Disease relevance of COI

• Applicability is demonstrated by comparative measurement of 4-methyl-2-oxopentanoate content in plasma of patients with maple syrup urine disease by the enzymatic and a reversed phase high performance liquid chromatographic method [1].
• A simple and rapid spectrophotometric method for the estimation of 4-methyl-2-oxopentanoate in plasma samples by use of NAD+-dependent D-2-hydroxyisocaproate dehydrogenase from Lactobacillus casei ssp. pseudoplantarum is described [1].

High impact information on COI

• Carnitine stimulated the oxidation of 4-methyl-2-oxopentanoate in rat liver homogenates and mitochondria; octanoate, DL-octanoylcarnitine, 4-pentenoate, and 3-methylbutyrate (isovalerate) were inhibitory, and 2-bromopalmitate had no effect [2].
• The oxidation of 4-methyl-2-oxopentanoate (alpha-ketoisocaproate) by rat liver mitochondria was shown to be independent of exogenous coenzyme A and exogenous NAD+ [2].
• Both NAD+ and 2-oxoisocaproate were identified in the electron density map; binding of the latter in the active site, however, competes with a sulphate ion, which is also defined by electron density [3].
• Thus the activity state of branched-chain 2-oxo acid dehydrogenase is underestimated in mitochondria isolated in media supplemented with fluoride plus 4-methyl-2-oxopentanoate [4].
• Hepatocytes isolated from chow-fed rats had greater flux rates (decarboxylation rates of 3-methyl-2-oxobutanoate and 4-methyl-2-oxopentanoate) than did hepatocytes isolated from rats fed on the low-protein diet [5].

Biological context of COI

• The oxidative decarboxylation of 4-methyl-2-oxopentanoate by the dehydrogenase appears to be the rate-limiting step for leucine oxidation in muscle homogenates and also in intact tissues [6].
• The amination of 4-methyl-2-oxopentanoate by islets was attributed to the presence of a branched-chain amino acid aminotransferase (EC 2.6.1.42) activity in the tissue [7].
• 1. Oxidative decarboxylation of 4-methyl-2-oxopentanoate (2-oxoisocaproate) by mitochondria of rat skeletal muscle showed biphasic kinetics [8].
• 4. The results of experiments with respiratory inhibitors and uncouplers, and the finding that 14CO2 production and islet respiration were linked in a 1:1 stoicheiometry suggested that 4-methyl-2-oxopentanoate catabolism was coupled to mitochondrial oxidative phosphorylation [7].
• The substrate specificity of the monomeric LdhA (36.5 kDa) indicated that 2-oxoisocaproate (K(m) = 68 muM, k(cat) = 31 s(-1)) and NADH were the native substrates [9].

Anatomical context of COI

• 4-Methyl-2-oxopentanoate oxidation by rat skeletal-muscle mitochondria [8].
• The metabolism of 4-methyl-2-oxopentanoate in rat pancreatic islets [7].
• 5. 2-Oxoglutarate stimulated the oxidation of the branched-chain amino acids by muscles and peripheral nerves and the oxidation of 4-methyl-2-oxopentanoate by hemidiaphragms but not by nerves [10].
• 6. Octanoate (0.1-1.0 mM) markedly stimulated the oxidation of branched-chain amino acids and of 4-methyl-2-oxopentanoate in hemidiaphragms, but inhibited oxidation of both by peripheral nerves and spinal cord [10].
• Leucine aminotransferase (EC 2.6.1.6) and 2-oxoisocaproate dehydrogenase (EC 1.2.4.3) were studied in rat cerebral cortex, cerebellum, brain stem, liver, and muscle in normal and animals starved for 48 hours [11].

Associations of COI with other chemical compounds

• Glucose (20 mM) and 4-methyl-2-oxopentanoate (10 mM) both caused a pronounced stimulation of insulin release and of [3H]inositol phosphate production in rat pancreatic islets prelabelled with myo-[3H]inositol [12].
• 6. In mitochondria and homogenates CO2 was only produced by oxidative decarbosylation of 4-methyl-2-oxopentanoate [8].
• 5. It is proposed that changes in the redox state of NADP and Ca transport may serve as mediators in the stimulus-secretion coupling mechanism of insulin release induced by 4-methyl-2-oxopentanoate [13].
• 2. Islet respiration, acetoacetate production and rates of substrate utilization, oxidation and amination all changed as a simple hyperbolic function of 4-methyl-2-oxopentanoate concentration and exhibited a maximal response at 25 mM [13].
• Neither valine nor 2-oxoisocaproate had an effect on glutamate dehydrogenase activity in rat or chick muscles [14].

Gene context of COI

• Although glutamate dehydrogenase activity was demonstrated in islet tissue, the reductive amination of 2-oxoacids did not seem to be of importance in the formation of leucine from 4-methyl-2-oxopentanoate [7].
• 9. Insulin did not affect the oxidation of 4-methyl-2-oxopentanoate by muscles or nerves [10].
• Maximal increase of label in plasma 4-methyl-2-oxopentanoate, the physiologic precursor of 13CO2, was 16.1 +/- 3.5 MPE in control subjects [15].

Analytical, diagnostic and therapeutic context of COI

• The HPLC of the purified ethyl acetate extract of the strains and standard 4-methyl-2-oxopentanoate (2-oxoisocaproate) revealed a single peak, similarly as the coinjection of the extract and the standard [16].
• The transport of 2-oxoisocaproate into isolated hepatocytes and liver mitochondria of rat was studied using [U-14C]2-oxoisocaproate and the silicone oil filtration procedure [17].

References