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Gene Review

MDH1  -  malate dehydrogenase MDH1

Saccharomyces cerevisiae S288c

Synonyms: Malate dehydrogenase, mitochondrial, YKL085W
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Disease relevance of MDH1

  • We have expressed the DNA of the fusion of CS1 to MDH1 in Escherichia coli gltA-. The fusion protein (CS1/MDH1) is the C-terminus of CS1 linked in-frame to the N-terminus of MDH1 with a short linker of glycyl-seryl-glycyl [1].

High impact information on MDH1

  • Supporting this, Mdh1p and Idh1p, both TCA cycle enzymes, were up-regulated in response to citric acid [2].
  • Disruption of the MDH2 gene in a haploid strain also containing a disruption in the chromosomal MDH1 gene encoding the mitochondrial isozyme produced a strain unable to grow with acetate but capable of growth on rich medium with glycerol as a carbon source [3].
  • These data provide the first direct in vivo evidence of interaction between two sequential tricarboxylic acid cycle enzymes, Cit1p and Mdh1p, and indicate that the characterization of assembly mutations by the reversible transdominant inhibition method may be a powerful way to study multienzyme complexes in their physiological context [4].
  • The MDH3 isozyme of Saccharomyces cerevisiae was purified from a haploid strain containing disruptions in genomic loci encoding the mitochondrial MDH1 and nonmitochondrial MDH2 isozymes [5].
  • The nucleotide sequence corresponding to codons for the 17-amino acid residues in the presumed targeting presequence for yeast mitochondrial malate dehydrogenase was removed by oligonucleotide-directed mutagenesis of the isolated gene (MDH1) [6].

Chemical compound and disease context of MDH1

  • To test the extent of functional conservation, the rat mitochondrial enzyme and the enzyme from Escherichia coli were expressed in a strain of Saccharomyces cerevisiae containing a disruption of the chromosomal MDH1 gene encoding yeast mitochondrial malate dehydrogenase [7].

Biological context of MDH1

  • The deduced amino acid sequence was closely related to those of MDH1 (50% residue identity) and of MDH2 (43% residue identity) [5].
  • Expression of mdhl- restores total cellular malate dehydrogenase activity to levels comparable to those in wild type cells and reverses the phenotype associated with strains containing MDH1 disruptions by restoring wild type rates of growth in media containing acetate as a carbon source [6].
  • The kinetics of CS1 and MDH1 activities of the fusion protein were compared to those of the free enzymes [1].
  • The contributions of two of these residues, Asp-43 and His-46, to structural stability and catalytic function were investigated by construction of mutant enzymes containing Asn-43 and Leu-46 substitutions using in vitro mutagenesis of the Saccharomyces cerevisiae gene (MDH1) encoding mitochondrial malate dehydrogenase [8].

Anatomical context of MDH1

  • Immunochemical analyses and enzyme assays show comparable levels of malate dehydrogenase in the matrix fractions from mitochondria isolated from mdhl- and MDH1 cells and give no evidence for accumulation of the mature enzyme in the cytosol of mdhl- cells [6].
  • The results show that the fusion proteins are transported into the mitochondria and that they restore the ability for the yeast mutants CS1-, MDH1-, and CS1-/MDH1- to grow on acetate [9].

Associations of MDH1 with chemical compounds

  • (v) Ethanol induction, as seen for ACS2, ADH3 and MDH1, might be mediated via the sequence CGGSGCCGRAG [10].
  • The high apparent Km of MDH2 for L-malic acid (11.8 mM) indicates a low affinity of the enzyme for this acid, which is consistent with the cytosolic function in the enzyme and differs from the previously published Km of the mitochondrial enzyme (MDH1, 0.28 mM) [11].

Analytical, diagnostic and therapeutic context of MDH1


  1. Preparation and kinetic characterization of a fusion protein of yeast mitochondrial citrate synthase and malate dehydrogenase. Lindbladh, C., Rault, M., Hagglund, C., Small, W.C., Mosbach, K., Bülow, L., Evans, C., Srere, P.A. Biochemistry (1994) [Pubmed]
  2. Evidence of a new role for the high-osmolarity glycerol mitogen-activated protein kinase pathway in yeast: regulating adaptation to citric acid stress. Lawrence, C.L., Botting, C.H., Antrobus, R., Coote, P.J. Mol. Cell. Biol. (2004) [Pubmed]
  3. Isolation, nucleotide sequence analysis, and disruption of the MDH2 gene from Saccharomyces cerevisiae: evidence for three isozymes of yeast malate dehydrogenase. Minard, K.I., McAlister-Henn, L. Mol. Cell. Biol. (1991) [Pubmed]
  4. Reversible transdominant inhibition of a metabolic pathway. In vivo evidence of interaction between two sequential tricarboxylic acid cycle enzymes in yeast. Vélot, C., Srere, P.A. J. Biol. Chem. (2000) [Pubmed]
  5. Isolation and characterization of the yeast gene encoding the MDH3 isozyme of malate dehydrogenase. Steffan, J.S., McAlister-Henn, L. J. Biol. Chem. (1992) [Pubmed]
  6. Dispensable presequence for cellular localization and function of mitochondrial malate dehydrogenase from Saccharomyces cerevisiae. Thompson, L.M., McAlister-Henn, L. J. Biol. Chem. (1989) [Pubmed]
  7. Expression and function of heterologous forms of malate dehydrogenase in yeast. Steffan, J.S., Minard, K.I., McAlister-Henn, L. Arch. Biochem. Biophys. (1992) [Pubmed]
  8. Structural and functional effects of mutations altering the subunit interface of mitochondrial malate dehydrogenase. Steffan, J.S., McAlister-Henn, L. Arch. Biochem. Biophys. (1991) [Pubmed]
  9. Metabolic studies on Saccharomyces cerevisiae containing fused citrate synthase/malate dehydrogenase. Lindbladh, C., Brodeur, R.D., Small, W.C., Lilius, G., Bülow, L., Mosbach, K., Srere, P.A. Biochemistry (1994) [Pubmed]
  10. Transient mRNA responses in chemostat cultures as a method of defining putative regulatory elements: application to genes involved in Saccharomyces cerevisiae acetyl-coenzyme A metabolism. van den Berg, M.A., de Jong-Gubbels, P., Steensma, H.Y. Yeast (1998) [Pubmed]
  11. Overexpression of cytosolic malate dehydrogenase (MDH2) causes overproduction of specific organic acids in Saccharomyces cerevisiae. Pines, O., Shemesh, S., Battat, E., Goldberg, I. Appl. Microbiol. Biotechnol. (1997) [Pubmed]
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