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Gene Review

MDH2  -  malate dehydrogenase 2, NAD (mitochondrial)

Homo sapiens

Synonyms: M-MDH, MDH, MGC:3559, MOR1, Malate dehydrogenase, mitochondrial
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Disease relevance of MDH2

  • The discovery that MDH reacts with intermediate metabolites of phenylalanine and tyrosine has implications in relation to the mechanism by which mental retardation may be produced in phenylketonuria (PKU), and the effect of MDH inhibition on oxidative phosphorylation in the various tyrosinaemias is discussed [1].
  • The interactions of methanol dehydrogenase (MDH, EC1.1.99.8) with its specific electron acceptor cytochrome cL has been investigated in Methylobacterium extorquens and Methylophilus methylotrophus [2].
  • The Aa MDH sequence is most closely related to the sequence of a thermophilic MDH from Thermus flavus (Tf MDH), showing 61% sequence identity and over 90% sequence similarity [3].
  • The present study demonstrates a conditional, agonist-dependent phosphorylation of the mu-opioid receptor (MOR-1) by cyclic AMP-dependent protein kinase (PKA) in membrane preparations of MOR-1-transfected neuroblastoma Neuro2A cells [4].
  • N-terminal amino acid sequence analysis showed that the enzyme belongs to the same family of alcohol dehydrogenases as Zymomonas mobilis ADH2 and Bacillus methanolicus MDH [5].

High impact information on MDH2

  • The MDH reaction was accelerated by vanadate, but we found thatr vanadate does not require the presence of any specific enzyme or substrate to mediate NADH oxidation [6].
  • Here we have studied the effect of vanadate on malate dehydrogenase (MDH, EC1.1.1.37) catalysed oxidation of NADH during the formation of malate from oxalacetate in vitro [6].
  • The CDKN2-like polymorphism maps to Xiphophorus linkage group V and exhibits recombination fractions with ES1 and MDH2 allozyme markers consistent with previous localization of the DIFF tumor suppressor locus [7].
  • However, a single allele of normal activity at one of the three loci encoding the mitochondrial MDHs is sufficient for normal development, whereas plants with essentially no cytosolic MDH activity function normally [8].
  • Five independently inherited loci on five distinct chromosomes encode the mitochondrial and cytosolic isozymes of NAD-dependent malate dehydrogenase (MDH; L-malate:NAD+ oxidoreductase, EC [8].

Chemical compound and disease context of MDH2

  • We investigated the influence of different molecular constructions on receptor expression levels: the receptor was fused either to an amino- or a carboxy-terminal histidine tag (hMOR-N-His and hMOR-C-His respectively), or to the cleavable sequence signal of the baculovirus gp64 glycoprotein (gp-hMOR and gp-hMOR-C-His) [9].

Biological context of MDH2

  • The N-terminal amino acid sequence of the alpha-subunit of MDH2 differed from that of MDH1 by having a histidine residue at a highly conserved glutamate position, but both sequences showed approximately 50% homology to the alpha-subunits of other MDHs [10].
  • M. destructor males displayed no heterozygosity at the Pgm3 locus, indicating that they were hemizygous as is the PGM locus in North America. In M. hordei, heterozygous males were observed at all loci, but strong heterozygote deficits were found at two loci (Mdh2 et Hk) [11].
  • Our data show that natural sequence variations in hMOR gene have little influence on ligand binding or receptor down-regulation but could otherwise modify receptor density and signaling [12].
  • For the corresponding phosphorylation site in the human mu-opioid receptor (hMOR), an allelic variation S268P has been recently identified [13].
  • The present study examined DNA-protein interactions in the human MOR (hMOR) -500 to -292 promoter region, and tested whether chronic opioid drug treatment could modulate these DNA-protein interactions [14].

Anatomical context of MDH2

  • 3. Some significant correlations were established, both between the activities of individual enzymes (TPDH, GPDH, HK, CS, HOADH) and between the enzymes and indicators of functional capacity (MDH, CS, HOADH, VO2max, HRmax, O2-pulse max, body fat, laboratory performance) [15].
  • Fiber type proportions (type I, type IIA, and type IIB) and activity levels of marker enzymes for the Krebs cycle (malate dehydrogenase, MDH) and for the fatty acid oxidation (3-hydroxyacyl CoA dehydrogenase, HADH) pathways were determined in vastus lateralis muscle samples [16].
  • Therefore, the morphine-binding site on mitogen-activated T-lymphocytes is unlikely to be closely related to hMOR-1 [17].
  • Whereas MDH showed a specific staining of autophagic vacuoles, the polar and acidic derivatives did not show any staining [18].
  • Mu opioid receptors (MOR-1) were expressed in Xenopus oocytes, a well recognized expression system, and glucose was tested for possible agonist, antagonist, and modulatory effects on the receptor [19].

