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FCH 532 Lecture 23. Chapter 26: Amino acid metabolism. Alanine aminotransferase Serine dehydratase Glycine cleavage system 4, 5. Serine hydroxymethyl-transferase Threonine dehydrogenase -amino- -ketobutyrate lyase. Page 996. Serine dehydratase.
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FCH 532 Lecture 23 Chapter 26: Amino acid metabolism
Alanine aminotransferase • Serine dehydratase • Glycine cleavage system 4, 5. Serine hydroxymethyl-transferase • Threonine dehydrogenase • -amino--ketobutyrate lyase. Page 996
Serine dehydratase • PLP-enzyme forms a PLP-amino acid Schiff base (like transamination) catalyzes removal of the amino-acid’s hydrogen. • Substrate loses the -OH group undergoing an elimination of H2O rather than deamination. • Aminoacrylate, the product of this dehydration reaction, tautomerizes to the imine which hydrolyzes to pyruvate and ammonia.
Figure 26-13 The serine dehydratase reaction. Page 997 1. Formation of Ser-PLP Schiff base, 2. Removal of the -H atom of serine, 3. elimination of OH-, 4. Hydrolysis of Schiff base, 5. Nonenzymatic tautomerization to the imine, 6. Nonenzymatic hydrolysis to form pyruvate and ammonia.
Alanine aminotransferase • Serine dehydratase • Glycine cleavage system 4, 5. Serine hydroxymethyl-transferase • Threonine dehydrogenase • -amino--ketobutyrate lyase. Page 996
Glycine conversion to pyruvate • Gly is converted to Ser before it is transformed to pyruvate. • Gly to serine is catalyzed by serine hydroxymethyltransferase (another PLP) enzyme that also uses N5, N10-methylene-tetrahydrofolate (N5, N10-methylene-THF) cofactor to proved the C1 unit necessary for this conversion. • The methylene group is derived from another Gly and the remaining parts are released as CO2 and ammonia catalyzed by the glycine cleavage system
Figure 26-14 The reactions catalyzed by the glycine cleavage system, a multienzyme complex. PLP-dependent glycine decarboxylase (P-protein) Lipoamide-containing protein (H-protein) THF requiring enzyme (T-protein) NAD+-dependent, FAD-requiring dihydrolipoyl dehydrogense (L-protein) Page 997
B: O H H H3C-HC--C-COO- N H H C O- 2-O3PO + N CH3 H Serine hydroxymethyltransferase catalyzes PLP-dependent C-C cleavage • Catalyzes the conversion of Thr to Gly and acetaldehyde • Cleaves C-C bond by delocalizing electrons of the resulting carbanion into the conjugated PLP ring:
Asn and Asp are degraded to OAA O H • Asp can be converted to Asp by L-asparaginase: O Asparagine C-CH2-C-C-O- H2N NH3+ H2O L-asparaginase NH4+ O H O Aspartate C-CH2-C-C-O- -O NH3+
Asn and Asp are degraded to OAA O H • Transamination of aspartate to oxaloacetate: O Aspartate C-CH2-C-C-O- -O NH3+ -ketoglutarate aminotransferse glutamate O O Oxaloacetate C-CH2-C-C-O- -O O
Arg, Glu, Gln, His, and Pro are degraded to -KG • Arg, Gln, His, and Pro are converted to Glu which is oxidized to -ketoglutarate by glutamate dehydrogenase. • Gln to Glu is catalyzed by glutaminase • His requires several reactions to get to Glu.
Figure 26-17 Degradation pathways of arginine, glutamate, glutamine, histidine, and proline to -ketoglutarate. Page 1001
Gln to Glu to -KG 2. Glutaminase 1. Glutamate dehydrogense Page 1001
His to Glu His is nonoxidatively deaminated, hydrated, and the imidazole ring is cleaved to form N-formiminoglutamate 8. Histidine ammonia lyase Urocanate hydratase Imidazolone proponase Glutamate formiminotransferase Page 1001
3. Arginase 4. Ornithine--aminotransferase 5. Glutamate-5-semialdehyde dehydrogenase Proline oxidase Spontaneous Arg and Pro to Glu Page 1001
Ile, Met and Val are degraded to succinyl-CoA • Ile, Met, and Val are degraded to propionyl-CoA • Propioyl-CoA is a product of odd-chain fatty acid degradation that is converted to succinyl-CoA via propionyl-CoA carboxylase (biotin cofactor), methylmalonyl-CoA racemase, and methylmalonyl-CoA mutase (B12 cofactor). • See Ch. 25-2E for review.
