MDH1 encodes mitochondrial malate dehydrogenase, a homodimeric NAD+-dependent enzyme of the mitochondrial matrix that oxidises (S)-malate to oxaloacetate in the tricarboxylic acid cycle (EC 1.1.1.37). It is the most abundant of the three yeast MDH isozymes (MDH1 mitochondrial, MDH2 cytosolic, MDH3 peroxisomal). MDH1 expression is glucose repressed; mdh1 null mutants cannot grow on acetate and are impaired on glycerol/lactate. Conserved subunit-interface residues (Asp43, His46) control dimer stability and catalysis. Mdh1p interacts in vivo with citrate synthase Cit1p, the next enzyme of the cycle, and co-purifies with other TCA-cycle enzymes and dehydrogenases in mitochondrial supramolecular complexes, consistent with substrate channelling of oxaloacetate. It has also been detected binding mRNAs in a proteome-wide screen.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0003729 mRNA binding | IDA PMID:21124907 A screen for RNA-binding proteins in yeast indicates dual fu... | KEEP AS NON CORE | Summary: IDA: Scherrer et al. found Mdh1p among candidate RNA-binding proteins on protein microarrays and confirmed reproducible mRNA association by RIP-Chip, proposing that NAD-binding Rossmann folds may bind RNA. A real observation, but no function of Mdh1p-mRNA association has been demonstrated, and Mdh1p is a matrix protein. Supporting Evidence: PMID:21124907 We tested four (Gre3, Dfr1, Mdh1, Mdh3) NAD binding proteins for association with cellular RNA with RIP-Chip and found that all of them were reproducibly associated with mRNAs |
| GO:0003824 catalytic activity | IEA GO_REF:0000002 | MODIFY | Summary: IEA from InterPro2GO (IPR015955 lactate dehydrogenase/glycoside hydrolase domain) mapping to the generic term "catalytic activity". Correct for MDH1 but uninformative; the specific NAD+-dependent L-malate dehydrogenase activity is established for this isozyme. Proposed replacements: L-malate dehydrogenase (NAD+) activity Supporting Evidence: file:yeast/MDH1/MDH1-uniprot.txt Reaction=(S)-malate + NAD(+) = oxaloacetate + NADH + H(+); |
| GO:0005515 protein binding | IPI PMID:16429126 Proteome survey reveals modularity of the yeast cell machine... | REMOVE | Summary: IPI from the Gavin et al. TAP-MS complex survey reporting co-purification with the Hsp70 Ssa2. "Protein binding" is uninformative; association with a cytosolic Hsp70 likely reflects chaperone-assisted biogenesis of the precursor rather than an Mdh1p function. Removal does not imply the interaction is false. Reason: Uninformative protein binding term from high-throughput affinity purification. Supporting Evidence: PMID:16429126 Here we report the first genome-wide screen for complexes in an organism, budding yeast, using affinity purification and mass spectrometry. |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: IBA (PTN000166149, a deep MDH node seeded by cytosolic and organellar MDHs incl. all three yeast isozymes and mouse MDH1). Because GO cytoplasm includes mitochondria this is not strictly false, but Mdh1p is a mitochondrial matrix enzyme and a more specific inherited assertion (mitochondrion, PTN000899493) already applies; "is_active_in cytoplasm" adds no information and invites misreading as cytosolic. Reason: Uninformative relative to the established mitochondrial matrix location. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH COMPARTMENT OR COMPLEX MISMATCH Sources checked: PANTHER:PTN000166149 SUPPORTS SOURCE BUT NOT TARGET Deep MDH node whose cytoplasm assertion is driven by cytosolic MDHs (e.g. mouse Mdh1, yeast Mdh2). MDH1 is an organellar isozyme (mitochondrial matrix); cytoplasm is only true via part_of and is uninformative. Supporting Evidence: file:yeast/MDH1/MDH1-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion matrix |
| GO:0005737 cytoplasm | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: IEA from ARBA00026971 (cytoplasm for MDH family). As above, technically encompassing mitochondria but uninformative for a matrix-localized isozyme. Reason: Uninformative relative to mitochondrial matrix. Supporting Evidence: file:yeast/MDH1/MDH1-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion matrix |