Associations of MDH2 with chemical compounds

  • MDH1 had higher specific activity than MDH2 with respect to methanol and ethanol as a substrate [10].
  • Both strains showed higher levels of CS, ICDH, and MDH and lower SDH and ME activities when more metacyclic promastigotes were present, but in VL these changes paralleled an increase in glucose consumption, whereas in CL these changes coincided with an NH3 hyperproduction [20].
  • The overall process consisted of cell-bound divalent reduction of quinones, followed by extracellular laccase-mediated oxidation of hydroquinones into semiquinones, which autoxidized to a certain extent producing O-.2 (at the pH values of natural degradation of lignin, some autoxidation of hydroquinones was observed only with DQH2 and MDH2) [21].
  • The reduction of aromatic alpha-keto acids is substantially inhibited by malate, the end-product of the MDH reaction [1].
  • The feasibility of the approach has been tested with malic enzyme (MDH, EC as the dehydrogenase, resulting in a novel L-malate sensor [22].

Other interactions of MDH2

  • Evidence shows that the ACP1 gene is in the region 2p24 leads to 2pter and that MDH is not [23].
  • The analysis of six enzymatic systems showed the existence of four monomorphic systems (IDH, MDH, SHDH and SOD) [24].
  • Inhibition with malate, the end product of the MDH reaction, substantially reduces or totally eliminates KAR activity [25].
  • Analyses of LDH, MDH, AcP, PGM, GPI, G6PDH and HK by isoelectric focusing provided no evidence for the involvement of S. rodhaini in the recent evolution of the schistosomes currently endemic in Guadeloupe [26].
  • MDH and tuna cytochrome c competed for the same domain on cytochrome cL [2].

