LDHA

UniProt ID: P00338
Organism: Homo sapiens
Review Status: INITIALIZED
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Gene Description

LDHA encodes the L-lactate dehydrogenase A chain (LDH-A / LDH-M, the "muscle" subunit; EC 1.1.1.27), a cytosolic NAD+-dependent oxidoreductase that catalyses the reversible interconversion of pyruvate + NADH and L-lactate + NAD+. The A/M subunit kinetically favours the reduction of pyruvate to lactate, thereby regenerating cytosolic NAD+ so that glycolysis can continue under anaerobic or high-flux conditions; this is the terminal step of lactate fermentation and a hallmark of the Warburg effect in tumours. The catalytically active enzyme is a tetramer assembled from LDHA (A/M) and LDHB (B/H) subunits, giving five isoenzymes (A4 through B4); the LDHA homotetramer (M4, LDH-5) predominates in skeletal muscle and liver. Loss-of-function of LDHA causes glycogen storage disease type XI (LDH-M deficiency), characterized by exertional myopathy, myoglobinuria and cramps.

Existing Annotations Review

GO Term Evidence Action Reason
GO:0019244 pyruvate fermentation to lactate
IBA
GO_REF:0000033 		ACCEPT
Summary: Phylogenetic (IBA) annotation to the specific process that LDHA terminates - reduction of pyruvate to lactate as the final step of lactate fermentation, regenerating NAD+ for glycolysis. This is a core biological process for the A/M subunit.
Reason: LDHA catalyses exactly this reaction, and the A/M subunit kinetically favours the pyruvate-to-lactate direction, which is the defining role of this isoform. UniProt assigns the pathway "pyruvate fermentation to lactate" to LDHA. Well-supported core BP.
Supporting Evidence:
PMID:24816116
predominantly found in skeletal muscle and catalyses the reversible conversion
file:human/LDHA/LDHA-uniprot.txt
pyruvate fermentation to lactate
GO:0004459 L-lactate dehydrogenase (NAD+) activity
IBA
GO_REF:0000033 		ACCEPT
Summary: Phylogenetic (IBA) annotation to the precise EC 1.1.1.27 molecular function of LDHA. This is the core molecular function of the gene product.
Reason: Directly supported by structural/enzymatic work on human LDH-A and by the UniProt catalytic-activity statement (RHEA:23444, EC 1.1.1.27). The IBA is at exactly the right level of specificity.
Supporting Evidence:
PMID:11276087
interconverts pyruvate and lactate with concomitant
file:human/LDHA/LDHA-uniprot.txt
Interconverts simultaneously and stereospecifically pyruvate
GO:0005739 mitochondrion
IBA
GO_REF:0000033 		MARK AS OVER ANNOTATED
Summary: Phylogenetic (IBA) annotation placing LDHA activity in the mitochondrion. LDHA is canonically a cytosolic enzyme; a mitochondrial LDH pool ("mLDH") has been proposed but remains contested and is not the core localization of the human A/M subunit.
Reason: UniProt records LDHA subcellular location as Cytoplasm, and the experimental/HPA/Reactome annotations consistently place it in the cytosol. Although some literature invokes a mitochondrial lactate-oxidation pool, this is disputed and not established for human LDHA; the IBA projection should not be treated as a core location. Retained as a possible non-core pool rather than removed, since it is a reviewed phylogenetic call.
Propagation Review
Root cause: PROPAGATION BAD
Failure modes: COMPARTMENT OR COMPLEX MISMATCH
Supporting Evidence:
PMID:33406399
competing with mitochondrial lactate dehydrogenase (mLDH) for nicotinamide
file:human/LDHA/LDHA-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0003824 catalytic activity
IEA
GO_REF:0000002 		MODIFY
Summary: InterPro2GO electronic annotation to the root catalytic-activity term. Correct but far too general given that LDHA has a precisely defined EC-level function.
Reason: LDHA is a well-characterized oxidoreductase with a specific NAD+-dependent lactate dehydrogenase activity; the generic "catalytic activity" term is uninformative and should be replaced by the specific function.
Supporting Evidence:
file:human/LDHA/LDHA-uniprot.txt
Interconverts simultaneously and stereospecifically pyruvate
GO:0004459 L-lactate dehydrogenase (NAD+) activity
IEA
GO_REF:0000120 		ACCEPT
Summary: Electronic (UniProt IEA, GO_REF:0000120) annotation to the precise EC 1.1.1.27 function, mapped via RHEA:23444/EC:1.1.1.27. Core molecular function; consistent with the experimental annotations.
Reason: Correct, specific MF supported by UniProt catalytic-activity data and experimental enzymology.
Supporting Evidence:
file:human/LDHA/LDHA-uniprot.txt
EC=1.1.1.27
GO:0005737 cytoplasm
IEA
GO_REF:0000120 		MODIFY
