Pathways of Amino Acid Degradation:- Six Amino Acids Are Degraded to Pyruvate
The carbon skeletons of six amino acids are converted in whole or in part to pyruvate. The pyruvate can then be converted to either acetyl-CoA (a ketone body precursor) or oxaloacetate (a precursor for gluconeogenesis). Thus, amino acids catabolized to pyruvate are both ketogenic and glucogenic. The six are alanine, tryptophan, cysteine, serine, glycine, and threonine (Fig. 18–19). Alanineyields pyruvate directly on transamination with α-ketoglutarate, and the side chain of tryptophan is cleaved to yield alanine and thus pyruvate. Cysteine is converted to pyruvate in two steps; one removes the sulfur atom; the other is a transamination. Serine is converted to pyruvate by serine dehydratase. Both the β-hydroxyl and the -amino groups of serine are re moved in this single pyridoxal phosphate–dependent re action (Fig. 18–20a). Glycine is degraded via three pathways, only one of which leads to pyruvate. Glycine is converted to ser ine by enzymatic addition of a hydroxymethyl group (Figs 18–19 and 18–20b). This reaction, catalyzed by serine hydroxymethyl transferase, requires the coenzymes tetrahydrofolate and pyridoxal phosphate. The serine is converted to pyruvate as described above. In the second pathway, which predominates in animals, glycine undergoes oxidative cleavage to CO2, NH+4, and a methylene group (-CH2-) (Fig. 18–19). This readily reversible reaction, catalyzed by glycine cleavage enzyme (also called glycine synthase), also requires tetrahydrofolate, which accepts the methylene group. In this oxidative cleavage pathway the two carbon atoms of glycine do not enter the citric acid cycle. One carbon is lost as CO2 and the other becomes the methylene group of N5,N10-methylenetetrahydrofolate (Fig.18–17), a one carbon group donor in certain biosynthetic pathways. This second pathway for glycine degradation ap pears to be critical in mammals. Humans with serious defects in glycine cleavage enzyme activity suffer from a condition known as nonketotic hyperglycinemia. The condition is characterized by elevated serum levels of glycine, leading to severe mental deficiencies and death in very early childhood. At high levels, glycine is an inhibitory neurotransmitter, perhaps explaining the neurological effects of the disease. Many genetic defects of amino acid metabolism have been identified in hu mans (Table 18–2). We will encounter several more in this chapter. ■ In the third and final pathway of glycine degradation, the achiral glycine molecule is a substrate for the enzyme D-amino acid oxidase. The glycine is converted to glyoxylate, an alternative substrate for hepatic lactate
FIGURE 18–19 Catabolic pathways for alanine, glycine, serine, cysteine, tryptophan, and threonine. The fate of the indole group of tryptophan is shown in Figure 18–21. Details of most of the reactions involving serine and glycine are shown in Figure 18–20. The pathway for threonine degradation shown here accounts for only about a third of threonine catabolism (for the alternative pathway, see Fig. 18–27). Several pathways for cysteine degradation lead to pyruvate. The sulfur of cysteine has several alternative fates, one of which is shown in Figure 22–15. Carbon atoms here and in subsequent figures are color-coded as necessary to trace their fates.
MECHANISM FIGURE 18–20 Interplay of the pyridoxal phosphate and tetrahydrofolate cofactors in serine and glycine metabolism. The first step in each of these reactions (not shown) involves the formation of a covalent imine linkage between enzyme-bound PLP and the substrate amino acid—serine in (a), glycine in (b)and (c).(a)The serine dehydratase reaction entails a PLP-catalyzed elimination of water across the bond between the and β carbons (step 1), leading eventually to the production of pyruvate (steps 2 through 4). (b) In the serine hydroxy methyltransferase reaction, a PLP-stabilized carbanion on the carbon of glycine (product of step 1) is a key intermediate in the transfer of the methylene group (as-CH2-OH) from N5, N10 methylenetetrahydrofolate to form serine. This reaction is reversible. (c)The glycine cleavage enzyme is a multienzyme complex, with com ponents P, H, T, and L. The overall reaction, which is reversible, con verts glycine to CO2and NH4, with the second glycine carbon taken up by tetrahydrofolate to form N5, N10 -methylenetetrahydrofolate. Pyridoxal phosphate activates the carbon of amino acids at critical stages in all these reactions, and tetrahydrofolate carries one-carbon units in two of them.
dehydrogenase (p. 538). Glyoxylate is oxidized in an NAD-dependent reaction to oxalate:
The primary function of D-amino acid oxidase, present at high levels in the kidney, is thought to be the detoxification of ingested D-amino acids derived from bacterial cell walls and from cooked foodstuffs (heat causes some spontaneous racemization of the L amino acids in proteins). Oxalate, whether obtained in foods or produced enzymatically in the kidneys, has medical significance. Crystals of calcium oxalate account for up to 75% of all kidney stones. There are two significant pathways for threonine degradation. One pathway leads to pyruvate via glycine (Fig. 18–19). The conversion to glycine occurs in two steps, with threonine first converted to 2-amino-3- ketobutyrate by the action of threonine dehydrogenase. This is a relatively minor pathway in humans, accounting for 10% to 30% of threonine catabolism, but is more important in some other mammals. The major pathway in humans leads to succinyl-CoA and is described later. In the laboratory, serine hydroxy methyltransferase will catalyze the conversion of threonine to glycine and acetaldehyde in one step, but this is not a significant pathway for threonine degradation in mammals.
