Disease relevance of D-threo-Isocitric acid

• Mycobacterium tuberculosis isocitrate lyases 1 and 2 are jointly required for in vivo growth and virulence [1].
• Kinetic analysis of purified recombinant TbACO expressed in Escherichia coli resulted in a K(m) (isocitrate) of 3 +/- 0.4 mM, similar to aconitases of other organisms [2].
• NADP+-dependent monomeric isocitrate dehydrogenase (IDH) from the nitrogen-fixing bacterium Azotobacter vinelandii (AvIDH) is one of members of the beta-decarboxylating dehydrogenase family and catalyzes the dehydration and decarboxylation of isocitrate to yield 2-oxoglutrate and CO2 in the Krebs cycle [3].
• We report a 16 year old boy with the abnormal karyotype 46,XY,del(2)(q32.2q33.1) who has mental retardation, microcephaly, epilepsy, craniofacial dysmorphism, distinctive scalloped skin pigmentation, and normal levels of isocitrate dehydrogenase [4].
• Mutation of phosphotransacetylase but not isocitrate lyase reduces the virulence of Salmonella enterica serovar Typhimurium in mice [5].

High impact information on D-threo-Isocitric acid

• Phosphorylation of isocitrate dehydrogenase as a demonstration of enhanced sensitivity in covalent regulation [6].
• Gene dosage for isocitrate dehydrogenase in mouse embryos trisomic for chromosome 1 [7].
• Mutagenesis and Laue structures of enzyme intermediates: isocitrate dehydrogenase [8].
• Peroxisomal beta-oxidation of polyunsaturated fatty acids in Saccharomyces cerevisiae: isocitrate dehydrogenase provides NADPH for reduction of double bonds at even positions [9].
• Malate synthase and isocitrate lyase, key enzymes of the glyoxylate cycle, consistently sedimented with mitochondrial enzymes in differential pellets while catalase, a major peroxisomal enzyme, was always soluble [10].

Chemical compound and disease context of D-threo-Isocitric acid

• The structures of NADP+ and magnesium isocitrate bound to the NADP(+)-dependent isocitrate dehydrogenase of Escherichia coli have been determined and refined at 2.5-A resolution [11].
• Evidence suggesting that the NADPH/NADP ratio modulates the splitting of the isocitrate flux between the glyoxylic and tricarboxylic acid cycles, in Escherichia coli [12].
• A Bacillus subtilis gene for malate dehydrogenase (citH) was found downstream of genes for citrate synthase and isocitrate dehydrogenase [13].
• Metabolic activities of metronidazole-sensitive and -resistant strains of Helicobacter pylori: repression of pyruvate oxidoreductase and expression of isocitrate lyase activity correlate with resistance [14].
• Itaconate, an isocitrate lyase-directed inhibitor in Pseudomonas indigofera [15].

Biological context of D-threo-Isocitric acid

• We have identified an isocitrate lyase cDNA clone containing the complete protein coding region [16].
• We conclude that glyoxysome biogenesis is regulated in part through the coordinate expression of isocitrate lyase and malate synthase genes [16].
• Along with upregulation of alpha-GDH by NaCl, isocitrate dehydrogenase genes, which provide 2-oxoglutarate, are also induced [17].
• Spatial patterns of gene expression in Brassica napus seedlings: identification of a cortex-specific gene and localization of mRNAs encoding isocitrate lyase and a polypeptide homologous to proteinases [18].
• Isozyme analysis performed on 12 primary and 19 secondary hybrid clones showed that aryl hydrocarbon hydroxylase activity was concordant with the expression of the human isozymes malate dehydrogenase (EC 1.1.1.37) and isocitrate dehydrogenase (EC 1.1.1.42), previously assigned to human chromosome 2 [19].

