Six Amino Acids Form Pyruvate

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

L-Proline

L-Proline

PROLINE DEHYDROGENASE

II II

L-Glutamate-y-semialdehyde

GLUTAMATE SEMIALDEHYDE DEHYDROGENASE

NAD+

L-Glutamate

a-Ketoglutarate

"CH2

L-Arginine

Urea

ARGINASE

L-Glutamate-y-semialdehyde

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.

CH2 C

h3N+ HN^NH

L-Histidine

HN NH

Urocanate

UROCANASE

HN NH

4-Imidazolone-5-propionate

IMIDAZOLONE PROPIONATE HYDROLASE

C CH

OO W-Formiminoglutamate (Figlu)

H4 folate

GLUTAMATE FORMIMINO TRANSFERASE

N5-Formimino ^ H4 folate

L-Glutamate \

a-Ketoglutarate

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.

HISTIDASE

NH3+

NH3+

H4 folate

Methylene H4 folate n3

NH3+

L-Serine

Glycine

Figure 30-5. Interconversion of serine and glycine catalyzed by serine hydroxymethyltransferase. (H4fo-late, tetrahydrofolate.)

Glycine

H4 folate ^N5,N10-CH2-H4 folate

Figure 30-6. Reversible cleavage of glycine by the mitochondrial glycine synthase complex. (PLP, pyri-doxal phosphate.)

NAD+

L-Cystine

NAD+

I II

SH O L-Cysteine

Figure 30-7. The cystine reductase reaction.

Cysteine H2C

CYSTEINE DIOXYGENASE

Cysteine sulfinate 21

-O2S

NH3+

TRANSAMINASE

a-Keto acid

^ a-Amino acid

Sulfinylpyruvate

DESULFINASE

Pyruvate

CYSTEINE

TRANSAMINASE

3-Mercaptopyruvate

(thiolpyruvate) h2C" "C 2' II O

Pyruvate

H2S NAD

3-Mercaptolactate

Figure 30-8. Catabolism of L-cysteine via the cysteine sulfinate pathway (top) and by the 3-mercaptopy-ruvate pathway (bottom).

NH3+

NH3+

NH3+

CH2 S S CH2

ch2 2

COO-

COO-

(Cysteine) (Homocysteine)

Figure 30-9. Mixed disulfide of cysteine and homocysteine.

OH O

L-Threonine

THREONINE ALDOLASE

Glycine

H3C.

"CH

II O

Acetaldehyde

H2O-

ALDEHYDE DEHYDROGENASE

NADH+H+

Acetate

ACETATE THIOKINASE

Mg-ADP

Acetyl-CoA

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.

4-Hydroxy-L-proline

HYDROXYPROLINE DEHYDROGENASE

II O

L-A1-Pyrroline-3-hydroxy-5-carboxylate

NONENZYMATIC

OH NH3+

HC CH2 C

y-Hydroxy-L-glutamate-y-semialdehyde

NAD+ H2O

jtamate-y-semii

DEHYDROGENASE

CH O

C CH2 C

Erythro-y-hydroxy-L-glutamate a-KA

a-AA

TRANSAMINASE

II II

o o a-Keto-y-hydroxyglutarate

AN ALDOLASE

Glyoxylate o II

II o

Pyruvate o o

NH3+

H3C^O

Fe2"

NH3+

L-Tyrosine

TYROSINE TRANSAMINASE

TYROSINE TRANSAMINASE

p-HYDROXYPHENYLPYRUVATE HYDROXYLASE

p-Hydroxyphenylpyruvate

p-HYDROXYPHENYLPYRUVATE HYDROXYLASE

p-Hydroxyphenylpyruvate

HOMOGENTISATE OXIDASE

11

= f 4

O

Maleylacetoacetate

Maleylacetoacetate

(rewritten)

Glutathione

O OH

Homogentisate

MALEYLACETOACETATE CIS, TRANS ISOMERASE

Fumarylacetoacetate

FUMARYLACETOACETATE HYDROLASE

II 6

C CH

Fumarate

CoASH

CC II II

Acetoacetate

ß-KETOTHIOLASE

H3C.

Acetyl-CoA

Acetate

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.

epidemiologic data suggesting a relationship between plasma homocysteine and cardiovascular disease, whether homocysteine represents a causal cardiovascular risk factor remains controversial.

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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