Analytical, diagnostic and therapeutic context of MDH2


  1. Biochemical and genetic identity of alpha-keto acid reductase and cytoplasmic malate dehydrogenase from human erythrocytes. Friedrich, C.A., Ferrell, R.E., Siciliano, M.J., Kitto, G.B. Ann. Hum. Genet. (1988) [Pubmed]
  2. The interaction of methanol dehydrogenase and its electron acceptor, cytochrome cL in methylotrophic bacteria. Cox, J.M., Day, D.J., Anthony, C. Biochim. Biophys. Acta (1992) [Pubmed]
  3. Structural basis for cold adaptation. Sequence, biochemical properties, and crystal structure of malate dehydrogenase from a psychrophile Aquaspirillium arcticum. Kim, S.Y., Hwang, K.Y., Kim, S.H., Sung, H.C., Han, Y.S., Cho, Y. J. Biol. Chem. (1999) [Pubmed]
  4. Distinct differences between morphine- and [D-Ala2,N-MePhe4,Gly-ol5]-enkephalin-mu-opioid receptor complexes demonstrated by cyclic AMP-dependent protein kinase phosphorylation. Chakrabarti, S., Law, P.Y., Loh, H.H. J. Neurochem. (1998) [Pubmed]
  5. Purification and characterization of an oxygen-labile, NAD-dependent alcohol dehydrogenase from Desulfovibrio gigas. Hensgens, C.M., Vonck, J., Van Beeumen, J., van Bruggen, E.F., Hansen, T.A. J. Bacteriol. (1993) [Pubmed]
  6. A specific enzyme is not necessary for vanadate-induced oxidation of NADH. Vyskocil, F., Teisinger, J., Dlouhá, H. Nature (1980) [Pubmed]
  7. A CDKN2-like polymorphism in Xiphophorus LG V is associated with UV-B-induced melanoma formation in platyfish-swordtail hybrids. Nairn, R.S., Kazianis, S., McEntire, B.B., Della Coletta, L., Walter, R.B., Morizot, D.C. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  8. Malate dehydrogenase: viability of cytosolic nulls and lethality of mitochondrial nulls in maize. Goodman, M.M., Newton, K.J., Stuber, C.W. Proc. Natl. Acad. Sci. U.S.A. (1981) [Pubmed]
  9. Parameters influencing human mu opioid receptor over-expression in baculovirus-infected insect cells. Massotte, D., Pereira, C.A., Pouliquen, Y., Pattus, F. J. Biotechnol. (1999) [Pubmed]
  10. Purification and characterization of two forms of methanol dehydrogenases from a marine methylotroph. Chang, A.K., Lim, C.Y., Kim, S.W., You, H.J., Hahm, K.S., Yoon, S.M., Park, J.K., Lee, J.S. J. Basic Microbiol. (2002) [Pubmed]
  11. Structure génétique des cécidomyies des céréales en Tunisie. Makni, H., Sellami, M., Marrakchi, M., Pasteur, N. Genet. Sel. Evol. (2000) [Pubmed]
  12. A single nucleotide polymorphic mutation in the human mu-opioid receptor severely impairs receptor signaling. Befort, K., Filliol, D., Decaillot, F.M., Gaveriaux-Ruff, C., Hoehe, M.R., Kieffer, B.L. J. Biol. Chem. (2001) [Pubmed]
  13. Allelic variation S268P of the human mu-opioid receptor affects both desensitization and G protein coupling. Koch, T., Kroslak, T., Averbeck, M., Mayer, P., Schröder, H., Raulf, E., Höllt, V. Mol. Pharmacol. (2000) [Pubmed]
  14. Binding of Sp1/Sp3 to the proximal promoter of the hMOR gene is enhanced by DAMGO. Xu, Y., Carr, L.G. Gene (2001) [Pubmed]
  15. Enzyme activity patterns of energy metabolism in skiers of different performance levels (M. quadriceps femoris). Macková, E.V., Bass, A., Sprynarová, S., Teisinger, J., Vondra, K., Bojanovský, I. European journal of applied physiology and occupational physiology. (1982) [Pubmed]
  16. Skeletal muscle metabolism and body fat content in men and women. Simoneau, J.A., Bouchard, C. Obes. Res. (1995) [Pubmed]
  17. The morphine-binding site on human activated T-cells is not related to the mu opioid receptor. Madden, J.J., Whaley, W.L., Ketelsen, D., Donahoe, R.M. Drug and alcohol dependence. (2001) [Pubmed]
  18. Fluorescence properties and staining behavior of monodansylpentane, a structural homologue of the lysosomotropic agent monodansylcadaverine. Niemann, A., Baltes, J., Elsässer, H.P. J. Histochem. Cytochem. (2001) [Pubmed]
  19. Sugar solution analgesia: the effects of glucose on expressed mu opioid receptors. Kracke, G.R., Uthoff, K.A., Tobias, J.D. Anesth. Analg. (2005) [Pubmed]
  20. Citric-acid cycle key enzyme activities during in vitro growth and metacyclogenesis of Leishmania infantum promastigotes. Louassini, M., Foulquié, M., Benítez, R., Adroher, J. J. Parasitol. (1999) [Pubmed]
  21. Quinone redox cycling in the ligninolytic fungus Pleurotus eryngii leading to extracellular production of superoxide anion radical. Guillén, F., Martínez, M.J., Muñoz, C., Martínez, A.T. Arch. Biochem. Biophys. (1997) [Pubmed]
  22. A bienzyme electrode for L-malate based on a novel and general design. Gajovic, N., Warsinke, A., Scheller, F.W. J. Biotechnol. (1998) [Pubmed]
  23. Further evidence by gene dosage for the regional assignment of erythrocyte acid phosphatase (ACP1) and malate dehydrogenase (MDH1) loci on chromosome 2p. Larson, L.M., Bruce, A.W., Saumur, J.H., Wasdahl, W.A. Clin. Genet. (1982) [Pubmed]
  24. Polyporus s. str. in southern South America: isoenzyme analysis. Borges da Silveira, R.M., Saidman, B.O., Wright, J.E. Mycol. Res. (2003) [Pubmed]
  25. The reduction of aromatic alpha-keto acids by cytoplasmic malate dehydrogenase and lactate dehydrogenase. Friedrich, C.A., Morizot, D.C., Siciliano, M.J., Ferrell, R.E. Biochem. Genet. (1987) [Pubmed]
  26. Schistosoma mansoni from naturally infected Rattus rattus in Guadeloupe: identification, prevalence and enzyme polymorphism. Rollinson, D., Imbert-Establet, D., Ross, G.C. Parasitology (1986) [Pubmed]
  27. Malate dehydrogenase from the thermophilic green bacterium Chloroflexus aurantiacus: purification, molecular weight, amino acid composition, and partial amino acid sequence. Rolstad, A.K., Howland, E., Sirevåg, R. J. Bacteriol. (1988) [Pubmed]
  28. The human mu opioid receptor gene: 5' regulatory and intronic sequences. Wendel, B., Hoehe, M.R. J. Mol. Med. (1998) [Pubmed]
  29. Early response to chemotherapy: a surrogate for final outcome of Hodgkin's disease patients that should influence initial treatment length and intensity? Carde, P., Koscielny, S., Franklin, J., Axdorph, U., Raemaekers, J., Diehl, V., Aleman, B., Brosteanu, O., Hasenclever, D., Oberlin, O., Bonvin, N., Björkholm, M. Ann. Oncol. (2002) [Pubmed]
  30. The opioid ligand binding of human mu-opioid receptor is modulated by novel splice variants of the receptor. Choi, H.S., Kim, C.S., Hwang, C.K., Song, K.Y., Wang, W., Qiu, Y., Law, P.Y., Wei, L.N., Loh, H.H. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
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