Summary: Electronic (UniProt IEA) annotation to cytoplasm, matching the UniProt subcellular-location statement. Correct but less precise than the cytosol annotations.
Reason: LDHA is a soluble cytosolic enzyme; the more specific term GO:0005829 cytosol (supported experimentally by HPA and Reactome) is preferable to the broad "cytoplasm".
Proposed replacements: cytosol
Supporting Evidence:
file:human/LDHA/LDHA-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0016491 oxidoreductase activity
IEA
GO_REF:0000002 		MODIFY
Summary: InterPro2GO annotation to the broad oxidoreductase parent. Correct in class but too general.
Reason: LDHA's oxidoreductase activity is specifically NAD+-dependent L-lactate dehydrogenase; replace the generic parent with the specific function.
Supporting Evidence:
file:human/LDHA/LDHA-uniprot.txt
EC=1.1.1.27
GO:0016616 oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor
IEA
GO_REF:0000002 		MODIFY
Summary: InterPro2GO annotation to the CH-OH/NAD(P) oxidoreductase parent. This is the correct branch (LDHA acts on the CH-OH group of lactate using NAD+), but a level too general.
Reason: The specific child term GO:0004459 L-lactate dehydrogenase (NAD+) activity is the appropriate function and is already supported experimentally.
Supporting Evidence:
file:human/LDHA/LDHA-uniprot.txt
EC=1.1.1.27
GO:0005515 protein binding
IPI
PMID:21988832
Toward an understanding of the protein interaction network o... 		MARK AS OVER ANNOTATED
Summary: IntAct-curated binary interaction (LDHA-LDHB, P07195) from a large-scale liver interactome study, annotated to the uninformative "protein binding" term.
Reason: Per curation guidelines, bare "protein binding" is uninformative and is not retained as a core function. The interaction itself (LDHA-LDHB) is real and biologically meaningful (A/B heterotetramer isoenzymes), but the generic MF term adds nothing beyond what identical/heterosubunit association already captures. Retained (not removed) as an experimental IPI.
Supporting Evidence:
PMID:21988832
Toward an understanding of the protein interaction network of the human liver
GO:0005515 protein binding
IPI
PMID:23523103
Lysine-5 acetylation negatively regulates lactate dehydrogen... 		MARK AS OVER ANNOTATED
Summary: IntAct interaction with HSPA8/HSC70 (P11142). HSC70 recognizes K5-acetylated LDHA and delivers it to lysosomes for chaperone-mediated degradation, a regulatory (turnover) interaction.
Reason: Bare "protein binding" is uninformative and non-core; retained as an experimental IPI. The underlying biology (acetylation-triggered HSC70-mediated degradation) is a regulatory mechanism, not the enzyme's molecular function.
Supporting Evidence:
PMID:23523103
LDH-A is recognized by the HSC70 chaperone and delivered to lysosomes for
GO:0005515 protein binding
IPI
PMID:28514442
Architecture of the human interactome defines protein commun... 		MARK AS OVER ANNOTATED
Summary: IntAct interaction (LDHA-LDHB, P07195) from a large-scale human interactome mapping study, annotated to the generic "protein binding" term.
Reason: Uninformative bare "protein binding"; non-core. Retained as an experimental IPI (LDHA-LDHB subunit association).
Supporting Evidence:
PMID:28514442
Architecture of the human interactome defines protein communities and disease
GO:0005515 protein binding
IPI
PMID:28514442
Architecture of the human interactome defines protein commun... 		MARK AS OVER ANNOTATED
Summary: IntAct interaction with LDHC (P07864) from the same human interactome study, annotated to the generic "protein binding" term.
Reason: Uninformative bare "protein binding"; non-core. Retained as an experimental IPI (LDHA-LDHC subunit association).
Supporting Evidence:
PMID:28514442
Architecture of the human interactome defines protein communities and disease
GO:0005515 protein binding
IPI
PMID:31515488
Extensive disruption of protein interactions by genetic vari... 		MARK AS OVER ANNOTATED
Summary: IntAct interaction (LDHA-LDHB, P07195) from a variant-effect interactome study, annotated to the generic "protein binding" term.
Reason: Uninformative bare "protein binding"; non-core. Retained as an experimental IPI.
Supporting Evidence:
PMID:31515488
Extensive disruption of protein interactions by genetic variants
GO:0005515 protein binding
IPI
PMID:33961781
Dual proteome-scale networks reveal cell-specific remodeling... 		MARK AS OVER ANNOTATED
Summary: IntAct interaction (LDHA-LDHB, P07195) from a proteome-scale interactome network study, annotated to the generic "protein binding" term.
