Disease relevance of alpha-ketovaline

• The crystal structure of a heterotetrameric (alpha2beta2) E1, 2-oxoisovalerate dehydrogenase from Pseudomonas putida, reveals a tightly packed arrangement of the four subunits with the beta2-dimer held between the jaws of a 'vise' formed by the alpha2-dimer [1].
• Thiamin-responsive maple-syrup-urine disease: decreased affinity of the mutant branched-chain alpha-keto acid dehydrogenase for alpha-ketoisovalerate and thiamin pyrophosphate [2].
• Some physical, catalytic, and regulatory properties of ketopantoate hydroxymethyltransferase (5,10-methylenetetrahydrofolate: alpha-ketoisovalerate hydroxymethyltranferase) from Escherichia coli are described [3].
• Limited digestion of the pyruvate dehydrogenase complex of Bacillus subtilis with either trypsin or chymotrypsin at 0 degrees C inhibited its ability to decarboxylate pyruvate and 2-oxoisovalerate oxidatively, without causing disassembly of the complex [4].
• Mycobacterium tuberculosis alpha-isopropylmalate synthase (MtIPMS) catalyzes the condensation of acetyl-coenzyme A (AcCoA) with alpha-ketoisovalerate (alpha-KIV) and the subsequent hydrolysis of alpha-isopropylmalyl-CoA to generate the products CoA and alpha-isopropylmalate (alpha-IPM) [5].

High impact information on alpha-ketovaline

• The alpha-ketoisovalerate substrate binds to an active site zinc ion, adjacent to a cavity that can accommodate acetyl-CoA [6].
• The branched chain ketoacids alpha-ketoisocaproate and alpha-ketoisovalerate were also potent inhibitors of hepatocyte MCT with K0.5 values of 270 and 340 microM, respectively [7].
• The steady state levels of mitochondrial acyl-CoAs produced during the oxidation of pyruvate, alpha-ketoisovalerate, alpha-ketoisocaproate, and octanoate during state 3 and state 4 respiration by rat heart and liver mitochondria were determined [8].
• Efflux of alpha-ketoisocaproate or alpha-ketoisovalerate from rat heart mitochondria obeyed first order kinetics [9].
• The inhibition of pyruvate carboxylase flux by alpha-ketoisovalerate was largely reversed by oleate addition, but pyruvate dehydrogenase flux was inhibited further [10].

Chemical compound and disease context of alpha-ketovaline

• Bacillus subtilis has a constitutive system for the uptake of alpha-keto-beta-methylvalerate, alpha-ketoisovalerate, and (probably) alpha-ketoisocaproate [11].
• Escherichia coli can synthesize alpha-ketoisovalerate, the precursor of valine, leucine, and pantothenate, by three routes: anabolically via dihydroxyacid dehydrase and catabolically via both the branched-chain amino acid transaminase (transaminase B) and the alanine-valine transaminase (transaminase C) [12].

Biological context of alpha-ketovaline

• Coinfusion of either alpha-ketoisovalerate or alpha-keto-beta-methylvalerate inhibited the rate of alpha-keto[1-14C]isocaproate decarboxylation [13].
• The rate of branched-chain amino acid- and alpha-keto acid-dependent oxygen consumption by intact Arabidopsis mitochondria was highest with Val and the Val-derived alpha-keto acid, alpha-ketoisovaleric acid [14].
• Initial-velocity and product-inhibition studies show that the reductive amination proceeds through a sequential ordered ternary-binary mechanism; NADH binds to the enzyme first, followed by 2-oxoisovalerate and NH3, and valine is released first, followed by NAD+ [15].
• A mutation, kauA1, which blocks the uptake of alpha-keto-beta-methylvalerate and alpha-ketoisovalerate, is located between metB and citK on the B. subtilis chromosome [11].
• Although the point of inhibitory attack of alpha-ketoacids in renal gluconeogenesis could not be localized, an impairment of the kidney to respond to metabolic acidosis with an increase of gluconeogenesis was observed, since the pH optimum of renal gluconeogenesis was shifted from pH 6.8 to pH 7.7 in the presence of alpha-ketoisovaleric acid [16].

Anatomical context of alpha-ketovaline

• Isolated colonocytes have more capacity for the oxidation of isobutyrate and alpha-ketoisovalerate than isolated enterocytes [17].
• The cerebrospinal fluid/plasma ratios for 5-carbon acids, alpha-ketoisovaleric acid and alpha-hydroxyisovaleric acid were much higher than for other branched-chain acids not only in the patient but also in normal controls [18].
• The concentrations in the umbilical vein for these keto acids were 10.9 +/- 3.8 microM (mean +/- SD: 2-keto isovalerate), 19.7 +/- 6.1 microM (2-keto isocaproate) and 14.8 +/- 5.3 microM (2-keto methylvalerate) respectively [19].
• Acetyl-CoA and isovaleryl-CoA inhibited only 3-methyl-2-oxobutanoate oxidation in muscle mitochondria [20].

Associations of alpha-ketovaline with other chemical compounds

• Decarboxylation of alpha-ketoisovalerate, alpha-keto-beta-methylvalerate, and alpha-ketoisocaproate was catalyzed by this multienzyme complex and this activity was co-purified for each substrate [21].
• 2. A wide variety of monocarboxylates and ketone bodies, including lactate, pyruvate, beta-hydroxybutyrate, acetoacetate, 2-oxoisovalerate and 2-oxoisohexanoate, were substrates of MCT2 [22].
• In rat hemidiaphragms clofibric acid inhibited the oxidative decarboxylation of 4-methyl-2-oxopentanoate and had no effect on that of 3-methyl-2-oxobutanoate [23].
• 4. With no octanoate there was a great accumulation of alpha-ketoisovalerate in both the muscle and the perfusion medium [24].
• Ethanol inhibited glucose synthesis from alpha-ketoisovalerate by isolated rat hepatocytes without significant inhibition of flux through the branched-chain alpha-ketoacid dehydrogenase complex [25].

Gene context of alpha-ketovaline

• The mechanism of inhibition of pyruvate carboxylase, pyruvate dehydrogenase, and carbamyl phosphate synthetase induced by alpha-ketoisovalerate metabolism has been investigated in isolated rat hepatocytes incubated with lactate, pyruvate, ammonia, and ornithine as substrates [10].
• Accumulation of 3-hydroxyisobutyrate, an intermediate in the catabolism of alpha-ketoisovalerate, was increased by ethanol, indicating inhibition of flux at the level of 3-hydroxyisobutyrate dehydrogenase [25].

Analytical, diagnostic and therapeutic context of alpha-ketovaline

• Decarboxylation of alpha-ketoisovaleric acid after oral administration in man [26].
• Consumption of a low-protein diet containing an additional 5% of leucine resulted in depression within one hour of the plasma concentrations of isoleucine, valine, alpha-keto-beta-methylvalerate, and alpha-ketoisovalerate [27].
• 5. Although the concentrations of alpha-ketoisovaleric acid and alpha-hydroxyisovaleric acid rose to the lesser extent in the CSF perfusate, changes in rousability of the animal and in the EEG recording were demonstrated [28].

References