Mdh1

UniProt ID: Q9VKX2
Organism: Drosophila melanogaster
Review Status: COMPLETE
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Gene Description

Mdh1 (CG5362) encodes the cytoplasmic NAD-dependent malate dehydrogenase of Drosophila melanogaster, a member of the LDH/MDH superfamily (MDH type 2 family) that reversibly oxidises L-malate to oxaloacetate with NAD+. Working with cytosolic aspartate aminotransferase (Got1) and their mitochondrial counterparts it forms the cytosolic arm of the malate-aspartate shuttle, reducing oxaloacetate to malate to carry glycolytic NADH equivalents into mitochondria, and it participates in pyruvate-malate and pyruvate-citrate cycling between mitochondria and cytosol. Natural allozymes and induced null alleles have been characterised biochemically; Mdh1 nulls are viable but have reduced adult ethanol tolerance, whereas partial reductions of cytosolic MDH activity can increase tolerance.

Existing Annotations Review

GO Term Evidence Action Reason
GO:0003824 catalytic activity
IEA
GO_REF:0000002 		MODIFY
Summary: Generic catalytic activity from InterPro LDH/glycoside hydrolase C-terminal domain.
Reason: Correct but uninformative; the enzyme is an NAD-dependent L-malate dehydrogenase, already annotated with experimental support.
Supporting Evidence:
file:DROME/Mdh1/Mdh1-uniprot.txt
DR InterPro; IPR011274; Malate_DH_NAD-dep_euk.
GO:0005737 cytoplasm
IDA
PMID:45555
Biochemical studies of supernatant malate dehydrogenase allo... 		MODIFY
Summary: Cytoplasm, from separation of cytoplasmic and mitochondrial MDH (Alahiotis 1979).
Reason: Mdh1 encodes the cytoplasmic (supernatant) MDH; correct but less specific, so MODIFY to cytosol, which Mdh1 already carries (IBA, IDA).
Proposed replacements: cytosol
Supporting Evidence:
PMID:45555
A simple method is presented for the separation of the cytoplasmic from the mitochondrial malate dehydrogenase.
GO:0005777 peroxisome
ISM
PMID:22758915
An inventory of peroxisomal proteins and pathways in Drosoph... 		UNDECIDED
Summary: Peroxisome, from a computational inventory of predicted peroxisomal proteins (Faust et al. 2012).
Reason: Sequence-based prediction (ISM). The fly protein ends in a non-canonical C-terminal tripeptide, and only five predicted proteins were experimentally confirmed in the inventory. Mammalian MDH1 reaches peroxisomes through a translational read-through isoform, so a minor peroxisomal pool is conceivable, but there are no Drosophila data. Left undecided.
Supporting Evidence:
PMID:22758915
The subcellular localization of five of these predicted peroxisomal proteins was confirmed.
GO:0005829 cytosol
IBA
GO_REF:0000033 		ACCEPT
Summary: Cytosol, phylogenetic inference.
Reason: Cytosolic MDH subfamily; consistent with biochemical data.
Supporting Evidence:
PMID:19033156
cytosolic malate dehydrogenase (Mdh1)
GO:0005829 cytosol
IDA
PMID:109448
Biochemical analyses of natural and induced null variants of... 		ACCEPT
Summary: Cytosol, from purification of cytoplasmic MDH (Lee et al. 1979).
Reason: Cytoplasmic MDH was purified separately from mitochondrial MDH; core location.
Supporting Evidence:
PMID:109448
cytoplasmic malate dehydrogenase
GO:0006094 gluconeogenesis
ISS
GO_REF:0000024 		KEEP AS NON CORE
Summary: Gluconeogenesis, transferred by sequence similarity.
Reason: Cytosolic MDH can regenerate oxaloacetate from malate exported from mitochondria for PEPCK in gluconeogenic tissues; plausible in the fly fat body but not demonstrated, and peripheral to its main role.
Supporting Evidence:
file:DROME/Mdh1/Mdh1-uniprot.txt
Reaction=(S)-malate + NAD(+) = oxaloacetate + NADH + H(+);
GO:0006099 tricarboxylic acid cycle
IBA
GO_REF:0000033 		MARK AS OVER ANNOTATED
Summary: Tricarboxylic acid cycle, phylogenetic inference from the MDH family node.
Reason: The TCA cycle runs in the mitochondrial matrix, where it uses the mitochondrial MDH (Mdh2). Mdh1 is the cytoplasmic isozyme; it catalyses the same chemistry but in the cytosol, where it serves the malate-aspartate shuttle and pyruvate-malate cycling rather than the TCA cycle. The IBA reflects a deep node shared with TCA-cycle MDHs; for the cytosolic member the process assignment is an over-propagation.
Propagation Review
Root cause: PROPAGATION BAD
Failure modes: COMPARTMENT OR COMPLEX MISMATCH
Sources checked:
PANTHER:PTN000600336 SUPPORTS SOURCE BUT NOT TARGET
Ancestral MDH node covering both mitochondrial (TCA-cycle) and cytosolic malate dehydrogenases; the TCA-cycle role holds for the mitochondrial descendants but not for the cytosolic Mdh1, whose matrix counterpart is Mdh2.
Supporting Evidence:
PMID:19033156
This observation strongly suggests the operation of pyruvate-malate and, in particular, pyruvate-citrate cycling in adaptation to alcohol exposure.
GO:0006107 oxaloacetate metabolic process
IBA
GO_REF:0000033 		ACCEPT
Summary: Oxaloacetate metabolic process, phylogenetic inference.
Reason: Oxaloacetate is a direct substrate/product.
Supporting Evidence:
file:DROME/Mdh1/Mdh1-uniprot.txt
Reaction=(S)-malate + NAD(+) = oxaloacetate + NADH + H(+);