Reason: Uninformative bare "protein binding"; non-core. Retained as an experimental IPI.
Supporting Evidence:
PMID:33961781
Dual proteome-scale networks reveal cell-specific remodeling of the human
GO:0005515 protein binding
IPI
PMID:33961781
Dual proteome-scale networks reveal cell-specific remodeling... 		MARK AS OVER ANNOTATED
Summary: IntAct interaction with LDHC (P07864) from the same proteome-scale study, annotated to the generic "protein binding" term.
Reason: Uninformative bare "protein binding"; non-core. Retained as an experimental IPI.
Supporting Evidence:
PMID:33961781
Dual proteome-scale networks reveal cell-specific remodeling of the human
GO:0005515 protein binding
IPI
PMID:35271311
OpenCell: Endogenous tagging for the cartography of human ce... 		MARK AS OVER ANNOTATED
Summary: IntAct interaction (LDHA-LDHB, P07195) from the OpenCell endogenous tagging study, annotated to the generic "protein binding" term.
Reason: Uninformative bare "protein binding"; non-core. Retained as an experimental IPI.
Supporting Evidence:
PMID:35271311
OpenCell: Endogenous tagging for the cartography of human cellular organization
GO:0005515 protein binding
IPI
PMID:35271311
OpenCell: Endogenous tagging for the cartography of human ce... 		MARK AS OVER ANNOTATED
Summary: IntAct interaction with LDHC (P07864) from the OpenCell study, annotated to the generic "protein binding" term.
Reason: Uninformative bare "protein binding"; non-core. Retained as an experimental IPI.
Supporting Evidence:
PMID:35271311
OpenCell: Endogenous tagging for the cartography of human cellular organization
GO:0005515 protein binding
IPI
PMID:40205054
Multimodal cell maps as a foundation for structural and func... 		MARK AS OVER ANNOTATED
Summary: IntAct interaction with LDHC (P07864) from a multimodal cell-map study, annotated to the generic "protein binding" term.
Reason: Uninformative bare "protein binding"; non-core. Retained as an experimental IPI.
Supporting Evidence:
PMID:40205054
Multimodal cell maps as a foundation for structural and functional genomics
GO:0042802 identical protein binding
IPI
PMID:21988832
Toward an understanding of the protein interaction network o... 		ACCEPT
Summary: IntAct self-interaction (LDHA-LDHA, P00338). Reflects the homotypic subunit association that builds the active LDHA homotetramer (M4/LDH-5).
Reason: Informative and biologically core - LDHA self-associates into a homotetramer, which is required for catalytic activity. Directly corroborated by crystallography showing homotetramerization.
Supporting Evidence:
PMID:11276087
the M form, predominantly found in
file:human/LDHA/LDHA-uniprot.txt
Homotetramer
GO:0042802 identical protein binding
IPI
PMID:25502805
A massively parallel pipeline to clone DNA variants and exam... 		ACCEPT
Summary: IntAct self-interaction (LDHA-LDHA) from a massively parallel variant-phenotyping pipeline, supporting homotetramer self-association.
Reason: Informative, core - consistent with the LDHA homotetramer required for function.
Supporting Evidence:
PMID:25502805
A massively parallel pipeline to clone DNA variants
GO:0042802 identical protein binding
IPI
PMID:31515488
Extensive disruption of protein interactions by genetic vari... 		ACCEPT
Summary: IntAct self-interaction (LDHA-LDHA), supporting homotetramer self-association.
Reason: Informative, core - consistent with the LDHA homotetramer required for catalytic activity.
Supporting Evidence:
PMID:31515488
Extensive disruption of protein interactions by genetic variants
GO:0004457 lactate dehydrogenase activity
IEA
GO_REF:0000107 		ACCEPT
Summary: Ensembl-Compara orthology (IEA) transfer of lactate dehydrogenase activity from the mouse ortholog. Correct; a slightly broader parent of the NAD+-specific term.
Reason: Accurately captures LDHA's function; retained even though it is one level broader than GO:0004459, as it is not incorrect and is well-supported.
Supporting Evidence:
file:human/LDHA/LDHA-uniprot.txt
EC=1.1.1.27
GO:0005829 cytosol
IEA
GO_REF:0000107 		ACCEPT
Summary: Ensembl-Compara orthology (IEA) transfer of cytosolic localization. Matches the experimental cytosol annotations.
Reason: LDHA is a soluble cytosolic glycolytic enzyme; localization is correct and core.
Supporting Evidence:
file:human/LDHA/LDHA-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0035686 sperm fibrous sheath
IEA
GO_REF:0000107 		MARK AS OVER ANNOTATED
Summary: Ensembl-Compara orthology (IEA) transfer of a sperm fibrous sheath localization from the mouse ortholog. This is a specialized germ-cell localization more characteristic of the testis-specific paralog LDHC, not a core localization of somatic LDHA.
