2-Methyl branched-chain acyl-CoA dehydrogenase

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. 

Komuniecki, R., Fekete, S. and Thissen, J. (1985) Purification and characterization of the 2-methyl-branched chain acyl CoA dehydrogenase, an enzyme involved in the enoyl CoA reduction in anaerobic mitochondria of the nematode Ascaris suum. J. Biol. Chem. 260 4770-4777. 

Mortensen, P.B., Gregersen, N., Kolvraa, S. Christensen, E. (19W) Biochem. Med 24, 1531-1561. The occurrence of C6-C10-dicarboxylic acids in urine from patients and rats treated with dipropylacetate. Ikeda, Y, Dabrowsly, C. Tanaka, K. (1983) J. Biol. Chem. 258, 1066-1076. Separation and properties of five distinct acyl-CoA dehydrogenases from rat liver mitochondria. Identification of a new 2-methyl branched chain acyl-CoA dehydrogenase. 

Ito, M., Ikeda, Y, Amez, J.G., Finocchiaro, G. Tanaka, K. (1990) Biochim. Biophys. Acta IftH 213-218. The enzymatic basis for the metabolism and inhibitory effects of valproic acid dehydrogenation of valproyl-CoA by 2-methyl-branched-chain acyl-CoA dehydrogenase. 

The acyl-Co A dehydrogenases are a family of mitochondrial flavoenzymes involved in fatty acid and branched chain amino-acid metabolism. In addition to long chain acyl-Co A dehydrogenases (LCADs), there are short/ branched chain acyl-CoA dehydrogenase (SBCAD) that act on 2-methyl branched chain acyl-CoA substrates of varying chain lengths. 

Fig. 3.2.5 Profiles of acylcarnitines as their butyl esters in plasma (precursor of m/z 85 scan) of a normal control (a) and patients with various organic acidemias. Propionylcarnitine (C> m/z 274 peak 3) is the primary marker for both propionic acidemia (b) and methylmalonic acidemias (c). Note that an elevation of methylmalonylcarnitine (C4-UC m/z 374) is not typically found in patients with methylmalonic acidemias. In the three cases of ethylmalonic encephalopathy (d) analyzed in our laboratory, elevations of ,- (m/z 288 peak 4) and C5-acylcarnitine (m/z 302 peak 5) species were noted. Isolated C5-acylcarnitine elevations are encountered in patients with isovaleric acidemia (e), where it represents isovalerylcarnitine. Cs-Acylcarnitine is also elevated in patients with short/branched chain acyl-CoA dehydrogenase deficiency, where it represents 2-methylbutyrylcarnitine (see Fig. 3.2.4), and in patients treated with antibiotics that contain pivalic acid, where it represents pivaloylcarnitine [20, 59, 60]. Patients with /3-ketothio-lase deficiency (f) present with elevations of tiglylcarnitine (C5 i m/z 300 peak 6) and C5-OH acylcarnitine (m/z 318 peak 7). In most cases of 3-methylcrotonyl-CoA carboxylase deficiency (g) Cs-OH acylcarnitine is the only abnormal acylcarnitine species present. The differential diagnosis of C5-OH acylcarnitine elevations includes eight different conditions (Table 3.2.1). Also note that C5-OH acylcarnitine represents 3-hydroxy isovalerylcarnitine in 3-methylcrotonyl-CoA carboxylase deficiency (g), and 2-methyl 3-hydroxy butyrylcarnitine in / -ketothiolase deficiency...

FIG. 4.2 Malate metabolism in mitochondria from body wall muscle of adult Ascaris smm. (1) Fumarase (2) malic enzyme (3) pyruvate dehydrogenase complex (4) complex I (5) succinate-coenzyme Q reductase (complex II, fumarate reductase) (6) acyl CoA transferase (7) methylmalonyl CoA mutase (8) methyl-malonyl CoA decarboxylase (9) propionyl CoA condensing enzyme (10) 2-methyl acetoacetyl CoA reductase (11) 2-methyl-3-oxo-acyl CoA hydratase (12) electron-transfer flavoprotein (13) 2-methyl branched-chain enoyl CoA reductase (14) acyl CoA transferase. 

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... 

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