Glycine

The glycine cleavage system of liver mitochondria splits glycine to CO2 and NH4 + and formsN5,N10-methylene tetrahydrofolate.

Glycine + H4 folate + NAD+ → CO₂ + NH₃⁺

5,10-CH2-H4 folate + NADH + H+

The glycine cleavage complex (Figure 1) consists of three enzymes and an “H-protein” that has a covalently attached dihydrolipoyl moiety. Figure 1 also illustrates the individual reactions and intermediates in glycine cleavage. In nonketotic hyperglycinemia, a rare inborn error of glycine degradation, glycine accumulates in all body tissues including the central nervous system. The defect in primary hyperoxaluria is the failure to catabolize glyoxylate formed by the deamination of glycine. Subsequent oxidation of glyoxylate to oxalate results in urolithiasis, nephrocalcinosis, and early mortality from renal failure or hypertension. Glycinuria results from a defect in renal tubular reabsorption.

Fig1. The glycine cleavage system of liver mitochondria. The glycine cleavage complex consists of three enzymes and an “H-protein” that has covalently attached dihyrolipoate. Catalysts for the numbered reactions are 1 glycine dehydrogenase (decarboxylating), 2 an ammonia-forming aminomethyltransferase, and 3 dihydrolipoamide dehydrogenase. (H4 folate, tetrahydrofolate).

Serine

Following conversion to glycine, catalyzed by glycine hydroxy methyltransferase (EC 2.1.2.1), serine catabolism merges with that of glycine (Figure 2).

Fig2. Interconversion of serine and glycine by glycine hydroxymethyltransferase. (H₄ folate, tetrahydrofolate.)

Alanine

Transamination of α-alanine forms pyruvate. Probably on account of its central role in metabolism, there is no known viable metabolic defect of α-alanine catabolism.

Cystine & Cysteine

Cystine is first reduced to cysteine by cystine reductase, EC 1.8.1.6 (Figure 3). Two different pathways then con vert cysteine to pyruvate (Figure 4). There are numerous abnormalities of cysteine metabolism. Cystine, lysine, arginine, and ornithine are excreted in cystine-lysinuria (cystinuria), a defect in renal reabsorption of these amino acids. Apart from cystine calculi, cystinuria is benign. The mixed disulfide of l-cysteine and l-homocysteine (Figure 5) excreted by cystinuric patients is more soluble than cystine and reduces formation of cystine calculi.

Fig3. Reduction of cystine to cysteine by cystine reductase.

Fig4. Two pathways catabolize cysteine: the cysteine sulfinate pathway (top) and the 3-mercaptopyruvate pathway (bottom).

Fig5. Structure of the mixed disulfide of cysteine and homocysteine.

Several metabolic defects result in vitamin B6-responsive or vitamin B6-unresponsive homocystinurias. These include a deficiency in the reaction catalyzed by cystathionine β-synthase, EC 4.2.1.22:

Serine + homocysteine → cystathionine + H2O

Consequences include osteoporosis and mental retardation. Defective carrier-mediated transport of cystine results in cystinosis (cystine storage disease) with deposition of cystine crystals in tissues and early mortality from acute renal failure. Epidemiologic and other data link plasma homocysteine levels to cardiovascular risk, but the role of homocysteine as a causal cardiovascular risk factor remains controversial.

Threonine

 Threonine aldolase (EC 4.1.2.5) cleaves threonine to glycine and acetaldehyde. Catabolism of glycine is discussed earlier. Oxidation of acetaldehyde to acetate is followed by formation of acetyl-CoA (Figure 6).

Fig6. Intermediates in the conversion of threonine to glycine and acetyl-CoA.

4-Hydroxyproline

 Catabolism of 4-hydroxy-l-proline forms, successively, l-Δ¹ pyrroline-3-hydroxy-5-carboxylate, γ-hydroxy-l-glutamate-γ semialdehyde, erythro-γ-hydroxy-l-glutamate, and α-keto-γ hydroxyglutarate. An aldol-type cleavage then forms glyoxylate plus pyruvate (Figure 7). A defect in4-hydroxyproline dehydrogenase results in hyperhydroxyprolinemia, which is benign. There is no associated impairment of proline catabolism. A defect in glutamate-γ-semialdehyde dehydrogenase is accompanied by excretion of Δ¹-pyrroline-3-hydroxy-5-carboxylate.

Fig7. Intermediates in hydroxyproline catabolism. (α-AA, α-amino acid; α-KA, α-keto acid.) Red bars indicate the sites of the inherited metabolic defects in 1 hyperhydroxyprolinemia and 2 type II hyperprolinemia.

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مواضيع ذات صلة

Transamination Typically Initiates amino acid Catabolism

Metabolic Disorders are Associated with Each Reaction of The Urea Cycle

Amino Acid Oxidases Remove Nitrogen as Ammonia

Biosynthesis of Urea

Interorgan Exchange Maintains Circulating Levels of Amino Acids

ATP & Ubiquitin-Dependent Degradation

Biosynthesis of the Nutritionally Nonessential Amino Acids

Nutritionally Essential & Nutritionally Nonessential Amino Acids

Cholesterol Synthesis, Transport, & Excretion: Clinical Aspects

Cholesterol is Excreted from The Body in The Bile as Cholesterol or as Bile Acids

Cholesterol is Transported Between Tissue in Plasma Lipoproteins

The Cholesterol Balance in Tissues is Tightly Regulated