Reason: LDHA is predominantly a cytosolic enzyme of muscle and liver; a sperm fibrous sheath localization is peripheral/germ-cell-specific and is not part of the core function. Retained as a possible non-core localization from orthology transfer rather than removed.
Supporting Evidence:
file:human/LDHA/LDHA-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0042867 pyruvate catabolic process
IEA
GO_REF:0000107 		ACCEPT
Summary: Ensembl-Compara orthology (IEA) transfer of pyruvate catabolic process. LDHA consumes pyruvate (reducing it to lactate), so this is a correct process annotation.
Reason: LDHA catalyses pyruvate reduction to lactate, a catabolic fate of pyruvate that regenerates NAD+. Correct, though the more specific fermentation term is the primary process.
Supporting Evidence:
PMID:24816116
predominantly found in skeletal muscle and catalyses the reversible conversion
GO:0005829 cytosol
IDA
GO_REF:0000052 		ACCEPT
Summary: HPA immunofluorescence (IDA) localization of LDHA to the cytosol. Direct experimental support for the core cytosolic localization.
Reason: Direct experimental evidence for cytosolic localization, consistent with LDHA being a soluble glycolytic enzyme.
Supporting Evidence:
file:human/LDHA/LDHA-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0004459 L-lactate dehydrogenase (NAD+) activity
EXP
PMID:11276087
Structural basis for altered activity of M- and H-isozyme fo... 		ACCEPT
Summary: Experimental (crystallography + enzymology) demonstration of the NAD+-dependent lactate dehydrogenase activity of human LDH-M (LDHA). Core molecular function.
Reason: Definitive experimental support - the study determined the crystal structure of the human M (LDHA) isoform as a ternary complex with NADH and the substrate analog oxamate and characterized its catalytic activity.
Supporting Evidence:
PMID:11276087
interconverts pyruvate and lactate with concomitant
GO:0006089 lactate metabolic process
IDA
PMID:24816116
Structural characterization of the apo form and NADH binary ... 		ACCEPT
Summary: ComplexPortal IDA linking the LDH complex to lactate metabolism, based on the structural/enzymatic characterization of human LDH-A. Core biological process.
Reason: LDHA directly interconverts pyruvate and lactate; participation in lactate metabolic process is well-supported experimentally.
Supporting Evidence:
PMID:24816116
predominantly found in skeletal muscle and catalyses the reversible conversion
GO:1990204 oxidoreductase complex
IPI
PMID:24816116
Structural characterization of the apo form and NADH binary ... 		ACCEPT
Summary: ComplexPortal annotation that LDHA is part of an oxidoreductase complex (the LDH tetramer). The active enzyme is an oligomeric oxidoreductase.
Reason: The functional LDH enzyme is a homo/heterotetramer that is a bona fide oxidoreductase complex; this correctly captures LDHA's participation in an oligomeric enzyme.
Supporting Evidence:
PMID:24816116
assemble to form hLDH-1 (B4), hLDH-2 (AB3), hLDH-3 (A2B2), hLDH-4 (A3B) and hLDH-5 (A4)
GO:0006089 lactate metabolic process
IDA
PMID:34381247
The tumor suppressor folliculin inhibits lactate dehydrogena... 		ACCEPT
Summary: UniProt IDA linking LDHA to lactate metabolic process, based on the FLCN study demonstrating that LDHA activity (lactate production) is directly regulated. Core process.
Reason: This study experimentally established LDHA as the enzyme driving lactate production (Warburg effect), directly supporting its role in lactate metabolism.
Supporting Evidence:
PMID:34381247
we identify the human tumor suppressor folliculin (FLCN) as a binding partner and uncompetitive inhibitor of LDHA
GO:0005829 cytosol
TAS
Reactome:R-HSA-9861563 		ACCEPT
Summary: Reactome TAS cytosolic localization (from the CTLH-ligase ubiquitination reaction). Consistent with the core cytosolic location.
Reason: Cytosolic localization is well-established for LDHA and supported by multiple independent sources.
Supporting Evidence:
file:human/LDHA/LDHA-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0004459 L-lactate dehydrogenase (NAD+) activity
IMP
PMID:34381247
The tumor suppressor folliculin inhibits lactate dehydrogena... 		ACCEPT
Summary: IMP annotation of the L-lactate dehydrogenase activity, from the FLCN study using the LDHA R106 mutant to probe activity regulation. Core molecular function.
Reason: The study functionally assayed LDHA enzymatic activity (including a mutagenesis of Arg-106 affecting FLCN binding), directly supporting the MF annotation.
