Disease relevance of COI

• Valine (62.5 mg per kg), leucine (70 mg per kg) and equal amounts of the calcium salts of the corresponding keto acids, i.e., alpha-ketoisovaleric acid (KIVA) and alpha-ketoisocaproic acid (KICA) were orally administered to patients with cirrhosis and to control subjects [1].
• Effect of experimental liver disease on the utilization for protein synthesis of orally administered alpha-ketoisocaproate [2].
• We studied the release of insulin, glucagon, and somatostatin in response to glucose, glyceraldehyde (GA), and alpha-ketoisocaproate (KIC) from rat kidneys containing transplanted insulinomas [3].
• The transport of all three substrates was sensitive to inhibition by low concentrations of either 2-oxo-3-methylbutanoate or 2-oxo-4-methylpentanoate, the 2-oxo acids that can accumulate in patients with maple-syrup-urine disease [4].
• Amino acid oxidation was increased 145% in rats with chronic metabolic acidosis relative to control rats receiving diets identical in protein and calories based on a reciprocal pool model and plasma alpha-ketoisocaproate specific radioactivity [5].

Psychiatry related information on COI

• The effects of acute food deprivation and subsequent refeeding with isonitrogenous oral liquid diets supplemented with arginine (ARG), ARG alpha-ketoglutarate (AKG), or ARG alpha-ketoisocaproate (AKIC) were examined in a Sprague-Dawley rat trauma model (bilateral femur fracture) [6].

High impact information on COI

• The ratio R, defined as (percent of dose of 14C)/(percent of dose of 3H) in the leucine of plasma fibrinogen, albumin, immunoglobulin G (IgG), red cell globin, and salivary mucin, was measured in 7 normal adults and in 5 cirrhotic patients during continuous intragastric infusion of 1-14C-labeled alpha-ketoisocaproate (KIC) and 3H-labeled leucine [7].
• Both the secretory response and the translocation of alpha-PKC were blocked by the addition of mannoheptulose, an inhibitor of glucose metabolism, in islets stimulated with glucose but not in islets stimulated with alpha-ketoisocaproate [8].
• We used plasma 13C alpha-ketoisocaproate (representing intracellular leucine labeling) as the precursor pool for the calculation of fractional muscle protein synthesis and leucine kinetics [9].
• In contrast, an uncoupler of mitochondrial respiration, sodium salicylate (375 mg per kg), increased the decarboxylation of alpha-ketoisocaproic acid (56.3% of the dose recovered as 14CO2 in 1 hr) [10].
• Ethanol (3 gm per kg) significantly decreased alpha-ketoisocaproic acid decarboxylation (21.8% of the dose appearing in breath in 1 hr), probably due to the ethanol-induced shift in the NAD+:NADH ratio [10].

Chemical compound and disease context of COI

• Bacteroides ruminicola is one of several species of anaerobes that are able to reductively carboxylate isovalerate (or isovaleryl-coenzyme A) to synthesize alpha-ketoisocaproate and thus leucine [11].
• Here, we determined concentrations of alpha-ketobutyrate, alpha-ketoglutarate, alpha-ketoisocaproate, alpha-ketoisovalerate, alpha-keto-beta-methylvalerate, phenylpyruvate, and pyruvate by a recently developed ultra-sensitive fluorescence HPLC method in ventricular myocardium of mice exposed to hypobaric hypoxia for up to 3 weeks [12].
• We have previously described that alpha-ketoisocaproic acid (KIC), the main metabolite accumulating in maple syrup urine disease (MSUD), increased the in vitro phosphorylation of cytoskeletal proteins in cerebral cortex of 17- and 21-day-old rats through NMDA glutamatergic receptors [13].
• Supplementation with beta-hydroxy-beta-methylbutyrate (HMB) and alpha-ketoisocaproic acid (KIC) reduces signs and symptoms of exercise-induced muscle damage in man [14].

Biological context of COI

• In functionally anhepatic animals, 14CO2 in breath amounted to 23% of that in control animals, indicating that alpha-ketoisocaproic acid decarboxylation reflects mainly hepatic mitochondrial function in vivo [10].
• Alpha-ketoisocaproic acid, a nonglycolytic substrate for the beta-cell, stimulated DNA replication [15].
• A soluble alpha-ketoisocaproate oxygenase from rat liver catalyzes the decarboxylation and hydroxylation of alpha-ketoisocaproate to form beta-hydroxyisovalerate [16].
• 9. The data indicate that the branched chain alpha-keto acid transporter is asymmetric, that is, binding sites for substrate on the inside and outside of the mitochondrial membrane are not identical. alpha-Ketoisocaproate oxidation was measured at 37 degrees C in isolated mitochondria over the pH range of 6.6 to 8 [17].
• These data suggest that enhanced oxidation of acetyl-CoA from alpha-ketoisocaproate by lactate addition is caused by a low activity of pyruvate dehydrogenase combined with increased flux through the citric acid cycle in response to the energy requirements for gluconeogenesis [18].

