Isobutyryl Pathway

A minor pathway of valine catabolism is concerned with its conversion to leucine. Because leucine is an essential amino acid, its synthesis from valine is clearly not sufficiently significant to meet the organism s daily demand for leucine. In this reaction, isobutyryl-CoA (see Figure 20.20) is condensed with a molecule of acetyl-CoA to give /3-ketoisocaproate, which is then transaminated to give (3-leucine. A mutase is then used to convert /3-leucine to leucine. This mutase... 

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. 

Fig. 4 A, B. Polyketide synthase substrate routes. Potential substrates have been boxed A enzymes performing one enzymatic conversion 1, acetyl-CoA synthetase (alternatively, 1 represents a two enzyme pathway, acetate kinase followed by acetylphosphotransferase) 2, acetyl-CoA carboxylase 3, mal-onyl-CoA decarboxylase 4, malonyl-CoA synthetase B enzymes performing one enzymatic conversion 1, propionyl-CoA synthetase (T, propionate kinase followed by propionylphosphotransferase) 2, propionyl-CoA carboxylase 3, methylmalonyl-CoA decarboxylase 4, methylmalonyl-CoA epimerase 5, methylmalonyl-CoA mutase 6, isobutyryl-CoA mutase...

The role of valine as a precursor to butyrate units in streptomycete metabolism has been observed in the biosynthesis of many secondary metabolites, such as tylosin and monensin (36,37). In these pathways, the valine is thought to be degraded to isobutyryl CoA, which is then isomerized to n-butyryl CoA. The stereochemistry of this latter isomerization has been investigated in vivo in Snreptomyces ctniurnionemis, the producer of the antibiotic monensin A (38). 

In the metabolism of L-leucine, the isovaleryl-CoA produced by the oxidative decarboxylation step is further metabolized by a series of enzyme-catalysed steps to acetoacetate and acetyl-CoA and thence into the tricarboxylic acid cycle. Specific enzyme deficiencies at every stage of this metabolic pathway are known and are described in Section 10.3. In contrast, only one disorder of L-isoleucine metabolism subsequent to the oxidative decarboxylation step has been recognized (Section 10.4), and no disorders of the L-valine pathway from isobutyryl-CoA have been described. This may be due to their relative rarity but possibly also to greater difficulty in their detection. The metabolism of valine and leucine is, however, of particular interest in the organic acidurias, since both are major precursors of propionyl-CoA and methylmalonyl-CoA, defects in the metabolism of which lead to propionic acidaemia and methylmalonic aciduria (Chapter 11). 

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