Supporting Evidence:
PMID:34381247
we identify the human tumor suppressor folliculin (FLCN) as a binding partner and uncompetitive inhibitor of LDHA
GO:0005515 protein binding
IPI
PMID:34381247
The tumor suppressor folliculin inhibits lactate dehydrogena... 		MARK AS OVER ANNOTATED
Summary: UniProt IPI for the direct LDHA-FLCN (folliculin, Q8NFG4) interaction. FLCN is a direct, uncompetitive inhibitor of LDHA - a physiologically important regulatory interaction, but annotated to the uninformative "protein binding" term.
Reason: Bare "protein binding" is uninformative per curation policy and is not retained as a core MF. The interaction itself is real, direct and functionally important (activity regulation), and is retained as an experimental IPI rather than removed.
Supporting Evidence:
PMID:34381247
we identify the human tumor suppressor folliculin (FLCN) as a binding partner and uncompetitive inhibitor of LDHA
file:human/LDHA/LDHA-uniprot.txt
the interaction is direct and inhibits enzymatic activity
GO:0042802 identical protein binding
IPI
PMID:34381247
The tumor suppressor folliculin inhibits lactate dehydrogena... 		ACCEPT
Summary: UniProt IPI self-interaction (LDHA-LDHA) reported in the FLCN study, consistent with the LDHA homotetramer / dimer-tetramer equilibrium described there.
Reason: Informative and core - LDHA self-association underlies the active tetramer; the FLCN study explicitly discusses the LDHA dimer/tetramer states.
Supporting Evidence:
PMID:34381247
FLCN prefers binding to the less active LDHA dimer, compared to the hyperactive LDHA tetramer
GO:0005515 protein binding
IPI
PMID:33406399
An Upstream Open Reading Frame in Phosphatase and Tensin Hom... 		MARK AS OVER ANNOTATED
Summary: UniProt IPI for the LDHA-MP31 (C0HLV8) interaction. MP31, a micropeptide from the PTEN uORF, competes with LDH for NAD+ and limits lactate-pyruvate conversion; annotated to the uninformative "protein binding" term.
Reason: Bare "protein binding" is uninformative and non-core. The MP31 interaction is real (mutagenesis of Asp-56 and Arg-99 abolishes it) and regulatory, retained as an experimental IPI rather than removed.
Supporting Evidence:
PMID:33406399
competing with mitochondrial lactate dehydrogenase (mLDH) for nicotinamide
GO:0045296 cadherin binding
HDA
PMID:25468996
E-cadherin interactome complexity and robustness resolved by... 		MARK AS OVER ANNOTATED
Summary: High-throughput BioID proximity-biotinylation proteomics detected LDHA in the vicinity of the E-cadherin cytoplasmic tail. This is a proximity hit, not a demonstrated direct/functional cadherin interaction.
Reason: BioID labels proteins within ~20-30 nm of the bait and captures many abundant cytosolic proteins; the authors note most identified proteins are not junctional. LDHA is an abundant glycolytic enzyme with no established cadherin adhesion role, so this is an over-annotation. Retained (not removed) as an experimental high-throughput observation.
Supporting Evidence:
PMID:25468996
we employed proximity biotinylation and quantitative proteomics to isolate and identify 612 proteins in the vicinity of E-cadherin
GO:0070062 extracellular exosome
HDA
PMID:11487543
Intestinal epithelial cells secrete exosome-like vesicles. 		MARK AS OVER ANNOTATED
Summary: High-throughput proteomic detection of LDHA in secreted exosome-like vesicles. LDHA is an abundant cytosolic protein commonly detected in exosome preparations.
Reason: Detection of a highly abundant cytosolic glycolytic enzyme in exosome proteomes does not establish exosome localization as a core function; likely reflects passive incorporation/contamination. Retained as a high-throughput observation, not core.
Supporting Evidence:
PMID:11487543
exosome-like vesicles
GO:0070062 extracellular exosome
HDA
PMID:23533145
In-depth proteomic analyses of exosomes isolated from expres... 		MARK AS OVER ANNOTATED
Summary: High-throughput proteomic detection of LDHA in prostatic-secretion exosomes.
Reason: As with other exosome-proteomics hits, this reflects the abundance of the cytosolic enzyme rather than a dedicated exosomal function; non-core, retained as an observation.
Supporting Evidence:
PMID:23533145
exosomes isolated from expressed prostatic secretions
GO:0016020 membrane
HDA
PMID:19946888
Defining the membrane proteome of NK cells. 		MARK AS OVER ANNOTATED
Summary: High-throughput membrane-proteome (NK cell) detection of LDHA. LDHA is a soluble cytosolic enzyme; membrane co-fractionation is likely peripheral association or contamination of the membrane fraction.
