Isovaleryl-CoA

Reaction 3 is analogous to the dehydrogenation of fatty acyl-CoA thioesters (see Figure 22—3). In isovaleric acidemia, ingestion of protein-rich foods elevates isovalerate, the deacylation product of isovaleryl-CoA. Figures 30-20, 30-21, and 30-22 illustrate the subsequent reactions unique to each amino acid skeleton. 

Mutation of the dihydrolipoate reductase component impairs decarboxylation of branched-chain a-keto acids, of pyruvate, and of a-ketoglutarate. In intermittent branched-chain ketonuria, the a-keto acid decarboxylase retains some activity, and symptoms occur later in life. The impaired enzyme in isovaleric acidemia is isovaleryl-CoA dehydrogenase (reaction 3, Figure 30-19). Vomiting, acidosis, and coma follow ingestion of excess protein. Accumulated... 

Glycine to promote acylation of isovaleryl-CoA Infancy vomiting, metabolic acidosis, hyperlactatemia, convulsions, coma... 

IMIDAZOLEACETATE HYDROXYLASE ISOVALERYL-CoA DEHYDROGENASE KYNURENINE 3-HYDROXYLASE d-LACTATE DEHYDROGENASE (CYTOCHROME)... 

For every step of the P oxidation sequence there is a small family of enzymes with differing chain length preferences.6 7 For example, in liver mitochondria one acyl-CoA dehydrogenase acts most rapidly on M-butyryl and other short-chain acyl-CoA a second prefers a substrate of medium chain length such as n-octanoyl-CoA a third prefers long-chain substrates such as pal-mitoyl-CoA and a fourth, substrates with 2-methyl branches. A fifth enzyme acts specifically on isovaleryl-CoA. Similar preferences exist for the other enzymes of the P oxidation pathway. In Escherichia coli... 

Leucine Isovaleric acidemia Neonatal vomiting, acidosis, lethargy, and coma survivors mentally retarded Isovaleryl-CoA dehydrogenase... 

Two acyl-CoA amino acid A-acyltransferases have been purified from liver mitochondria of cattle, Rhesus monkeys, and humans. One is a benzoyltransferase CoA that utilizes benzyl-CoA, isovaleryl-CoA, and tiglyl-CoA, but not phenylacetyl CoA, malonyl-CoA, or indolacetyl-CoA. The other is a phenylacetyl transferase that utilizes phenylacetyl-CoA and indolacetyl-CoA but is inactive toward benzoyl-CoA. Neither is specific for glycine, as had been supposed from studies using less defined systems both also utilize asparagine and glutamine, although at lesser rates than glycine. 

Figure 11 The putative catabolic pathway of L-leucine and its implications for strain improvement. For a promising host strain, the pathway to be blocked is indicated with thick double lines and the pathways to be fortified are indicated with thick arrows. Abbreviations for enzymes participating in the L-leucine catabolism and the acylation of tylosin VDH, valine (branched-chain amino acid) dehydrogenase BCDFI, branched-chain a-keto acid dehydrogenase IVD (AcdH), isovaleryl-CoA dehydrogenase (acyl-CoA dehydrogenase) MCC, 3-methylcrotonyl-CoA carboxylase EH, enoyl-CoA hydratase AcyA, mac-rolide 3-O-acyltransferase AcyBl, macrolide 4"-(9-acyltransferase.

Poston (1984) showed that, in isolated rat tissues, about 5% of the catabolic flux of leucine was by way of aminomutase action to yield /S-leucine, and then isobutyryl CoA, with the remainder provided by the more conventional a-transamination pathway leading to the formation of isovaleryl CoA. In patients suffering from vitamin B12 deficiency, there is an elevation of plasma /S-leucine, suggesting that the aminomutase may act to metabolize /S -leucine arising from intestinal bacteria, rather than as a pathway for leucine catabolism. 

The degradation of the hranched-chain amino acids employs reactions that we have encountered previously in the citric acid cycle and fatty acid oxidation. Leucine is transaminated to the corresponding a-ketoacid, a-ketoisocaproate. This a-ketoacid is oxidatively decarboxylated to isovaleryl CoA by the branched-chain a-ketoacid dehydrogenase complex. 

The isovaleryl CoA derived from leucine is dehydrogenated to yield -methylcrotonyl CoA. This oxidation is catalyzed by isovaleryl CoA dehydrogenase. The hydrogen acceptor is FAD, as in the analogous reaction in fatty acid oxidation that is catalyzed by acyl CoA dehydrogenase. -Methylglutaconyl CoA is then formed by the carboxylation of P-methylcrotonyl CoA at the expense of the hydrolysis of a molecule of ATP. As might be expected, the carboxylation mechanism of P-methylcrotonyl CoA carboxylase is similar to that of pyruvate carboxylase and acetyl CoA carboxylase. 

Therapeutic glycine. Isovaleric acidemia is an inherited disorder of leucine metabolism caused by a deficiency of isovaleryl CoA dehydrogenase. Many infants having this disease die in the first month of life. The administration of large amounts of glycine sometimes leads to marked clinical improvement. Propose a mechanism for the therapeutic action of glycine. 

The normal branched chain isovaleryl CoA (149) is then desaturated to the a,)3-enonyl CoA (150) by a flavin-linked branched chain acyl CoA dehydrogenase (equation 24). When the methylenecyclopropane acyl CoA (151) is exposed to acyl CoA dehydrogenase, time-dependent inactivation ensues with covalent modification of the bound FAD coenzyme (equation 25), possibly via a 6,5-adduct although the structure is unproven. ... 

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