Textbook - BIOLOGICAL CHEMISTRY - Gubsky Yu.I. - 2000

Section III. METABOLISM OF THE MAIN CLASSES OF BIOMOLECULES

CHAPTER 18. AMINO ACID METABOLISM. II. SPECIALIZED PATHWAYS OF METABOLISM

18.2. SPECIALIZED METABOLIC PATHWAYS OF ACYCLIC AMINO ACIDS

Class="center">METABOLISM of Glycine and Serine

Glycine (α-aminoacetic acid) is a vital participant in numerous biochemical processes. The two-carbon Skeleton of glycine is utilized in diverse synthetic reactions leading to the Formation of other Biomolecules, including physiologically active compounds.

In the animal Organism, glycine is synthesized from L-serine, a non-essential amino acid whose carbon skeleton is derived from glucose According to the following scheme:

A prominent role in the biochemical transformations of glycine is played by the coenzyme form of vitamin B_c, tetrahydrofolic acid (H₄-folate).

1. Formation of glycine from serine:

2. Oxidation of glycine to carbon dioxide and ammonia:

3. Reversible conversion of glycine to serine:

Tetrahydrofolate as a Carrier of One-Carbon Radicals

The discussed reactions of glycine metabolism serve as a major source of one-carbon radicals involved in various synthesis PATHWAYS OF AMINO acids, NUCLEOTIDES, and physiologically active compounds.

The intermolecular transport of one-carbon radicals is mediated by the coenzyme form of Folic acid (pteroylglutamic acid, vitamin B_c), namely 5,6,7,8-tetrahydrofolic acid (H₄-folate). Tetrahydrofolate is synthesized in the body from dietary folate. The conversion of folic acid into tetrahydrofolic acid (which acts as an acceptor and carrier of one-carbon groups) proceeds via NADPH-dependent reductases: folate reductase, which yields 7,8-dihydrofolic acid (H₂-folate), and Dihydrofolate Reductase, which generates 5,6,7,8-tetrahydrofolic acid (H₄-folate).

The conversion of folate to tetrahydrofolate occurs through The addition of hydrogen atoms to the carbon and nitrogen atoms of the pteridine ring at positions C-6, C-7 and N-5, N-8, respectively.

Tetrahydrofolate performs The biochemical function of a coenzyme in the intermolecular transport of one-carbon groups with varying oxidation states: methyl (-СН₃), methylene (-СН-), methenyl (-СН=), hydroxymethyl (-СН₂ОН), formyl (-СНО), and formimino (CHNH) groups.

The transport of one-carbon radicals by the tetrahydrofolate molecule is accomplished by their attachment at the N⁵ and N¹⁰ positions of pteroylglutamate, resulting in The formation of interconvertible coenzyme forms:

Physiologically active compounds that act as dihydrofolate reductase inhibitors suppress biosynthetic Reactions Involving the Coenzyme forms of H₄-folate and can be used as antitumor agents (Chapter 19).

It should be noted that tetrahydrofolate is primarily involved in the intermolecular transport of oxidized single-carbon radicals, whereas the active form of The amino acid Methionine, S-adenosylmethionine, plays a significant role in Methyl group transfer alongside tetrahydrofolate (see below).

Metabolism of Sulfur-Containing Amino Acids

Methionine and Methylation Reactions

L-Methionine is an amino acid that plays a vital role in intracellular metabolism and serves as a donor of the methyl (-CH₃) group in numerous methylation reactions.

Methionine is synthesized in the body from the amino acid L-homocysteine, with N⁵-methyltetrahydrofolate acting as the methyl group donor in this reaction:

The enzyme catalyzing this reaction is homocysteine methyltransferase; the coenzyme for this reaction (acting as an intermediate methyl group carrier) is the coenzyme form of vitamin B₁₂, methylcobalamin.

Methylation Reactions

The biochemically active form of methionine, which serves as the direct -CH₃ group donor in Transmethylation reactions, is S-adenosylmethionine. It is synthesized in The Human Body from methionine through the action of the enzyme methionine adenosyltransferase.

S-Adenosylmethionine, having lost its active methyl group during the methylation of biomolecules, is converted into S-adenosylhomocysteine, and subsequently into homocysteine and back to methionine. Since methionine is lost in catabolic reactions (via the formation of succinyl-CoA), the functioning of this active methyl cycle (Fig. 18.2) depends on a continuous dietary supply of methionine as an essential amino acid.