Reason: No evidence that LDHA is an integral or functionally membrane-associated protein; this large-scale fractionation hit is non-core. Retained as an observation rather than removed.
Supporting Evidence:
PMID:19946888
membrane proteome of NK cells
GO:0005634 nucleus
HDA
PMID:21630459
Proteomic characterization of the human sperm nucleus. 		MARK AS OVER ANNOTATED
Summary: High-throughput proteomic detection of LDHA in the human sperm nucleus fraction. A nuclear pool of LDHA has been reported in some contexts, but this HDA hit does not establish a core nuclear function.
Reason: LDHA is predominantly cytosolic; nuclear detection in a sperm-nucleus proteome is peripheral/context-specific and non-core. Retained as a high-throughput observation.
Supporting Evidence:
PMID:21630459
sperm nucleus
GO:0070062 extracellular exosome
HDA
PMID:19056867
Large-scale proteomics and phosphoproteomics of urinary exos... 		MARK AS OVER ANNOTATED
Summary: High-throughput proteomic detection of LDHA in urinary exosomes.
Reason: Abundant cytosolic enzyme detected in exosome proteomics; non-core. Retained as a high-throughput observation.
Supporting Evidence:
PMID:19056867
proteomics and phosphoproteomics of urinary exosomes
GO:0070062 extracellular exosome
HDA
PMID:20458337
MHC class II-associated proteins in B-cell exosomes and pote... 		MARK AS OVER ANNOTATED
Summary: High-throughput proteomic detection of LDHA in B-cell exosomes.
Reason: As with other exosome-proteomics hits, non-core; reflects abundance rather than dedicated exosomal function. Retained as an observation.
Supporting Evidence:
PMID:20458337
exosomes and potential functional
GO:0005829 cytosol
TAS
Reactome:R-HSA-70510 		ACCEPT
Summary: Reactome TAS cytosolic localization (LDH tetramer oxidises lactate to pyruvate reaction). Consistent with core cytosolic location.
Reason: Well-established cytosolic localization for the glycolytic LDH enzyme.
Supporting Evidence:
file:human/LDHA/LDHA-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0005829 cytosol
TAS
Reactome:R-HSA-71849 		ACCEPT
Summary: Reactome TAS cytosolic localization (LDH tetramer reduces pyruvate to lactate reaction). Consistent with core cytosolic location.
Reason: Well-established cytosolic localization for the glycolytic LDH enzyme.
Supporting Evidence:
file:human/LDHA/LDHA-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0004459 L-lactate dehydrogenase (NAD+) activity
TAS
PMID:2334430
Molecular characterization of genetic mutation in human lact... 		ACCEPT
Summary: Traceable-author-statement MF annotation from the molecular characterization of human LDH-A(M) deficiency. Core molecular function.
Reason: This genetics paper characterizes the LDH-A (Muscle) subunit and its deficiency, treating the L-lactate dehydrogenase activity of LDHA as established. Core MF, consistent with all other evidence.
Supporting Evidence:
PMID:2334430
deficient in LDH-A (Muscle) subunit
GO:0005829 cytosol
TAS
PMID:2434947
Centrosomal proteins and lactate dehydrogenase possess a com... 		ACCEPT
Summary: Traceable-author-statement cytosolic localization from an older study. Consistent with the core cytosolic location.
Reason: Cytosolic localization is robustly established for LDHA across many sources.
Supporting Evidence:
file:human/LDHA/LDHA-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0004459 L-lactate dehydrogenase (NAD+) activity
NAS
PMID:1953713
Analysis of genetic mutations in human lactate dehydrogenase... 		ACCEPT
Summary: Non-traceable-author-statement MF annotation from a study of LDH-A(M) deficiency mutations. Core molecular function.
Reason: The paper analyzes disease-causing mutations in the human LDH-A gene, treating the lactate dehydrogenase activity of LDHA as established. Core MF, concordant with the experimental annotations.
Supporting Evidence:
PMID:1953713
Human lactate dehydrogenase (LDH)-A mutant gene was analyzed
GO:0006096 glycolytic process
NAS
PMID:1953713
Analysis of genetic mutations in human lactate dehydrogenase... 		ACCEPT
Summary: Author-stated involvement of LDHA in the glycolytic process. LDHA regenerates cytosolic NAD+ (by reducing pyruvate to lactate) required to sustain glycolytic flux; a core process for the A/M subunit under anaerobic / high-flux conditions.
Reason: LDHA is a canonical glycolysis-associated enzyme - its lactate-forming reaction recycles NAD+ that keeps glycolysis (specifically GAPDH) running. Correct core process annotation.
Supporting Evidence:
PMID:1953713
Human lactate dehydrogenase (LDH)-A mutant gene was analyzed

