Disease relevance of NSC62343

• Treatment of pure 2-keto-4-hydroxyglutarate aldolase from Escherichia coli, a "lysine-type," Schiff-base mechanism enzyme, with the substrate analog bromopyruvate results in a time- and concentration-dependent loss of enzymatic activity [1].
• Crystalline pyruvate, phosphate dikinase from Bacteroides symbiosus. Modification of essential histidyl residues and bromopyruvate inactivation [2].
• One such candidate is 3-bromopyruvate that has been shown recently to eradicate advanced stage, PET positive hepatocellular carcinomas in an animal model without apparent harm to the animals [3].
• Bromopyruvate inactivation of 2-keto-3-deoxy-6-phosphogalactonate aldolase of Pseudomonas saccharophila. Kinetics and stereochemistry [4].
• Renal and spermatozoal toxicity of alpha-bromohydrin, 3-bromolactate and 3-bromopyruvate [5].

Psychiatry related information on NSC62343

• Holeboard maze-learning deficits and brain monoaminergic neurotransmitter concentrations in rats after intracerebroventricular injection of 3-bromopyruvate [6].
• Because comparable changes of PDHc and muscarinic receptors are found in dementia of Alzhemier type, the model of bromopyruvate inhibition of PDHc in rats is suggested to be useful for experimental dementia research [7].

High impact information on NSC62343

• Covalent modification of an active site residue, Cys 191, by the inhibitor 3-bromopyruvate traps the enzyme in a catalytic conformation with the active site completely inaccessible to solvent [8].
• Although glucose metabolism was preserved, indicating that the neuronal activities were enhanced, cerebral blood flow increase during cortical neuronal activation was abolished by bromopyruvate injection into only the cerebral cortex and not other cholinergic systems [9].
• In extending these studies, 3-bromopyruvate was found to be over 20 times less effective in inhibiting glyceraldehyde-3-phosphate dehydrogenase in intact erythrocytes than in trypanosomal cells [10].
• 2. Moreover the dependence of the reactivity of Cys-47 toward bromopyruvate and iodoacetamide with pH resembles that found for the functional sulfhydryls of thiol proteases, which have very low pKa values and exist mainly as a mercaptide-imidazole ion pair [11].
• The phenylalanine-sensitive isozyme of 3-deoxy-D-arabino-heptulosonate-7-phosphate synthase from Escherichia coli was inactivated by the sulfhydryl modifying reagents 5,5-dithiobis-(2-nitrobenzoate), bromopyruvate, and N-ethylmaleimide and protected from inactivation by the presence of its metal activator, Mn2+, and substrate, phosphoenolpyruvate [12].

Chemical compound and disease context of NSC62343

• Active-site residues of 2-keto-4-hydroxyglutarate aldolase from Escherichia coli. Bromopyruvate inactivation and labeling of glutamate 45 [1].
• Escherichia coli pyruvate dehydrogenase complex. Thiamin pyrophosphate-dependent inactivation by 3-bromopyruvate [13].
• The PrpB protein reacted with stoichiometric amounts of 3-bromopyruvate whereby the activity was lost and one amino-acid residue per subunit became modified, most likely a cysteine as shown for isocitrate lyase of E. coli [14].
• Cross-linking between 16S ribosomal RNA and protein S4 in Escherichia coli ribosomal 30S subunits effected by treatment with bisulfite/hydrazine and bromopyruvate [15].
• 3-bromopyruvate (3-Br PA), a strong alkylating agent, was found to cause a dramatic disruption of pH gradients in acidic compartments of Ehrlich ascites tumour cells (EATCs), as well as of rat thymocytes, at concentrations similar to those reported to cause ATP depletion in hepatocellular carcinoma cells [16].

