.

Acetylcholine is synthesized in Nervous Tissue and is one of the most important excitatory neurotransmitters of the Autonomic nervous system. Its precursor is the amino acid Serine:

In Nerve Cells, the decarboxylation of glutamate (removal of the α-carboxyl group) leads to the Formation of γ-aminobutyric acid (GABA), which serves as the primary inhibitory neurotransmitter in higher Brain regions:

The cycle of GABA conversion in the brain comprises three coupled reactions known as the GABA shunt. The first reaction is catalyzed by glutamate decarboxylase, a pyridoxal-dependent enzyme. This is a regulatory reaction that controls The rate of GABA synthesis in brain cells, with GABA being the product. The subsequent two reactions represent GABA Catabolism. GABA aminotransferase, which is also pyridoxal-dependent, converts GABA into succinic semialdehyde, which is then dehydrogenated to form succinic acid. Succinate is subsequently utilized in The Citric Acid Cycle. The inactivation of GABA can also occur via an oxidative pathway mediated by monoamine oxidase.

The GABA content in the brain is tens of times higher than that of other neurotransmitters. It increases the permeability of postsynaptic membranes to K⁺ ions, thereby inhibiting nerve impulses, enhances the metabolic and respiratory activity of nervous tissue, and improves cerebral blood flow.

GABA preparations, such as Gamalon or Aminalon, are used to treat cerebrovascular disorders (atherosclerosis, Hypertension), impaired cerebral Circulation, mental retardation, endogenous depression, and TRAUMATIC BRAIN INJURIES, as well as central nervous system disorders associated with excessive cortical excitation (e.g., Epilepsy).

Free amino acids play a crucial role in the brain as precursors of Proteins and biologically active substances such as Neuropeptides, hormones, and biogenic amines. Certain amino acids participate in synaptic transmission by functioning as neurotransmitters. The energetic role of amino acids in the brain is also highly significant. The concentration of free amino acids in the brain reaches ~35 µmol/g of tissue, which is significantly higher than their levels in Blood Plasma (~3.5 µmol/L) and CEREBROSPINAL FLUID. Glutamic acid, glutamine, aspartic acid, Glycine, GABA, and N-acetylaspartate predominate.

The amino acids glycine and glutamate are key neurotransmitters.

Glutamate is present in the brain in very high concentrations (up to ~10 µmol/g of tissue) and performs diverse Functions:

✵ it is one of the major excitatory neurotransmitters in the Cerebral Cortex, hippocampus, striatum, and Hypothalamus;

✵ it participates in the regulation of memory processes;

✵ it is a structural component of various small and medium-sized brain regulatory Peptides, such as Glutathione. In the form of pyroglutamate (a cyclic Structure), it is incorporated into numerous neuropeptides, including luliberin, thyroliberin, neurotensin, and bombesin;

✵ plays an energetic role, as glutamate serves as a supplier of α-ketoglutarate, a component of The Citric Acid cycle;

✵ takes part in the detoxification of ammonia to form glutamine, which is transported in large quantities across membranes into Neurons, where the enzyme glutaminase is present. Under the action of this enzyme, glutamate is regenerated and used for GABA synthesis. Given that Introduction/36.html">Biological Membranes are less permeable to glutamate than to glutamine, the latter can be regarded as a glial-neuronal carrier of glutamate (and consequently of GABA).

Dysfunction of the glutamatergic system occurs in numerous central nervous system pathologies, including epilepsy, vestibular disorders, and ischemia. Glutamate and its analogues are used as therapeutic agents in chronic Amino acid METABOLISM disorders, vegetative-vascular dystonia, and epilepsy (as a precursor to GABA, an inhibitory neurotransmitter).

Another amino acid neurotransmitter is glycine. Its concentration in blood plasma is low, meaning only small amounts enter the brain. A significant portion of glycine is synthesized from glucose supplied by the blood (the synthesis pathways are described above). Glycine is the most important inhibitory neurotransmitter (after GABA) in the Spinal Cord, Diencephalon, and certain Regions of the brain. High levels of glycine in blood plasma and urine typically indicate impaired brain function.

The degradation of glycine can proceed through three pathways:

✵ conversion of glycine into serine by the action of serine hydroxymethyltransferase;

✵ Cleavage of glycine into ammonia, carbon dioxide, and methylene-H₄-folate;

✵ oxidation mediated by amino acid oxidase.

Hyperglycinemia develops in early childhood and is accompanied by episodic vomiting, suppressed motor activity, electroencephalographic abnormalities, and frequently proves fatal. Hyperglycinemia may result from impaired standard pathways of glycine degradation within nerve cells.