Core Functions

NAD+-dependent L-lactate dehydrogenase - reversibly interconverts pyruvate + NADH and L-lactate + NAD+, with the A/M subunit favouring reduction of pyruvate to lactate to regenerate cytosolic NAD+

Molecular Function:
L-lactate dehydrogenase (NAD+) activity
Directly Involved In:
pyruvate fermentation to lactate
Cellular Locations:
cytosol
Supporting Evidence:
  • PMID:11276087
    interconverts pyruvate and lactate with concomitant
  • file:human/LDHA/LDHA-uniprot.txt
    Interconverts simultaneously and stereospecifically pyruvate

Lactate/NAD+ recycling supporting glycolytic flux - reducing pyruvate to lactate regenerates NAD+ so that glycolysis can continue under anaerobic or high-flux (e.g. Warburg-effect) conditions

Molecular Function:
L-lactate dehydrogenase (NAD+) activity
Directly Involved In:
lactate metabolic process
Cellular Locations:
cytosol
Supporting Evidence:
  • PMID:24816116
    predominantly found in skeletal muscle and catalyses the reversible conversion
  • PMID:34381247
    we identify the human tumor suppressor folliculin (FLCN) as a binding partner and uncompetitive inhibitor of LDHA

Homotetramer assembly - LDHA self-associates (and heteroassociates with LDHB/LDHC) into the catalytically active tetrameric oxidoreductase complex (M4/LDH-5 and A/B isoenzymes)

Molecular Function:
identical protein binding
Directly Involved In:
pyruvate fermentation to lactate
Cellular Locations:
cytosol
In Complex:
oxidoreductase complex
Supporting Evidence:
  • PMID:11276087
    the M form, predominantly found in
  • PMID:24816116
    assemble to form hLDH-1 (B4), hLDH-2 (AB3), hLDH-3 (A2B2), hLDH-4 (A3B) and hLDH-5 (A4)

