Isovaleryl-CoA dehydrogenase

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... 

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

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

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.

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. 

Isovaleric acidemia (IVA) is a disorder of leucine catabolism caused by a deficiency of isovaleryl-CoA dehydrogenase. Since the initial report 40 years ago, IVA has been the main focus of the work of Dr. Kay Tanaka, one of the pioneers and arguably most productive contributors to our current... 

In addition to the four acyl-CoA dehydrogenases involved in fatty acid oxidation, three acyl-CoA dehydrogenases specific for metabolites of branched-chain amino acids have been characterized, niey are isovaleryl-CoA dehydrogenase, 2-methyl-branched-chain acyl-CoA dehydrogenase, and isobutyryl-CoA dehydrogenase, which may also function in the P-oxidation of branched-chain carboxylic acids. 

Isovaleric acidemia is a rare disorder of leucine metabolism caused by the deficiency of isovaleryl-CoA dehydrogenase this leads to mild neurological impairment and, at its severest, to coma and death. Dietary management aims to hmit leucine intake by means of a low-protein diet, and by supplementing the diet with a leucine-free amino acid mixture if necessary. 

Parimoo, B. Tanaka, K. (1993) Genomics 15, 582-590. Structual organization of the human isovaleryl-CoA dehydrogenase gene. 

IVA was initially described in 1966 and became the first organic acidemia described. IVA is caused by a deficiency of the enzyme isovaleryl-CoA dehydrogenase, an enzyme important in leucine catabolism and also important in the transfer of electrons to the respiratory chain [7, 13]. The consequent accumulating metabolites include isovaleric add, isovalerylglydne, 3-hydroxyisovaleric acid, and isovalerylcamitine (C5) [7, 13] (Fig. 17.3). These are easily identified on urine organic acid analysis and acylcamitine profile. The excretion of isovalerylglydne and 3-hydroxyisovaleric acid is diagnostic. 

Isovaleryl-CoA dehydrogenase (EC 1.3.99.10). Defective conversion of isovaleryl-CoA to methylcro-tonyl-CoA (see Leudne). Elevated isovalerate in plasma and urine also increased urinary isovaleryl-glydne, isovalerylcamitine and sometimes 3-hydro-xyisovalerate. Ketoacidotic crises, sometimes with fatal coma. Slight mental retardation in survivors. Treated with low leucine diet and supplements of glycine and/or carnitine to increase excretion of isovaler-yl conjugates. Peritoneal dialysis in crises. 

Isovaleric acidemia (isovaleryl-CoA dehydrogenase deficiency) WBC, FB 15ql4-ql5 243500... 

Fig. 6.1. The L-leucine degradative pathway. Reactions for which inherited metabolic disorders have not been conclusively identified include A, leucine-isoleucine aminotransferase and the majority of the 3-methylglutaconic acidurias (6.6-6.7). 6.1, Branched-chain a-ketoacid dehydrogenase (BCKD) complex, a reaction also occurring in the initial steps of L-isoleucine and L-valine degradation 6.2, isovaleryl-CoA dehydrogenase 6.3, 3-methylcrotonyl-CoA carboxylase 6.4, 3-methylglutaconyl-CoA hydra-tase 6.8, HMG-CoA lyase. Pathologic urinary metabolites used as specific markers in the differential diagnosis are presented in squares. Abbreviation Co A, coenzyme A...

Isovaleric acidaemia Isovaleric and 3-hydroxyisovaleric acids and isovalerylglycine Isovaleryl-CoA dehydrogenase 10.3.1... 

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