Disease relevance of Homocitrate

• Citrate substitutes for homocitrate in nitrogenase of a nifV mutant of Klebsiella pneumoniae [1].
• Purification of the Azotobacter vinelandii nifV-encoded homocitrate synthase [2].
• E. coli cells in which a high level of nifV expression is induced excrete homocitrate into the growth medium [2].
• The nifV and leuA genes, which encode homocitrate synthase and alpha-isopropylmalate synthase, respectively, were cloned from the filamentous cyanobacterium Anabaena sp. strain PCC 7120 by a PCR-based strategy [3].
• Nucleotide sequence and genetic analysis of the Rhodobacter capsulatus ORF6-nifUI SVW gene region: possible role of NifW in homocitrate processing [4].

High impact information on Homocitrate

• Further, we establish that Mo/homocitrate mobilization by the Fe protein likely involves hydrolysis of MgATP and protein-protein interaction between the Fe protein and NifEN [5].
• Inactivation of homocitrate synthase causes lysine auxotrophy in copper/zinc-containing superoxide dismutase-deficient yeast Schizosaccharomyces pombe [6].
• Regulatory mechanism of histidine-tagged homocitrate synthase from Saccharomyces cerevisiae. II. Theory [7].
• The localization of homocitrate synthase to the nucleus is unexpected given previous reports that homocitrate synthase is present in mitochondria and the cytoplasm in S. cerevisiae [8].
• These two open reading frames are predicted to encode homocitrate synthase isozymes of 47 and 49 kDa, respectively [8].

Chemical compound and disease context of Homocitrate

• Effects of homocitrate, homocitrate lactone, and fluorohomocitrate on nitrogenase in NifV- mutants of Azotobacter vinelandii [9].
• ORF D1298 shows the characteristics of alpha-isopropylmalate and homocitrate synthase genes and is similar to the nifV gene of Azotobacter vinelandii [10].
• We do not observe HACN-catalysed 'homocitrate dehydratase' activity; however, we have observed that ACN can catalyse the dehydration of (R)-homocitrate to cis-homoaconitate, but HACN is required for subsequent conversion of cis-homoaconitate into homoisocitrate [11].

Biological context of Homocitrate

• With appropriate homocitrate analogues, aberrant forms of FeMo-co are synthesized that exhibit altered substrate specificity and inhibitor susceptibility [12].
• Fluorohomocitrate does not inhibit the uptake of homocitrate because the wild-type phenotype resulted when both compounds were added to the medium during nitrogenase derepression [9].
• A 2071-bp DNA fragment, containing a gene (lys1) encoding a protein that showed 71.1% identical amino acids with the Yarrowia lipolytica homocitrate synthase and 71.7% identity with the Saccharomyces cerevisiae homologous enzyme, was cloned from a genomic library of Penicillium chrysogenum [13].
• In Saccharomyces cerevisae, feedback inhibition of homocitrate synthase isoenzymes by lysine modulates the activation of LYS gene expression by Lys14p [14].
• Some of these transformants, particularly Ti-C4 (integrative) and TAR-L9 (with autonomously replicating plasmids) showed very high levels of lys1 transcript and, in the case of TAR-L9, high levels of homocitrate synthase activity in cultures of 120 h [15].

Associations of Homocitrate with other chemical compounds

• NifB-co-dependent in vitro FeMo-co synthesis is absolutely dependent on the presence of molybdate, homocitrate and active NIFNE protein in the reaction mixture [16].
• Substrate reduction properties of dinitrogenase activated in vitro are dependent upon the presence of homocitrate or its analogues during iron-molybdenum cofactor synthesis [17].
• The general acid then acts as a base in deprotonating Zn-OH(2) in the hydrolysis of homocitryl-CoA to give homocitrate and CoA [18].
• Sequence identity between nifV and leuA gene products suggests that nifV may catalyze a condensation reaction analogous to that carried out by isopropylmalate synthase (LEUA) but in which acetyl coenzyme and alpha-ketoglutarate are substrates for the formation of homocitrate, the proposed product of NIFV activity [19].
• Histidine-tagged homocitrate synthase from Saccharomyces cerevisiae was purified to about 98% using a Ni-NTA resin and stabilized using a combination of 100 mM guanidine hydrochloride, 100 mM alpha-cyclodextrin, and 600 mM ammonium sulfate [20].

Gene context of Homocitrate

• Lysine overproduction by one of the mutants seemed to be due to, at least, the loss of repression of the homocitrate synthase encoded by the LYS20 gene [21].
• In this report we demonstrate that Saccharomyces cerevisiae possesses two genes, LYS20 and LYS21, encoding two homocitrate synthase isoenzymes which are located in the nucleus [14].
• In spite of extensive genetic analysis, no mutation affecting this step has been isolated until now in model organisms such as Saccharomyces cerevisiae or Neurospora crassa, although identification of mutations affecting the structural gene (LYS1) for homocitrate synthase was reported in the yeast Yarrowia lipolytica several years ago [22].
• Urinary excretion of homocitric acid and methylhomocitric acid in propionic acidaemia: minor metabolic products of the citrate synthase aldol condensation reaction [23].

Analytical, diagnostic and therapeutic context of Homocitrate

• Native homocitrate synthase shows a molecular mass of 155 +/- 10 kDa as determined by gel filtration and a pH of 4.9 +/- 0.1 as determined by chromatofocusing [24].
• HPLC and 1H-NMR analyses revealed that LysF88 accumulated homocitric acid in the culture supernatant [25].
• The identity of two formerly novel citric acid analogues, homocitric acid and methylhomocitric acid, in urine samples from patients with propionic acidaemia was confirmed by gas chromatography and mass spectrometry [23].

References