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IDH2  -  isocitrate dehydrogenase (NAD(+)) IDH2

Saccharomyces cerevisiae S288c

Synonyms: Isocitric dehydrogenase, NAD(+)-specific ICDH, O3326, YOR136W, YOR3326W
 
 
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High impact information on IDH2

  • The expression of four additional TCA cycle genes downstream of IDH1 and IDH2 is independent of the RTG genes [1].
  • In this study, we also demonstrate that a prerequisite for holoenzyme binding of NAD(+) is binding of isocitrate/Mg(2+) at the IDH2 catalytic site [2].
  • A K189A substitution in IDH2 was found to produce a decrease in activation of the enzyme by AMP and a loss of cooperativity with respect to isocitrate [3].
  • Collectively, these results suggest that the basic structural/functional unit of yeast isocitrate dehydrogenase is a heterodimer of IDH1 and IDH2 subunits and that each subunit contributes to the isocitrate binding site of the other [3].
  • In contrast, alanine replacement of the homologous Asp-286 and Ile-287 residues in IDH2 does not alter the allosteric response to AMP, but produces a 160-fold reduction in Vmax due to a 70-fold increase in the S0.5 value for NAD+ [4].
 

Biological context of IDH2

  • 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) [5].
  • Mutations in the IDH2 gene encoding the catalytic subunit of the yeast NAD+-dependent isocitrate dehydrogenase can be suppressed by mutations in the CIT1 gene encoding citrate synthase and other genes of oxidative metabolism [6].
  • Spontaneous suppressor mutants that restore fast growth on glycerol medium to strains harboring two idh2 alleles were isolated, and a large percentage of the suppressor mutations have been identified within the CIT1 gene and at several other loci [6].
  • These results suggest that the nucleotide cofactor binding site is primarily contributed by the IDH2 subunit, whereas the homologous nucleotide binding site in IDH1 has evolved for regulatory binding of AMP [2].
  • The amino acid sequence deduced from the gene indicates that IDH2 is synthesized as a precursor of 369 amino acids (Mr 39,694) and is processed upon mitochondrial import to yield a mature protein of 354 amino acids (Mr 37,755) [7].
 

Anatomical context of IDH2

 

Associations of IDH2 with chemical compounds

  • Mutations in 7 TCA cycle genes were capable of functioning as suppressors for growth of idh2 mutants on glycerol [5].
  • A model is presented for the primary function of IDH2 in catalysis and of IDH1 in regulation, with crucial roles for these single aspartate residues in the communication and functional interdependence of the two subunits [4].
  • These results suggest that the targeted aspartate/isoleucine residues may contribute to regulator binding in IDH1 and to cofactor binding in IDH2, i.e. that these homologous residues are located in regions that have evolved for binding the adenine nucleotide components of different ligands [4].
 

Physical interactions of IDH2

 

Regulatory relationships of IDH2

  • These and other studies indicate that any mutation within CIT1 was capable of suppressing the idh2 mutations [6].
 

Other interactions of IDH2

  • Null and nonsense idh2 mutants grow poorly on glycerol, but growth can be enhanced by extragenic mutations, termed glycerol suppressors, in the CIT1 gene encoding the TCA cycle citrate synthase and in other genes of oxidative metabolism [5].
 

Analytical, diagnostic and therapeutic context of IDH2

References

  1. A transcriptional switch in the expression of yeast tricarboxylic acid cycle genes in response to a reduction or loss of respiratory function. Liu, Z., Butow, R.A. Mol. Cell. Biol. (1999) [Pubmed]
  2. Homologous binding sites in yeast isocitrate dehydrogenase for cofactor (NAD+) and allosteric activator (AMP). Lin, A.P., McAlister-Henn, L. J. Biol. Chem. (2003) [Pubmed]
  3. Subunit interactions of yeast NAD+-specific isocitrate dehydrogenase. Panisko, E.A., McAlister-Henn, L. J. Biol. Chem. (2001) [Pubmed]
  4. Affinity purification and kinetic analysis of mutant forms of yeast NAD+-specific isocitrate dehydrogenase. Zhao, W.N., McAlister-Henn, L. J. Biol. Chem. (1997) [Pubmed]
  5. Genetic and biochemical interactions involving tricarboxylic acid cycle (TCA) function using a collection of mutants defective in all TCA cycle genes. Przybyla-Zawislak, B., Gadde, D.M., Ducharme, K., McCammon, M.T. Genetics (1999) [Pubmed]
  6. Mutations in the IDH2 gene encoding the catalytic subunit of the yeast NAD+-dependent isocitrate dehydrogenase can be suppressed by mutations in the CIT1 gene encoding citrate synthase and other genes of oxidative metabolism. Gadde, D.M., McCammon, M.T. Arch. Biochem. Biophys. (1997) [Pubmed]
  7. NAD(+)-dependent isocitrate dehydrogenase. Cloning, nucleotide sequence, and disruption of the IDH2 gene from Saccharomyces cerevisiae. Cupp, J.R., McAlister-Henn, L. J. Biol. Chem. (1991) [Pubmed]
  8. Subunit structure, expression, and function of NAD(H)-specific isocitrate dehydrogenase in Saccharomyces cerevisiae. Keys, D.A., McAlister-Henn, L. J. Bacteriol. (1990) [Pubmed]
  9. Kinetic and physiological effects of alterations in homologous isocitrate-binding sites of yeast NAD(+)-specific isocitrate dehydrogenase. Lin, A.P., McCammon, M.T., McAlister-Henn, L. Biochemistry (2001) [Pubmed]
 
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