3,5-dihydroxy-3-methylvaleric acid

Dihydroxyacid dehydratase is involved in the biosynthesis of valine and isoleucine. L-a,/3-dihydroxyisovaleric acid and L-aj3-dihydroxy-/3-methylvaleric acid are dehydrated to form the a-keto acid precursors of valine and isoleucine. 

Key discoveries leading to the elucidation of the pathways of biosynthesis of valine and isoleucine were the isolation of the dihydroxy precursors, a,j9-dihydrox3dsovaleric acid and a, 8-dihydroxy-/3-methylvaleric acid (141, 10), the transamination between the a-keto analogs of these amino acids and glutamic acid 10), and isotopic labeling that was consistent with the conclusion that valine biossmthesis was initiated by a condensation of two molecules of P3mivic acid and isoleucine biosynthesis by a corresponding... 

Following the ketol condensation to yield a-acetolactate and a-aceto-a-hydroxybutyrate the question arises as to whether the pinacol rearrangement occurs first to form a-keto-jS-hydroxyisovaleric acid and a-keto-i9-hydroxy- 8-methylvaleric acid (Fig. 7, III), or whether there is prior reduction. The evidence favoring pinacol rearrangement followed by reduction of the a-keto- 3-hydroxy acids is that enzymes have been found in Neurospora and E. coli which catalyze the reduction of synthetically prepared a-keto-(8-hydroxyisovaleric acid and a-keto-j8-hydroxy-/3-methyl-valeric acid to the corresponding a,/8-dihydroxy acids (166, 167). 

Tavormina PA, Gibbs MH. The metabolism of B,8-dihydroxy-l3-methylvaleric acid by liver homogenates. J Am Chem Soc, 1956 78 6210. 

The syntheses of valine, leucine, and isoleucine from pyruvate are illustrated in Figure 14.9. Valine and isoleucine are synthesized in parallel pathways with the same four enzymes. Valine synthesis begins with the condensation of pyruvate with hydroxyethyl-TPP (a decarboxylation product of a pyruvate-thiamine pyrophosphate intermediate) catalyzed by acetohydroxy acid synthase. The a-acetolactate product is then reduced to form a,/3-dihydroxyisovalerate followed by a dehydration to a-ketoisovalerate. Valine is produced in a subsequent transamination reaction. (a-Ketoisovalerate is also a precursor of leucine.) Isoleucine synthesis also involves hydroxyethyl-TPP, which condenses with a-ketobutyrate to form a-aceto-a-hydroxybutyrate. (a-Ketobutyrate is derived from L-threonine in a deamination reaction catalyzed by threonine deaminase.) a,/3-Dihydroxy-/3-methylvalerate, the reduced product of a-aceto-a-hydroxybutyrate, subsequently loses an HzO molecule, thus forming a-keto-/kmethylvalerate. Isoleucine is then produced during a transamination reaction. In the first step of leucine biosynthesis from a-ketoisovalerate, acetyl-CoA donates a two-carbon unit. Leucine is formed after isomerization, reduction, and transamination. 

Subsequently, the enzymic conversion of a-acetolactate to a,6-dihydroxyisovalerate and a-aceto-a-hydroxybutyrate to a,/3-dihydroxy-jS-methylvalerate was shown by Wagner et al. 166) with extracts of Neurospora and by Umbarger 167) with extracts of appropriately blocked E. coU mutants. These acids were then shown to be utUized for valine and isoleucine formation. 

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