Disease relevance of 2-isopropylmalate

• Slow-onset feedback inhibition: inhibition of Mycobacterium tuberculosis alpha-isopropylmalate synthase by L-leucine [1].
• The deduced amino acid sequences of nifV omega and nifV alpha were also found to have sequence similarity when compared with the primary sequence of the leuA gene product from Salmonella typhimurium, which encodes alpha-isopropylmalate synthase [2].
• Alpha-Isopropylmalate synthase from Alcaligenes eutrophus H 16 I. Purification and general properties [3].
• It is suggested that in these anaerobic bacteria the alpha-isopropylmalate pathway is present in addition to the pathway via the ferrodoxin-dependent, reductive carboxylation of branched chain fatty acids [4].
• Alpha-Isopropylmalate synthase (EC 4.1.3.12) is present in extracts of Bacteroides fragilis, Clostridium thermoaceticum, Clostridium formicoaceticum, Clostridium pasteurianum, and Clostridium kluyveri with specific activities (micromol alpha-isopropylmalate formed per min and g protein) of 8.6, 8.9, 2.4, 1.9, and 0.3, respectively [4].

Psychiatry related information on 2-isopropylmalate

• The response time of transcription and translation of the leu-2 gene of Neurospora to its inducer, alpha-isopropylmalate, approaches the permissible minimum [5].

High impact information on 2-isopropylmalate

• In vitro transcriptional activation by a metabolic intermediate: activation by Leu3 depends on alpha-isopropylmalate [6].
• The metabolic importance of alpha-isopropylmalate appears to be reflected in the surprisingly multifaceted regulation of LEU4 expression [7].
• The role of alpha-isopropylmalate in the regulation of LEU2 expression appears to be that of a co-activator [8].
• Yeast alpha-isopropylmalate isomerase. Factors affecting stability and enzyme activity [9].
• 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) [10].

Chemical compound and disease context of 2-isopropylmalate

• Mn++-specific reactivation of EDTA inactivated alpha-isopropylmalate synthase from Alcaligenes eutrophus H 16 [11].
• The alpha-isopropylmalate synthase (EC 4.1.3.12) from Alcaligenes eutrophus H 16 was inhibited by L-leucine and alpha-ketoisocaproate [12].
• The products of translation of these reading frames display significant homologies with the alpha-isopropylmalate isomerase subunit (leuD) gene of Salmonella typhimurium, the beta-isopropylmalate dehydrogenase (leuB) genes of several organisms, and the dihydroxyacid dehydrase (ilvD) gene of E. coli [13].

Biological context of 2-isopropylmalate

• By this assay, Leu3p was found to occupy its binding site under all conditions tested, including high and low levels of leucine and in the presence and absence of alpha-isopropylmalate [14].
• Phosphorylation did not appear to affect the DNA binding function of Leu3, but (indirect) effects on the activation function or effects on the modulation by alpha-isopropylmalate have not been ruled out [15].
• In one segment the direct repetitive sequences were within the putative coding sequence of alpha-isopropylmalate synthase gene [16].
• Comparative genomics of transcriptional regulation in yeasts and its application to identification of a candidate alpha-isopropylmalate transporter [17].
• A variable number of tandem repeats result in polymorphic alpha -isopropylmalate synthase in Mycobacterium tuberculosis [18].

Anatomical context of 2-isopropylmalate

• Furthermore, the experimental data indicate that the main activities of homocitrate synthase and alpha-isopropylmalate synthase are located in the cytosol [19].

Associations of 2-isopropylmalate with other chemical compounds

• Based on this and on the fact that the fragment weakly complements a leu1 auxotroph of S. cerevisiae, we concluded that the Mucor leu gene encodes alpha-isopropylmalate (alpha-IPM) isomerase and designated it leuA+ accordingly [20].
• alpha-Isopropylmalate synthase catalyses the aldol condensation of alpha-ketoisovalerate and acetyl coenzyme A to produce alpha-isopropylmalate [21].

Gene context of 2-isopropylmalate

• In vivo and in vitro studies have shown that activation by Leu3 requires the presence of alpha-isopropylmalate [22].
• The metal involvement and some of the other properties of alpha-isopropylmalate isomerase reveal a similarity to aconitase [9].
• The cloned 7.2 kb DNA consisting of HindIII fragments of 4.0 kb and 3.2 kb could substitute for leucine genes (alpha-isopropylmalate (alpha-IPM) synthetase gene, beta-IPM dehydrogenase gene, and alpha-IPM isomerase gene) of E. coli and B. subtilis, but not ilvB gene of B. subtilis [23].
• A locus of variable number of the tandem repeat, VNTR4155, resides in the putative leuA gene, encoding for alpha -isopropylmalate synthase (alpha -IPMS) of Mycobacterium tuberculosis, a repeat that is unique to the bacterium [18].
• In vitro activity of the mutant isopropylmalate isomerase was demonstrated; the Km values for alpha-isopropylmalate of both the S. typhimurium leuC-newD isomerase and the S. typhimurium-E. coli hybrid isomerase were as much as 100 times higher than the Km values for alpha-isopropylmalate of the wild-type enzyme, which was 3 x 10(-4) M [24].

Analytical, diagnostic and therapeutic context of 2-isopropylmalate

• Employing mobility shift assays, we show that specific interaction between the LEU3 protein and a 30-base pair DNA fragment carrying the upstream activating sequence of LEU2 takes place irrespective of the presence or absence of alpha-isopropylmalate [8].
• The product alpha-isopropylmalate was identified by gas chromatography combined with mass spectroscopy [4].

References