Anatomical context of D-threo-Isocitric acid

• Oilseed isocitrate lyases lacking their essential type 1 peroxisomal targeting signal are piggybacked to glyoxysomes [20].
• Mycobacterium tuberculosis (Mtb) isocitrate dehydrogenases show strong B cell response and distinguish vaccinated controls from TB patients [21].
• Surprisingly, NADPH does not seem to be supplied by the pentose phosphate pathway in the unfertilised oocyte but rather by cytosolic NADP-dependent isocitrate dehydrogenase [22].
• We conclude that export of citrate and/or isocitrate from the mitochondria to the cytosol is an important step in control of GSIS [23].
• Spectrophotometric investigation of solubilized peroxisomal incubations showed that 2,4-dienoyl-CoA esters accumulated during peroxisomal beta-oxidation of fatty acids possessing double bond(s) at even-numbered carbon atoms. beta-Oxidation of [1-14C]docosahexaenoic acid by isolated peroxisomes was markedly stimulated by added NADPH or isocitrate [24].

Associations of D-threo-Isocitric acid with other chemical compounds

• Coordinate expression of transcriptionally regulated isocitrate lyase and malate synthase genes in Brassica napus L [16].
• Our results show that S711 is a target of phosphorylation capable of conferring distinct effects on c-acon function potentially dictating changes in cytosolic citrate/isocitrate metabolism [25].
• The data show that with substrate, only the carboxyl at C-2 of the propane backbone is strongly bound in addition to H2O or OH- (HxO) from the solvent, whereas in an isocitrate analogue that has a nitro group at C-2, the carboxyl and hydroxyl at C-1 are bound along with solvent HxO [26].
• However, we have found that a zwf1Delta ald6Delta mutant can be constructed by mating when tetrads are dissected on plates with a nonfermentable carbon source (lactate), a condition associated with expression of another enzymatic source of NADPH, cytosolic NADP+-specific isocitrate dehydrogenase (Idp2p) [27].
• Growth phenotype analyses of the mutants indicate that either cytosolic NADP+-specific isocitrate dehydrogenase (Idp2p) or the hexose monophosphate shunt is essential for growth with fatty acids as carbon sources and for sporulation of diploid strains, a condition associated with high levels of fatty acid synthesis [28].

Gene context of D-threo-Isocitric acid

• One of the ECA mutations was found to be in the gene encoding cytosolic NADP(+)-dependent isocitrate dehydrogenase (IDP2) [29].
• This loss of viability is not observed following transfer of a DeltaIDP3 strain lacking peroxisomal isocitrate dehydrogenase to medium with docosahexaenoate, a nonpermissive carbon source that requires function of IDP3 for beta-oxidation [30].
• Growth of Saccharomyces cerevisiae with a fatty acid as carbon source was shown previously to require function of either glucose-6-phosphate dehydrogenase (ZWF1) or cytosolic NADP+-specific isocitrate dehydrogenase (IDP2), suggesting dependence of beta-oxidation on a cytosolic source of NADPH [30].
• Thus, we speculate that the IDH2 site is catalytic and that the IDH1 site may bind but not catalytically alter isocitrate [31].
• We have previously reported a novel phenotype associated with mutants defective in the IDH2 gene encoding the Idh2p subunit of the NAD+-dependent isocitrate dehydrogenase (NAD-IDH) [32].

Analytical, diagnostic and therapeutic context of D-threo-Isocitric acid

• Site-directed mutagenesis and Laue diffraction data to 2.5 A resolution were used to solve the structures of two sequential intermediates formed during the catalytic actions of isocitrate dehydrogenase [8].
• RNA blot and in situ hybridization studies with isocitrate lyase and malate synthase cDNA clones from B. napus showed that the genes exhibit similar expression patterns [16].
• NAD-specific pig heart isocitrate dehydrogenase was earlier reported, on the basis of gel filtration experiments, to have a molecular weight of approximately 340,000 [33].
• Conformational changes induced by binding of ligands to cytosolic NADP(+)-specific isocitrate dehydrogenase from lactating bovine mammary gland were assessed using circular dichroism and fluorescence techniques [34].
• The molecular weight of the monomer was 60,000 +/- 2,500 with an s20,w of 4.8 +/- 0.1 and a Stokes radius of 29 A. The molecular weight of the dimer was 115,000 +/- 5,000 with an s20,w of 6.7 +/- 0.2 and a Stokes radius of 39 A. Active enzyme centrifugation showed that the dimer was the active species in the oxidative decarboxylation of isocitrate [35].

References