GO:0006107 oxaloacetate metabolic process
IDA
PMID:45555
Biochemical studies of supernatant malate dehydrogenase allo... 		ACCEPT
Summary: Oxaloacetate metabolic process from kinetic studies of MDH allozymes (Alahiotis 1979).
Reason: Kinetic characterisation with oxaloacetate as substrate.
Supporting Evidence:
PMID:45555
distinguishable in terms of NADH and OAA saturation conditions
GO:0006108 malate metabolic process
IBA
GO_REF:0000033 		ACCEPT
Summary: Malate metabolic process, phylogenetic inference.
Reason: Malate is a direct substrate/product.
Supporting Evidence:
file:DROME/Mdh1/Mdh1-uniprot.txt
Reaction=(S)-malate + NAD(+) = oxaloacetate + NADH + H(+);
GO:0006108 malate metabolic process
IDA
PMID:45555
Biochemical studies of supernatant malate dehydrogenase allo... 		ACCEPT
Summary: Malate metabolic process from kinetic studies of MDH allozymes (Alahiotis 1979).
Reason: Kinetic characterisation with L-malate as substrate.
Supporting Evidence:
PMID:45555
indistinguishable in terms of NAD and L-malate optima
GO:0006108 malate metabolic process
IEA
GO_REF:0000002 		ACCEPT
Summary: Malate metabolic process from InterPro.
Reason: Consistent with other evidence.
Supporting Evidence:
file:DROME/Mdh1/Mdh1-uniprot.txt
DR InterPro; IPR001252; Malate_DH_AS.
GO:0016491 oxidoreductase activity
IEA
GO_REF:0000002 		MODIFY
Summary: Oxidoreductase activity from InterPro.
Reason: Correct but a general parent; MODIFY to L-malate dehydrogenase (NAD+) activity, which Mdh1 already carries (IBA, IDA, IEA).
Supporting Evidence:
file:DROME/Mdh1/Mdh1-uniprot.txt
DR InterPro; IPR001236; Lactate/malate_DH_N.
GO:0016615 malate dehydrogenase activity
IEA
GO_REF:0000002 		MODIFY
Summary: Malate dehydrogenase activity from InterPro.
Reason: Correct parent; MODIFY to L-malate dehydrogenase (NAD+) activity, which Mdh1 already carries (IBA, IDA, IEA).
Supporting Evidence:
file:DROME/Mdh1/Mdh1-uniprot.txt
DR PROSITE; PS00068; MDH; 1.
GO:0016616 oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor
IEA
GO_REF:0000002 		MODIFY
Summary: Oxidoreductase activity acting on CH-OH group with NAD(P) from InterPro.
Reason: Correct parent; MODIFY to L-malate dehydrogenase (NAD+) activity, which Mdh1 already carries (IBA, IDA, IEA).
Supporting Evidence:
file:DROME/Mdh1/Mdh1-uniprot.txt
DR InterPro; IPR001557; L-lactate/malate_DH.
GO:0030060 L-malate dehydrogenase (NAD+) activity
IBA
GO_REF:0000033 		ACCEPT
Summary: L-malate dehydrogenase (NAD+) activity, phylogenetic inference.
Reason: Core activity, consistent with direct biochemistry.
Supporting Evidence:
file:DROME/Mdh1/Mdh1-uniprot.txt
DR InterPro; IPR011274; Malate_DH_NAD-dep_euk.
GO:0030060 L-malate dehydrogenase (NAD+) activity
IDA
PMID:109448
Biochemical analyses of natural and induced null variants of... 		ACCEPT
Summary: L-malate dehydrogenase (NAD+) activity of purified cytoplasmic MDH and null variants (Lee et al. 1979).
Reason: Cytoplasmic MDH purified to homogeneity and null mutants characterised; core activity.
Supporting Evidence:
PMID:109448
Two low-dose-rate gamma-radiation-induced null mutants of cytoplasmic malate dehydrogenase were shown to be positive to cross-reacting material.
GO:0030060 L-malate dehydrogenase (NAD+) activity
IDA
PMID:4313528
Purification and properties of Drosophila malate dehydrogena... 		ACCEPT
Summary: L-malate dehydrogenase (NAD+) activity of purified Drosophila MDHs (McReynolds and Kitto 1970).
Reason: Purification and characterisation of the fly MDHs; abstract not available in the cache but the activity is undisputed and curators had the full text.
Supporting Evidence:
PMID:45555
A biochemical comparison was made among cytoplasmic malate dehydrogenase allozymic variants from Drosophila melanogaster.
GO:0030060 L-malate dehydrogenase (NAD+) activity
IDA
PMID:45555
Biochemical studies of supernatant malate dehydrogenase allo... 		ACCEPT
Summary: L-malate dehydrogenase (NAD+) activity, kinetic characterisation of allozymes (Alahiotis 1979).
Reason: NAD/malate and NADH/oxaloacetate kinetics measured for cytoplasmic MDH allozymes.
Supporting Evidence:
PMID:45555
indistinguishable in terms of NAD and L-malate optima
GO:0030060 L-malate dehydrogenase (NAD+) activity
IEA
GO_REF:0000120 		ACCEPT
Summary: L-malate dehydrogenase (NAD+) activity from combined IEA methods (EC 1.1.1.37).
Reason: Consistent with experimental evidence.
Supporting Evidence:
file:DROME/Mdh1/Mdh1-uniprot.txt
Reaction=(S)-malate + NAD(+) = oxaloacetate + NADH + H(+);
GO:0043490 malate-aspartate shuttle
IBA
GO_REF:0000033 		ACCEPT
Summary: Malate-aspartate shuttle, phylogenetic inference.
Reason: Cytosolic MDH reduces oxaloacetate to malate in the cytosolic arm of the conserved malate-aspartate shuttle.
Supporting Evidence:
PMID:19033156
cytosolic malate dehydrogenase (Mdh1)
GO:0043490 malate-aspartate shuttle
ISS
GO_REF:0000024 		ACCEPT
Summary: Malate-aspartate shuttle, transferred by sequence similarity.
Reason: As for the IBA.
Supporting Evidence:
PMID:19033156
cytosolic malate dehydrogenase (Mdh1)

