BIOCHEMISTRY - Textbook - Ostapchenko L. I. - 2012

Chapter 6. AMINO ACID METABOLISM AND FUNCTIONS. PROTEIN BIOSYNTHESIS

6.8. Metabolism of Individual Amino Acids

6.8.1. Metabolism of Serine and Glycine

Serine is a non-essential amino acid synthesized from 3-phosphoglycerate, an intermediate of Glycolysis, by receiving an amino group from glutamic acid.

Glycine is also a non-essential amino acid, with serine serving as its primary source. The synthesis of glycine from serine is catalyzed by the enzyme serine hydroxymethyltransferase, which requires H₄-folate as a coenzyme:

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The conversion of serine to Glycine is a reversible reaction. The principal pathway of Glycine Catabolism in humans and other vertebrates is also associated with the utilization of H₄-folate:

This reaction is reversible and is catalyzed by glycine synthase, an enzyme complex similar to the Pyruvate dehydrogenase complex located in Liver Cell Mitochondria. According to recent findings, the glycine Cleavage system differs slightly from glycine synthase and comprises four protein components: the P-protein (containing a PLP coenzyme), the H-protein (containing Lipoic Acid), the T-protein (which utilizes H₄-folate as a coenzyme), and the L-protein, which is dihydrolipoyl dehydrogenase with NAD⁺ as its coenzyme.

The Amino Acids serine and glycine perform diverse and vital Functions in The Human Body. The Role of serine and glycine in the synthesis of numerous biologically important compounds is illustrated in Fig. 6.24.

Fig. 6.24. Biological Role of serine and glycine

As shown in the figure, both Amino acids are essential not only for the synthesis of Proteins and glucose (when cellular levels are low), but also for NUCLEOTIDES, Coenzymes, heme, Complex Lipids, creatine, and Other Compounds. Many of these reactions will be discussed in subsequent chapters of the textbook.

Enzymes whose coenzymes are Folic acid derivatives play a central role in serine and glycine transformations. This vitamin is widely distributed in animal and plant foods. The folic acid (folate) molecule consists of three parts: a pteridine derivative, p-aminobenzoic acid, and glutamic acid:

Folic acid (folate) is also referred to as pteroylglutamic acid. Pterins are widely distributed in nature. Some of them, such as xanthopterin, serve as pigments in insect (butterfly) eyes and wings.

The reduced form of folate, tetrahydrofolic acid (THFA, or H₄-folate), acts as the coenzyme:

Folic acid is converted into H₄-folate in the liver through several stages involving folate reductase and Dihydrofolate Reductase, with NADPH serving as the coenzyme.

H₄-folate acts as an acceptor for the β-carbon atom of serine. This reaction forms a methylene bridge between the nitrogen atoms at positions 5 and 10 of the H₄-folate molecule, yielding methylene-H₄-folate:

The special significance of serine and glycine catabolism lies in the fact that it yields a single-carbon methylene fragment (-CH₂-). The methylene group in the methylene-H₄-folate molecule can be converted into other one-carbon groups (fragments): methenyl, formyl, methyl, and formimino groups (Fig. 6.25).

Fig. 6.25. Formation of H₄-folate derivatives

Another source of formyl and formimino groups is Histidine. The catabolism of histidine occurs mainly in the liver (with a very small percentage in the Skin) through the following reactions:

The End products of Histidine Catabolism are glutamate, NH₃, and one-carbon units, specifically formimino-H₄-folate and formyl-H₄-folate.

All the resulting H₄-folate derivatives act as intermediate carriers and serve as Donors of one-carbon units in the synthesis of several compounds, such as purine bases and thymidylic acid (which are essential for DNA and RNA Synthesis), in the regeneration of Methionine, and in the synthesis of various formimino derivatives (such as formiminoglycine) (Fig. 6.26). Consequently, The transfer of one-carbon units to an acceptor is necessary for synthesizing A number of compounds and for regenerating free H₄-folate in the liver.

Folic acid is a vitamin for humans and animals. However, many pathogenic Bacteria are able to synthesize this compound using Para-aminobenzoic Acid (PABA), which is a constituent part of folate. PABA enters bacterial Cells from the external environment. Sulfonamide drugs—derivatives of sulfonamide (white streptocide)—are structurally similar to para-aminobenzoic acid. They differ only in their radicals:

Fig. 6.26. Formation and utilization of H₄-folate derivatives

These drugs inhibit the synthesis of folic acid in bacteria because they:

✵ competitively inhibit bacterial folate-synthesizing enzymes, as they act as structural analogs of para-aminobenzoic acid, one of the process substrates;

✵ can act as pseudosubstrates due to the relative substrate Specificity of the enzymes, resulting in the synthesis of a compound that resembles folic acid but is unable to perform its functions.

In both cases, one-carbon METABOLISM and, consequently, nucleic acid synthesis are disrupted in bacterial cells, thereby halting bacterial reproduction. In the patient's cells, sulfonamide drugs do not cause similar changes because humans obtain preformed folic acid from their diet.

Today, several disorders associated with impaired glycine metabolism are known. Their causes include enzymatic deficiencies or defects in the transport system for this amino acid. Let us consider some of these disorders.

Hyperglycinemia is characterized by an elevated concentration of glycine in the Blood due to a defect in the glycine cleavage enzyme system. The most severe manifestations of hyperglycinemia include rapid Brain damage, seizures, hypotonia, and respiratory disorders.

Glycinuria is characterized by increased urinary excretion of glycine (up to 1 g/day) while blood levels remain normal. One of the symptoms of this condition is The formation of oxalate Kidney stones, whereas the urinary oxalate content remains within the normal range. The excess oxalate is of endogenous origin, most likely formed from glycine through deamination, which yields glyoxylate—the precursor of oxalate. The metabolic effect presumably involves a disruption in glyoxylate metabolism, namely the inability to convert it back into glycine due to a defect in glycine aminotransferase. The cause of glycinuria is apparently impaired renal reabsorption of glycine. This pathology is inherited as a dominant trait, likely linked to the X chromosome.

Primary hyperoxaluria is characterized by persistently high urinary oxalate excretion, regardless of dietary intake. Over time, bilateral oxalate stone formation in the Urinary Tract progresses, leading to nephrocalcinosis and urinary tract infections. Affected children typically die at an early age from renal failure or Hypertension.