| GO:0005739 mitochondrion | HDA PMID:16823961 Toward the complete yeast mitochondrial proteome: multidimen... | ACCEPT | Summary: HDA: Mdh1p identified in the PROMITO mitochondrial proteome. Consistent with its known matrix localization. Supporting Evidence: PMID:16823961 A total of 851 different proteins (PROMITO dataset) were identified |
| GO:0005739 mitochondrion | HDA PMID:24769239 Quantitative variations of the mitochondrial proteome and ph... | ACCEPT | Summary: HDA: Mdh1p quantified in mitochondrial proteomes from fermentative and respiratory growth. Consistent. Supporting Evidence: PMID:24769239 Label free quantitative analysis of protein accumulation revealed significant variation of 176 mitochondrial proteins |
| GO:0005739 mitochondrion | IBA GO_REF:0000033 | ACCEPT | Summary: IBA from PTN000899493 (mitochondrial MDH clade; seeded by Mdh1p and S. pombe Mdh1). Mdh1p is inside this clade and carries its own experimental localization; appearing among the donors reflects that grounding. Supporting Evidence: PMID:3312168 The mitochondrial tricarboxylic acid cycle enzyme malate dehydrogenase was purified from Saccharomyces cerevisiae |
| GO:0005739 mitochondrion | IDA PMID:11502169 Yeast mitochondrial dehydrogenases are associated in a supra... | ACCEPT | Summary: IDA: Mdh1p identified by native PAGE/MS in a mitochondrial supramolecular dehydrogenase complex with other TCA enzymes. Supports mitochondrial location. Supporting Evidence: PMID:11502169 four tricarboxylic acids cycle enzymes (malate dehydrogenase Mdh1p, citrate synthase Cit1p, succinate dehydrogenase Sdh1p, and fumarate hydratase Fum1p) |
| GO:0005739 mitochondrion | IMP PMID:10777592 Reversible transdominant inhibition of a metabolic pathway. ... | ACCEPT | Summary: IMP: Velot & Srere showed that Mdh1p co-overexpression relieves the dominant TCA-cycle inhibition by a Cit1p peptide, evidence of in vivo interaction with mitochondrial citrate synthase. Location consistent (abstract-only; deferring to curator on evidence code). Supporting Evidence: PMID:10777592 the inhibitory phenotype is overcome by a co-overexpression of Mdh1p, the mitochondrial malate dehydrogenase |
| GO:0005739 mitochondrion | IPI PMID:16962558 Enolase takes part in a macromolecular complex associated to... | ACCEPT | Summary: IPI (with enolase, SGD:S000001217): Mdh1p co-purified in an enolase-containing macromolecular complex associated with mitochondria. Mitochondrial location is correct regardless of the complex details. Supporting Evidence: PMID:16962558 The identified components included additional glycolytic enzymes, mitochondrial membrane carriers, and enzymes of the TCA cycle. |
| GO:0005739 mitochondrion | IPI PMID:16962558 Enolase takes part in a macromolecular complex associated to... | ACCEPT | Summary: IPI (with SGD:S000003486) from the same mitochondria-associated enolase complex study. Location correct. Supporting Evidence: PMID:16962558 The identified components included additional glycolytic enzymes, mitochondrial membrane carriers, and enzymes of the TCA cycle. |
| GO:0005739 mitochondrion | RCA GO_REF:0000123 | ACCEPT | Summary: YeastPathways RCA placing the TCA-cycle malate dehydrogenase step in mitochondria. Correct for Mdh1p. Supporting Evidence: PMID:3312168 The mitochondrial tricarboxylic acid cycle enzyme malate dehydrogenase was purified from Saccharomyces cerevisiae |
| GO:0005759 mitochondrial matrix | IDA PMID:9774331 Identification of in vivo substrates of the yeast mitochondr... | ACCEPT | Summary: IDA: Mdh1p identified as a matrix chaperonin (Hsp60/Hsp10) substrate in the mitochondrial matrix folding screen of Dubaquie et al. (abstract-only; deferring to curator). Matrix is the core location of Mdh1p. Supporting Evidence: PMID:9774331 We have devised a novel screen to test the folding of a large variety of homologous substrates in the mitochondrial matrix |