Biological context of NSC62343

• It is concluded that 3-bromopyruvate inactivates this complex by initially undergoing the first two steps of the usual catalytic pathway, TPP-dependent decarboxylation followed by reductive bromoacetylation of lipoyl moieties [13].
• Inactivation studies with [14C] bromopyruvate show the incorporation of 1.1 mol of 14C-labeled compound/enzyme subunit; isolation of a radioactive peptide and determination of its amino acid sequence indicate that the radioactivity is associated with glutamate 45 [1].
• Mechanism of pigeon liver malic enzyme: kinetics, specificity, and half-site stoichiometry of the alkylation of a cysteinyl residue by the substrate-inhibitor bromopyruvate [17].
• At various concentrations of bromopyruvate which affect the inactivation rate, the ratio of nanomoles of bromopyruvate turned over/unit of enzyme inactivated remains constant averaging 12:1, consistent with both inactivation and catalysis occurring at a single protein site, the catalytic site [4].
• The oxidation products (R,S)-3-bromolactate and 3-bromopyruvate produced brief phases of diuresis but not glucosuria, and severely inhibited the metabolic activity of rat kidney tubules in vitro. alpha-Bromohydrin had no effect on the metabolic activity of boar spermatozoa whereas the oxidation products severely affected mitochondrial metabolism [5].

Anatomical context of NSC62343

• We now report the action of 3-bromopyruvate on the metabolic activity of boar spermatozoa [18].
• A stereotaxic injection of 0.2 mumol 3-bromopyruvate was given twice into the cerebral ventricles of male Wistar rats [6].
• Moreover, control myocytes incubated for 6 h in the presence of an inhibitor of pyruvate dehydrogenase, 3-bromopyruvate, exhibited a concentration-dependent decrease in Ito density compared with untreated cells [19].
• Bromopyruvate caused a reduction of PDHc activity in the 3 brain regions examined, however, reaching significance only in the cerebral cortex and the hippocampus and not in the striatum, 24 h after injection [7].

Associations of NSC62343 with other chemical compounds

• The Cys-294----Ser mutant enzyme is virtually identical to the wild type with respect to pyridoxal phosphate binding (KCO = 2 microM), cofactor absorption spectrum (lambda max = 420 and 337 nm) and pH dependence (pK alpha = 7.3), pH profile for catalysis, and rate of bromopyruvic acid inactivation [20].
• A possible impact of this observation with respect to the different responses of isocitrate lyases and PrpB upon treatment with the common inhibitor 3-bromopyruvate is discussed [21].
• In both types of inhibition of E1, reaction of 1 mol of bromopyruvate/mol of E1 chain is required for complete inactivation, and all the evidence is consistent with reaction taking place at or near the pyruvate binding site [22].
• It is based on reaction of bromine with enolpyruvate in acid, derivatization of formed bromopyruvate with thionitrobenzoate, and resolution by reversed-phase HPLC of the thioether derivative [23].
• Malic enzyme from pigeon liver is alkylated by the substrate analogue bromopyruvate, resulting in the concomitant loss of its oxidative decarboxylase and oxalacetate decarboxylase activities, but not its ability to reduce alpha-keto acids [17].

Gene context of NSC62343

• Activities of carbonic anhydrase II and I isoenzymes were determined with CO2-hydratase activity method by using selective inactivation with bromopyruvate [24].
• Modification of yeast pyruvate kinase by an active site-directed reagent, bromopyruvate [25].
• 3-Bromopyruvate inhibits DHDPS with a Ki of 1.6 mM [26].
• Inactivation of the pyruvate dehydrogenase complex by 3-bromopyruvate is thiamin pyrophosphate (TPP)-dependent [13].
• Two different crystal forms of isocitrate lyase (ICL) from Escherichia coli have been grown following the chemical modification of the enzyme by either 3-bromopyruvate or ethyl mercuri thiosalicylate (EMTS), contrasting strongly with difficulties in obtaining ordered crystals of the native enzyme [27].

Analytical, diagnostic and therapeutic context of NSC62343

• Based on these observations and a report that KDO 8-P synthase is inactivated in a time-dependent manner with 3-bromopyruvate and that the substrate PEP protects against this inactivation, all four cysteines (38, 166, 206, and 249) were individually mutated to alanines via a modified PCR methodology [28].

References