Fig. 18.2. The active methyl cycle.

Reactions involving S-adenosylmethionine include the synthesis of creatine, the formation of Choline from the amino alcohol ethanolamine, adrenaline from noradrenaline, and the methylation of nitrogenous bases in nucleotides, among others.

Creatine Synthesis

Creatine is a nitrogenous compound which, in the form of creatine phosphate, plays a crucial role in the energy supply for Muscle Function.

The Biosynthesis of creatine involves the amino acids glycine, Arginine, and methionine. The synthesis process consists of two stages:

Stage 1 takes place in the Kidneys and involves the formation of glycocyamine (guanidinoacetate) from arginine and glycine (catalyzed by the enzyme glycine amidinotransferase):

Stage 2 takes place in the Liver, where glycocyamine is transported via the bloodstream, and involves the methylation of glycocyamine to creatine utilizing S-adenosylmethionine (catalyzed by the enzyme guanidinoacetate methyltransferase):

The phosphorylation of creatine by creatine phosphokinase generates creatine phosphate, a source for the rapid regeneration of ATP During Muscle contraction. Irreversible non-enzymatic dehydration and dephosphorylation of creatine phosphate lead to the formation of creatine anhydride, creatinine:

Pathway of the conversion of glycocyamine to Creatine and Creatinine.

A significant portion of Amino Acid Nitrogen is excreted from the human body in the form of creatinine via urine; in a healthy individual, creatinine excretion is proportional to muscle mass and increases substantially during TRAUMATIC MUSCLE INJURIES.

Cysteine and Glutathione

L-Cysteine is an amino acid whose biological Functions primarily involve maintaining the SH groups of numerous BIOREGULATORS and Enzymes in a reduced state, notably through the synthesis of glutathione.

Glutathione is a tripeptide, γ-glutaminyl-cysteinyl-glycine, which contains a free sulfhydryl group:

Glutathione is present in animal Cells in high concentrations (approximately 5 mM). It is reversibly converted from its reduced (G-SH) to its oxidized (G-S-S-G) form, functioning as an SH-group buffer.

The biochemical function of glutathione in the body is associated with the reduction and detoxification of organic peroxides—derivatives of hydrogen peroxide HO-OH, in which one hydrogen atom (hydroperoxides) or both hydrogen atoms (alkyl peroxides) are substituted with alkyl radicals:

The reaction of glutathione with hydroperoxide yields harmless organic alcohols that undergo further oxidation:

The reaction is catalyzed by the enzyme glutathione peroxidase, which contains a selenium (Se) atom in its active center.

The reverse reduction of G-S-S-G to G-SH is catalyzed by NADPH-dependent glutathione reductase:

Hydroperoxides and alkyl peroxides are formed As a result of dioxygenase reactions involving the direct incorporation of an oxygen atom into biomolecules. The generation of organic peroxides results from the activation of free-radical oxidation reactions in biological systems; the primary substrate for such reactions is the Unsaturated Fatty acids of membrane Phospholipids—a process known as Lipid Peroxidation in Introduction/36.html">Biological Membranes.

The activation of lipid peroxidation is a fundamental biological mechanism underlying biostructure damage and The Development of cellular pathology caused by various damaging factors, particularly ionizing radiation and foreign chemical compounds known as xenobiotics. An example of Cell membrane damage resulting from lipid peroxidation products is peroxide hemolysis of erythrocytes, which occurs due to an inherited deficiency of glucose-6-phosphate dehydrogenase—the generator of NADPH required for the functioning of glutathione reductase and the maintenance of glutathione in its reduced form.

Compounds similar to glutathione that neutralize organic peroxides or counteract their formation are termed antioxidants. Biologically important antioxidants include α-tocopherol (vitamin E), ascorbic acid, and urate.

Taurine

A physiologically important reaction of cysteine metabolism is the formation of taurine (aminoethanesulfonate), which, along with glycine, is utilized by the body to form the conjugated Bile acid forms glycocholic and taurocholic acids, respectively.