| GO:0005759 mitochondrial matrix | IEA GO_REF:0000044 | ACCEPT | Summary: IEA from UniProt subcellular location (SL-0170 Mitochondrion matrix). Correct and core. Supporting Evidence: file:yeast/MDH1/MDH1-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion matrix |
| GO:0005829 cytosol | RCA GO_REF:0000123 | REMOVE | Summary: YeastPathways RCA from the superpathway of TCA cycle and glyoxylate cycle (PWY3O-94), which places the malate dehydrogenase step in the cytosol and attaches all three MDH isozymes. Mdh1p is the mitochondrial matrix isozyme; the cytosolic reaction belongs to Mdh2p. Reason: Superpathway compartment artefact contradicted by mitochondrial matrix localisation of Mdh1p. Supporting Evidence: file:yeast/MDH1/MDH1-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion matrix PMID:3312168 The mitochondrial tricarboxylic acid cycle enzyme malate dehydrogenase was purified from Saccharomyces cerevisiae |
| GO:0006099 tricarboxylic acid cycle | IBA GO_REF:0000033 | ACCEPT | Summary: IBA from PTN000899493 (mitochondrial MDH clade). Mdh1p is the TCA-cycle malate dehydrogenase; correct and core. Supporting Evidence: PMID:3312168 The mitochondrial tricarboxylic acid cycle enzyme malate dehydrogenase was purified from Saccharomyces cerevisiae |
| GO:0006099 tricarboxylic acid cycle | IEA GO_REF:0000002 | ACCEPT | Summary: IEA from InterPro IPR010097 (MDH type 1). Correct for the mitochondrial isozyme (though the same mapping over-propagates to MDH2/MDH3). Supporting Evidence: PMID:3312168 The mitochondrial tricarboxylic acid cycle enzyme malate dehydrogenase was purified from Saccharomyces cerevisiae |
| GO:0006099 tricarboxylic acid cycle | IMP PMID:3312168 Isolation and expression of the gene encoding yeast mitochon... | ACCEPT | Summary: IMP: mdh1 disruption mutants cannot grow on acetate and are impaired on glycerol/lactate, consistent with loss of the TCA-cycle MDH step. Core process. Supporting Evidence: PMID:3312168 Disruption of the chromosomal malate dehydrogenase gene in haploid S. cerevisiae produces mutants unable to grow on acetate and impaired in growth on glycerol plus lactate as carbon sources. |
| GO:0006108 malate metabolic process | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: IEA from InterPro IPR001252 (MDH active site). True (malate is the substrate) but broader than and implied by the TCA-cycle role. Supporting Evidence: file:yeast/MDH1/MDH1-uniprot.txt Reaction=(S)-malate + NAD(+) = oxaloacetate + NADH + H(+); |
| GO:0009060 aerobic respiration | IMP PMID:3312168 Isolation and expression of the gene encoding yeast mitochon... | ACCEPT | Summary: IMP: mdh1 mutants are impaired on respiratory carbon sources (glycerol + lactate) and cannot use acetate. The TCA cycle is part of aerobic respiration, so this is a correct, broader parent of the core process. Supporting Evidence: PMID:3312168 Disruption of the chromosomal malate dehydrogenase gene in haploid S. cerevisiae produces mutants unable to grow on acetate and impaired in growth on glycerol plus lactate as carbon sources. |
| GO:0009060 aerobic respiration | RCA GO_REF:0000123 | ACCEPT | Summary: YeastPathways RCA from TCA cycle, aerobic respiration (TCA-EUK-PWY). Correct for Mdh1p. Supporting Evidence: PMID:3312168 Disruption of the chromosomal malate dehydrogenase gene in haploid S. cerevisiae produces mutants unable to grow on acetate and impaired in growth on glycerol plus lactate as carbon sources. |
| GO:0016491 oxidoreductase activity | IEA GO_REF:0000002 | MODIFY | Summary: IEA from InterPro2GO (IPR001236 LDH/MDH N-terminal) mapping to the generic term "oxidoreductase activity". Correct for MDH1 but uninformative; the specific NAD+-dependent L-malate dehydrogenase activity is established for this isozyme. Proposed replacements: L-malate dehydrogenase (NAD+) activity Supporting Evidence: file:yeast/MDH1/MDH1-uniprot.txt Reaction=(S)-malate + NAD(+) = oxaloacetate + NADH + H(+); |