Anatomical context of COI

• Direct inhibition of the pancreatic beta-cell ATP-regulated potassium channel by alpha-ketoisocaproate [19].
• Regulation of leucine and alpha-ketoisocaproic acid metabolism in skeletal muscle. Effects of starvation and insulin [20].
• The ability of alpha-ketoisocaproate (KIC) to induce ATP production in isolated mitochondria from pancreatic beta-cells was examined with a bioluminometric method [21].
• Glucose stimulation of beta-cell DNA replication in the intact rat and in pancreatic islets in suspension culture. Effects of alpha-ketoisocaproic acid, dibutyryl cyclic AMP, and 3-isobutyl-1-methylxanthine in the in vitro system [15].
• The results suggest that enhancement of B-cell energy production and a consequent rise in [ATP] (or [ATP]/[ADP]) are a necessary event for the hormone release elicited by high glucose and alpha-ketoisocaproic acid [22].

Associations of COI with other chemical compounds

• The presence of pyruvate in the perfusion medium resulted in an inhibition of the flux through the branched chain complex with either alpha-ketoisocaproate or alpha-ketoisovalerate as the substrate [23].
• The final possibility was that a pyruvate decarboxylase-like enzyme encoded by YDL080c appears to be the major route of decarboxylation of alpha-ketoisocaproate to isoamyl alcohol although disruption of this gene reveals that at least one other unidentified decarboxylase can substitute to a minor extent [24].
• Regulation of alpha-ketoisocaproate oxidation in liver mitochondria by adenine nucleotides and calcium [25].
• The purified enzyme is stable in the presence of 5% monothioglycerol for 3 weeks at 4 degrees C and at least 10 weeks at -80 degrees C. The molecular weight of the alpha-ketoisocaproate oxygenase as determined to be 46,000 and 51,000 using denaturing and nondenaturing conditions, respectively, indicating a monomer [26].
• Model building of the second half-reaction substrate alpha-ketoisocaproate in the pyridoxamine 5'-phosphate-hBCATm structure suggests that disruption of the CXXC center results in altered substrate orientation and deprotonation of the amino group of pyridoxamine 5'-phosphate, which inhibits catalysis [27].

Gene context of COI

• The nutrient secretagogues, methylpyruvate (10 mm) and alpha-ketoisocaproate (20 mm), also stimulated DeltaO2, but this was unaffected by somatostatin [28].
• The branched-chain keto acid, alpha-ketoisocaproate, a metabolite of leucine catabolism produced by BCAT1/ECA39, was previously found to inhibit cell growth [29].
• Pyruvate decarboxylase encoded by the PDC1 gene contributes, at least partially, to the decarboxylation of alpha-ketoisocaproate for isoamyl alcohol formation in Saccharomyces cerevisiae [30].
• The UCP1-expressing cells showed an inability to increase cytosolic Ca(2+) concentration ([Ca(2+)](i)) in response to glucose or alpha ketoisocaproate and this resulted in less insulin secretion, whereas initial reduction in [Ca(2+)](i) occurring upon either nutrient addition was not affected [31].
• The soluble, active recombinant enzyme was shown to contain both 4HPPD and alpha-ketoisocaproate dioxygenase (alpha KICD) activity [32].

Analytical, diagnostic and therapeutic context of COI

• Assessment of mitochondrial function in vivo with a breath test utilizing alpha-ketoisocaproic acid [10].
• In the present study we have used the patch-clamp technique to study the direct effects of alpha-ketoisocaproate on the KATP channel in isolated patches and intact pancreatic beta-cells [19].
• Finally, dose-dependent increases in extracellular kynurenate levels in response to an intracerebral perfusion with pyruvate or alpha-ketoisocaproate were demonstrated by in vivo microdialysis [33].
• This quantitative "surrogate analyte" approach was applied during the development of an HPLC/MS method for alpha-ketoisocaproic acid (KIC), which was identified as a potential biomarker for branched chain amino acid transferase inhibitor activity [34].
• The release of branched chain KA, in particular that of alpha-ketoisocaproate, reflects an effective transamination activity in the bioreactor system [35].

References