Figure 25-18 Conversion of propionyl-CoA to succinyl-CoA. Page 922
Met degradation • Met reacts with ATP to form S-adenosylmethionine (SAM). • SAM’s sulfonium ion is a highly reactive methyl group so this compound is involved in methylation reactions. • Methylation reactions catalyzed by SAM yield S-adenosylhomocysteine and a methylated acceptor molecule. • S-adenosylhomocysteine is hydrolyzed to homocysteine. • Homocysteine may be methylated to regenerate Met, in a B12 requiring reaction with N5-methyl-THF as the methyl donor. • Homocysteine can also combine with Ser to form cystathionine in a PLP catalyzed reaction and -ketobutyrate. • -ketobutyrate is oxidized and CO2 is released to yield propionyl-CoA. • Propionyl-CoA proceeds thorugh to succinyl-CoA.
Methionine adenosyltransferase Methyltransferase Adenosylhomocysteinase Methionine synthase (B12) Cystathionine -synthase (PLP) Cystathionine -synthase (PLP) -ketoacid dehydrogenase Propionyl-CoA carboxylase (biotin) Methylmalonyl-CoA racemase Methylmalonyl-CoA mutase Glycine cleavage system or serine hydroxymethyltransferase N5,N10-methylene-tetrahydrofolate reductase (coenzyme B12 and FAD) Page 1002
Figure 25-18 Conversion of propionyl-CoA to succinyl-CoA. Page 922
Ile, Met and Val are degraded to succinyl-CoA • Ile, Met, and Val are degraded to propionyl-CoA • Propioyl-CoA is a product of odd-chain fatty acid degradation that is converted to succinyl-CoA via propionyl-CoA carboxylase (biotin cofactor), methylmalonyl-CoA racemase, and methylmalonyl-CoA mutase (B12 cofactor). • See Ch. 25-2E for review.
Branched chain amino acid degradation • Degradation of Ile, Leu, and Val use common enzymes for the first three steps • Transamination to the corresponding -keto acid • Oxidative decarboxylation to the corresponding acyl-CoA • Dehydrogenation by FAD to form a double bond. First three enzymes • Branched-chain amino acid aminotransferase • Branched-chain keto acid dehydrogenase (BCKDH) • Acyl-CoA dehydrogeanse
Figure 26-21 The degradation of the branched-chain amino acids (A) isoleucine, (B) valine, and (C) leucine. Page 1004
After the three steps, for Ile, the pathway continues similar to fatty acid oxidation (propionyl-CoA carboxylase, methylmalonyl-CoA racemase, methylmalonyl-CoA mutase). • Enoyl-CoA hydratase - double bond hydration • -hydroxyacyl-CoA dehydrogenase- dehydrognation by NAD+ • Acetyl-CoA acetyltransferase - thiolytic cleavage Page 1004
For Valine: • Enoyl-CoA hydratase - double bond hydration • -hydroxy-isobutyryl-CoA hydrolase -hydrolysis of CoA • hydroxyisobutyrate dehydrogenase - second dehydration • Methylmalonate semialdehyde dehydrogenase - oxidative carboxylation Last 3 steps similar to fatty acid oxidation Page 1004
For Leucine: • -methylcronyl-CoA carboxylase-carboxylation reaction (biotin) • -methylglutaconyl-CoA hydratase-hydration reaction • HMG-CoA lyase Acetoacetate can be converted to 2 acetyl-CoA Leucine is a ketogenic amino acid! Page 1004
Lys is also ketogenic • Leu proceeds through a typical branched amino acid breakdown but the final products are acetyl-CoA and acetoacetate. • Most common Lys degradative pathway in liver goes through the formation of the -ketoglutarate-lysine adduct saccharopine. • 7 of 11 reactions are found in other pathways. • Reaction 4: PLP-dependent transamination • Reaction 5: oxidative decarboxylation of an a-keto acid by a multienzyme complex similar to pyruvate dehydragense and a-ketoglutarate dehydrogenase. • Reactions 6,8,9: fatty acyl-CoA oxidation. • Reactions 10 and 11 are standard ketone body formation reactions.