| GO:0016615 malate dehydrogenase activity | IEA GO_REF:0000002 | MODIFY | Summary: IEA from InterPro2GO (IPR001252 MDH active site) mapping to the generic term "malate dehydrogenase activity". Correct for MDH1 but uninformative; the specific NAD+-dependent L-malate dehydrogenase activity is established for this isozyme. Proposed replacements: L-malate dehydrogenase (NAD+) activity Supporting Evidence: file:yeast/MDH1/MDH1-uniprot.txt Reaction=(S)-malate + NAD(+) = oxaloacetate + NADH + H(+); |
| GO:0016616 oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor | IEA GO_REF:0000002 | MODIFY | Summary: IEA from InterPro2GO (IPR001557/IPR015955/IPR022383) mapping to the generic term "oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor". Correct for MDH1 but uninformative; the specific NAD+-dependent L-malate dehydrogenase activity is established for this isozyme. Proposed replacements: L-malate dehydrogenase (NAD+) activity Supporting Evidence: file:yeast/MDH1/MDH1-uniprot.txt Reaction=(S)-malate + NAD(+) = oxaloacetate + NADH + H(+); |
| GO:0030060 L-malate dehydrogenase (NAD+) activity | IBA GO_REF:0000033 | ACCEPT | Summary: IBA from PTN000166149 (NAD+-MDH family node incl. all three yeast MDHs, mouse Mdh1/2, Arabidopsis MDHs). Correct; Mdh1p has its own experimental support. Supporting Evidence: file:yeast/MDH1/MDH1-uniprot.txt Reaction=(S)-malate + NAD(+) = oxaloacetate + NADH + H(+); PMID:1898005 The D43N substitution results in a mutant enzyme that is essentially inactive in in vitro assays |
| GO:0030060 L-malate dehydrogenase (NAD+) activity | IDA PMID:1898005 Structural and functional effects of mutations altering the ... | ACCEPT | Summary: IDA: purified wild-type and mutant Mdh1p were assayed; the D43N subunit-interface mutant is inactive and H46L shifts the pH optimum. Direct biochemical evidence of Mdh1p malate dehydrogenase activity. Core. Supporting Evidence: PMID:1898005 The D43N substitution results in a mutant enzyme that is essentially inactive in in vitro assays PMID:1898005 The enzyme containing the H46L substitution, as compared to the wild type enzyme, exhibits a dramatic shift in the pH profile for catalysis toward an optimum at low pH values. |
| GO:0030060 L-malate dehydrogenase (NAD+) activity | IEA GO_REF:0000120 | ACCEPT | Summary: IEA (GO_REF:0000120) from ARBA, InterPro IPR010097, RHEA:21432 and EC 1.1.1.37. Correct. Supporting Evidence: file:yeast/MDH1/MDH1-uniprot.txt Reaction=(S)-malate + NAD(+) = oxaloacetate + NADH + H(+); |
| GO:0030060 L-malate dehydrogenase (NAD+) activity | IMP PMID:10777592 Reversible transdominant inhibition of a metabolic pathway. ... | ACCEPT | Summary: IMP (Velot & Srere): Mdh1p overexpression and mutant analysis in the context of TCA-cycle function. The activity is well established for Mdh1p; deferring to the curator on this evidence (abstract-only in cache). Supporting Evidence: PMID:10777592 the inhibitory phenotype is overcome by a co-overexpression of Mdh1p, the mitochondrial malate dehydrogenase |
| GO:0030060 L-malate dehydrogenase (NAD+) activity | RCA GO_REF:0000123 | ACCEPT | Summary: YeastPathways RCA (TCA/glyoxylate superpathway PWY3O-94) assigning EC 1.1.1.37. The activity is correct for Mdh1p even though the compartment from this superpathway is wrong. Supporting Evidence: file:yeast/MDH1/MDH1-uniprot.txt Reaction=(S)-malate + NAD(+) = oxaloacetate + NADH + H(+); |
| GO:0030060 L-malate dehydrogenase (NAD+) activity | RCA GO_REF:0000123 | ACCEPT | Summary: YeastPathways RCA (TCA-EUK-PWY) assigning EC 1.1.1.37. Correct. Supporting Evidence: file:yeast/MDH1/MDH1-uniprot.txt Reaction=(S)-malate + NAD(+) = oxaloacetate + NADH + H(+); |
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Experiment: Map the Mdh1p surface required for Cit1p association by crosslinking-MS and test interface mutants for TCA flux (13C labelling) without loss of catalytic activity.
Mitochondrial malate dehydrogenase; catalyzes interconversion of malate and oxaloacetate; involved in the tricarboxylic acid (TCA) cycle; phosphorylated; mutation in human homolog MDH2 causes early-onset severe encephalopathy
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