Core Functions

Mdh1 reversibly interconverts L-malate and oxaloacetate with NAD+/NADH in the cytosol, forming the cytosolic arm of the malate-aspartate shuttle.

Molecular Function:
L-malate dehydrogenase (NAD+) activity
Directly Involved In:
malate-aspartate shuttle
Cellular Locations:
cytosol
Supporting Evidence:
  • PMID:45555
    A biochemical comparison was made among cytoplasmic malate dehydrogenase allozymic variants from Drosophila melanogaster.

References

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Suggested Questions for Experts

Q: How do partial versus complete losses of Mdh1 produce opposite effects on ethanol tolerance, and which cycle (pyruvate-malate or pyruvate-citrate) mediates this?

Suggested Experiments

Experiment: Use 13C-glucose tracing in Mdh1 null and hypomorphic adults to quantify flux through the malate-aspartate shuttle and pyruvate-citrate cycling.

Deep Research

Falcon

(Mdh1-deep-research-falcon.md)

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FlyBase

(Mdh1-deep-research-flybase.md)
FlyBase gene description for Mdh1 (DROME) FlyBase

FlyBase gene description for Mdh1 (DROME)

Malate dehydrogenase 1 (Mdh1) encodes a cytosolic enzyme that reversibly catalyzes the oxidation of S-malate to oxaloacetate using the reduction of NAD+ to NADH. It is involved in gluconeogenesis and the malate-aspartate shuttle.

📚 Additional Documentation

Notes

(Mdh1-notes.md)

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📄 View Raw YAML

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