0-Hydroxyisobutyrate 3-Hydroxyisobutyric dehydrogenase

The /3-hydroxyisobutyrate dehydrogenase from pig kidney has been purified about 200-fold by Robinson and Coon (88) employing the usual procedures for protein fractionation. The enzyme is present in kidney, liver, and heart of vertebrates and in a number of microorganisms. The most active somrce observed was rabbit liver. The dehydrogenase has no activity on 3-hydroxybutyric acid or the CoA ester. 

Fig. 10.23 Metabolism of L-isoleucine and of L-valine in man. Principal enzymes involved are 1, branched-chain keto acid decarboxylase 2, acyl-CoA hydratase 3, enoyl CoA hydratase 4, 3-hydroxyacyl-CoA dehydrogenase 5, 3-hydroxyisobutyryl-CoA hydrolase 6,2-methylacetoacetyl-CoA thiolase 7,3-hydroxyisobutyrate dehydrogenase.

Hydroxisobutyrate is oxidized by a DPN-specific dehydrogenase TPN is not attacked and the enzyme does not attack any known analogs of either 8-hydroxyisobutyrate or the oxidation product, methylmalonate semialdehyde. The further degradation of the branched chain has not... 

Hydroxyisobutyric aciduria 2-Ketoglutarate dehydrogenase complex def. Fumarase def. 

Methylmalonate semialdehyde dehydrogenase deficiency [8] has been described in a single patient. This patient, a boy, came to attention because of an elevated concentration of methionine on routine neonatal screening. The value exceeded 1000 imol/l. By 4 years of age he had developed normally. A valine load was followed by an increase in 3-hydroxyisobutyric acid excretion. Incubation of fibroblasts from the patient with 2-valine or p-[1- C]-alanine led to no production of C02 from valine and very little from )ff-alanine in contrast to control cells. 

Examination of plasma and urine revealed elevated quantities of jff-ala-nine, 3-hydroxypropionic acid, (R)- and (S)-3-aminoisobutyric acid, (R)-and (S)-3-hydroxyisobutyric acid and (S)-2-hydroxymethylbutyric acid. Direct enzymatic assay of methylmalonate semialdehyde dehydrogenase is unavailable revealed homozygosity for DNA analysis 1336 G>A transversion which substituted an arginine for a highly conserved glycine at amino acid residue 446. 

Hydroxyisobutyric aciduria and no defined defect in the methylmalo-nate semialdehyde dehydrogenase. 

Table 7.5. 3-Hydroxyisobutyric acidemia due to methylmalonate semialdehyde dehydrogenase deficiency...

Table 7.6. 3-Hydroxyisobutyric acidemia with normal methylmalonate semialdehyde dehydrogenase ...

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