Metabolism of Branched-Chain Amino Acids

Owing to the structural similarity of the amino acids L-valine, L-leucine, and L-isoleucine, the Initial Stages of their Catabolism follow similar pathways and share common mechanisms:

As follows from the presented scheme, the common reactions for the conversion of branched-chain Amino acids are:

(1) Transamination to the corresponding branched-chain α-keto acids, catalyzed by an aminotransferase capable of transaminating any of the branched-chain L-amino acids;

(2) oxidative decarboxylation yielding acyl-CoA thioesters, catalyzed by the mitochondrial multienzyme complex branched-chain α-keto acid dehydrogenase; in its Structure and MOLECULAR MECHANISMS OF catalytic action, this dehydrogenase complex is analogous to the mitochondrial dehydrogenases of pyruvic and α-ketoglutaric acids;

(3) dehydrogenation yielding α,β-unsaturated acyl-CoA thioesters; the reaction is catalyzed by an enzyme (or enzymes) similar to the FAD-dependent straight-chain acyl-CoA dehydrogenase.

The similarity in the initial stages of L-valine, L-leucine, and L-isoleucine catabolism stems from the mechanisms of the three following transformation reactions:

Maple syrup urine disease (leucinosis) is a hereditary enzymopathy of branched-chain Amino acid metabolism.

The disorder is caused by a defect in the Gene controlling the synthesis of branched-chain α-keto acid dehydrogenase. Due to the block in the enzymatic reaction (2)—The oxidative decarboxylation of leucine, valine, and isoleucine—these Amino Acids and their corresponding α-keto acids accumulate in the Blood and Internal Organs of patients (another name for this enzymopathy is branched-chain ketoaciduria); the patients' urine has a characteristic maple syrup odor (maple syrup urine disease). If an affected child is not placed on a special low-branched-chain amino acid diet from an early age, the pathology leads to delayed overall development and severe neurological disorders.

Coenzymes of Vitamins H and B₁₂ in Amino Acid Metabolism

Succinyl-CoA serves as an entry point into the citrate cycle for two branched-chain amino acids—valine and isoleucine—as well as for the methyl group carrier amino acid methionine (Fig. 18.1).

The catabolism of these Three amino acids converges through the Formation of the common intermediates propionyl-CoA and methylmalonyl-CoA. The transformations of propionyl-CoA, which is also produced during the β-oxidation of odd-chain fatty acids, are of considerable biochemical interest:

- reaction (1) is catalyzed by propionyl-CoA carboxylase, a biotin (vitamin H)-dependent enzyme whose MECHANISM OF ACTION is analogous to that of carboxylases that add CO₂ to acetyl-CoA (in the formation of malonyl-CoA) and Pyruvate (in the formation of oxaloacetate);

- reaction (2) is catalyzed by the enzyme methylmalonyl-CoA mutase, whose coenzyme form is the vitamin B₁₂ derivative deoxyadenosylcobalamin.

As noted previously (Chapter 6, Section 6.3), vitamin B₁₂ forms two coenzymes: methylcobalamin and deoxyadenosylcobalamin. In mammalian Tissues, these coenzyme forms of vitamin B₁₂ participate in two enzymatic reactions:

1) the methylation of homocysteine to form methionine, where methylcobalamin acts as a methyl group carrier in the reaction of methionine with N⁵-methyl-H₄-folate (see above);

2) the isomerization of methylmalonyl-CoA to succinyl-CoA, where deoxyadenosylcobalamin acts as the coenzyme for methylmalonyl-CoA mutase; the reaction mechanism involves an intramolecular exchange of two chemical groups attached to adjacent carbon atoms—hydrogen atoms and a radical that may be substituted by a hydrocarbon, hydroxyl, or amino group:

Arginine Metabolism

The Role of arginine in urea synthesis as the end product of amino acid metabolism in mammals was discussed above. In recent years, significant attention has been drawn to the metabolic role of arginine as a precursor in the generation of nitric oxide (NO), a short-lived molecule that functions as an intracellular messenger for signals from physiologically active compounds.

The formation of nitric oxide from arginine occurs via a reaction catalyzed by nitric oxide synthase (NOS):

Three isoforms of nitric oxide synthase have been identified, named after The Cell type in which they were first discovered: NOS-1 (neuronal, or Brain), NOS-2 (macrophage), and NOS-3 (endothelial isoform).

The Biological Role of NO in the body is mediated through its Participation in the modulation of physiological functions such as The regulation of smooth muscle tone (specifically vasodilation), immune responses, neurotransmission, etc.