All of the carbons of glycine, serine, alanine, and cys-teine and two carbons of threonine form pyruvate and subsequently acetyl-CoA.
Glycine. The glycine synthase complex of liver mitochondria splits glycine to CO2 and NH4+ and forms N5,N 10-methylene tetrahydrofolate (Figure 30-5).
Glycinuria results from a defect in renal tubular reabsorption. The defect in primary hyperoxaluria is the failure to catabolize glyoxylate formed by deamination of glycine. Subsequent oxidation of glyoxylate to oxalate results in urolithiasis, nephrocalcinosis, and early mortality from renal failure or hypertension.
Serine. Following conversion to glycine, catalyzed by serine hydroxymethyltransferase (Figure 30-5), serine catabolism merges with that of glycine (Figure 30-6).
Alanine. Transamination of alanine forms pyru-vate. Perhaps for the reason advanced under glutamate and aspartate catabolism, there is no known metabolic defect of alanine catabolism. Cysteine. Cystine is first reduced to cysteine by cystine reductase (Figure 30-7). Two different pathways then convert cysteine to pyruvate (Figure 30-8).
There are numerous abnormalities of cysteine metabolism. Cystine, lysine, arginine, and ornithine are excreted in cystine-lysinuria (cystinuria), a defect in renal reabsorption. Apart from cystine calculi, cystin-uria is benign. The mixed disulfide of L-cysteine and L-homocysteine (Figure 30-9) excreted by cystinuric patients is more soluble than cystine and reduces formation of cystine calculi. Several metabolic defects result in vitamin B6-responsive or -unresponsive ho-mocystinurias. 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. Despite
GLUTAMATE SEMIALDEHYDE DEHYDROGENASE
Figure 30-3. Top: Catabolism of proline. Numerals indicate sites of the metabolic defects in © type I and © type II hyper-prolinemias. Bottom: Catabolism of arginine. Glutamate-y-semialdehyde forms a-ketoglutarate as shown above. ©, site of the metabolic defect in hyperargininemia.
IMIDAZOLONE PROPIONATE HYDROLASE
OO W-Formiminoglutamate (Figlu)
GLUTAMATE FORMIMINO TRANSFERASE
N5-Formimino ^ H4 folate
Figure 30-4. Catabolism of L-histidine to a-ketoglu-tarate. (H4 folate, tetrahydrofolate.) Histidase is the probable site of the metabolic defect in histidinemia.
Methylene H4 folate n3
Figure 30-5. Interconversion of serine and glycine catalyzed by serine hydroxymethyltransferase. (H4fo-late, tetrahydrofolate.)
H4 folate ^N5,N10-CH2-H4 folate
Figure 30-6. Reversible cleavage of glycine by the mitochondrial glycine synthase complex. (PLP, pyri-doxal phosphate.)
SH O L-Cysteine
Figure 30-7. The cystine reductase reaction.
Cysteine sulfinate 21
^ a-Amino acid
(thiolpyruvate) h2C" "C 2' II O
Figure 30-8. Catabolism of L-cysteine via the cysteine sulfinate pathway (top) and by the 3-mercaptopy-ruvate pathway (bottom).
CH2 S S CH2
Figure 30-9. Mixed disulfide of cysteine and homocysteine.
Figure 30-10. Conversion of threonine to glycine (see Figure 30-6) and acetyl-CoA.
Figure 30-11. Intermediates in L-hydroxyproline catabolism. (a-KA, a-keto acid; a-AA, a-amino acid.) Numerals identify sites of metabolic defects in © hyperhydroxyprolinemia and © type II hyperprolinemia.
HC CH2 C
C CH2 C
o o a-Keto-y-hydroxyglutarate
Glyoxylate o II
Pyruvate o o
= f 4
MALEYLACETOACETATE CIS, TRANS ISOMERASE
CC II II
Figure 30-12. Intermediates in tyrosine catabolism. Carbons are numbered to emphasize their ultimate fate. (a-KG, a-ketoglutarate; Glu, glutamate; PLP, pyridoxal phosphate.) Circled numerals represent the probable sites of the metabolic defects in © type II tyrosinemia; © neonatal tyrosinemia; © alkaptonuria; and © type I tyrosinemia, or tyrosinosis.
Threonine. Threonine is cleaved to acetaldehyde and glycine. Oxidation of acetaldehyde to acetate is followed by formation of acetyl-CoA (Figure 30-10). Ca-tabolism of glycine is discussed above.
4-Hydroxyproline. Catabolism of 4-hydroxy-L-pro-line forms, successively, L-A1-pyrroline-3-hydroxy-5-car-boxylate, y-hydroxy-L-glutamate-y-semialdehyde, erythro-y-hydroxy-L-glutamate, and a-keto-y-hydroxyglutarate. An aldol-type cleavage then forms glyoxylate plus pyru-vate (Figure 30-11). A defect in 4-hydroxyproline dehydrogenase results in hyperhydroxyprolinemia, which is benign. There is no associated impairment of proline catabolism.
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