References

GO_REF:0000002
Gene Ontology annotation through association of InterPro records with GO terms
GO_REF:0000033
Annotation inferences using phylogenetic trees
GO_REF:0000052
Gene Ontology annotation based on curation of immunofluorescence data
GO_REF:0000107
Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
GO_REF:0000120
Combined Automated Annotation using Multiple IEA Methods
PMID:11276087
Structural basis for altered activity of M- and H-isozyme forms of human lactate dehydrogenase.
PMID:11487543
Intestinal epithelial cells secrete exosome-like vesicles.
PMID:19056867
Large-scale proteomics and phosphoproteomics of urinary exosomes.
PMID:1953713
Analysis of genetic mutations in human lactate dehydrogenase-A(M) deficiency using DNA conformation polymorphism in combination with polyacrylamide gradient gel and silver staining.
PMID:19946888
Defining the membrane proteome of NK cells.
PMID:20458337
MHC class II-associated proteins in B-cell exosomes and potential functional implications for exosome biogenesis.
PMID:21630459
Proteomic characterization of the human sperm nucleus.
PMID:21988832
Toward an understanding of the protein interaction network of the human liver.
PMID:2334430
Molecular characterization of genetic mutation in human lactate dehydrogenase-A (M) deficiency.
PMID:23523103
Lysine-5 acetylation negatively regulates lactate dehydrogenase A and is decreased in pancreatic cancer.
PMID:23533145
In-depth proteomic analyses of exosomes isolated from expressed prostatic secretions in urine.
PMID:2434947
Centrosomal proteins and lactate dehydrogenase possess a common epitope in human cell lines.
PMID:24816116
Structural characterization of the apo form and NADH binary complex of human lactate dehydrogenase.
PMID:25468996
E-cadherin interactome complexity and robustness resolved by quantitative proteomics.
PMID:25502805
A massively parallel pipeline to clone DNA variants and examine molecular phenotypes of human disease mutations.
PMID:28514442
Architecture of the human interactome defines protein communities and disease networks.
PMID:31515488
Extensive disruption of protein interactions by genetic variants across the allele frequency spectrum in human populations.
PMID:33406399
An Upstream Open Reading Frame in Phosphatase and Tensin Homolog Encodes a Circuit Breaker of Lactate Metabolism.
PMID:33961781
Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
PMID:34381247
The tumor suppressor folliculin inhibits lactate dehydrogenase A and regulates the Warburg effect.
PMID:35271311
OpenCell: Endogenous tagging for the cartography of human cellular organization.
PMID:40205054
Multimodal cell maps as a foundation for structural and functional genomics.
Reactome:R-HSA-70510
LDH tetramer oxidises LACT to PYR
Reactome:R-HSA-71849
LDH tetramer reduces PYR to LACT
Reactome:R-HSA-9861563
CTLH E3 ligase ubiquitinates LDHA
file:human/LDHA/LDHA-uniprot.txt
UniProtKB entry P00338 (LDHA_HUMAN)

Suggested Questions for Experts

Q: Is there a genuine, functionally significant mitochondrial pool of human LDHA ("mLDH"), or is the mitochondrial IBA annotation an over-projection?

Q: To what extent do the reported nuclear and cadherin-proximal localizations of LDHA reflect moonlighting functions versus abundance-driven proteomics artifacts?

Suggested Experiments

Experiment: Quantitative subcellular fractionation with activity assays to test whether a catalytically active mitochondrial LDHA pool exists in human cells.

Experiment: Structure-guided mutagenesis of the FLCN- and MP31-interaction interfaces to define how these regulators modulate LDHA activity and oligomeric state in vivo.

📚 Additional Documentation

Notes

(LDHA-notes.md)

LDHA (P00338) review notes

Identity and core biology

  • LDHA = L-lactate dehydrogenase A chain, a.k.a. LDH-A / LDH-M (muscle) subunit; EC 1.1.1.27.
  • Catalyses reversible, NAD+-dependent interconversion of pyruvate + NADH ↔ L-lactate + NAD+.
    UniProt FUNCTION: "Interconverts simultaneously and stereospecifically pyruvate and lactate with
    concomitant interconversion of NADH and NAD(+)" [file:human/LDHA/LDHA-uniprot.txt].
  • Catalytic activity (RHEA:23444, EC 1.1.1.27): (S)-lactate + NAD(+) = pyruvate + NADH + H(+).
  • A/M subunit kinetically favours pyruvate→lactate (regenerates cytosolic NAD+ for glycolysis /
    lactate fermentation), whereas B/H favours the reverse PMID:24816116.
  • Active enzyme is a tetramer; LDHA (A/M) and LDHB (B/H) subunits assemble into five isoenzymes
    hLDH-1 (B4) … hLDH-5 (A4) PMID:24816116. LDHA homotetramer = M4 = LDH-5 [PMID:11276087
    "HOMOTETRAMERIZATION"; UniProt SUBUNIT "Homotetramer"].
  • Cytosolic/cytoplasmic (UniProt SUBCELLULAR LOCATION: Cytoplasm; HPA IDA cytosol; Reactome TAS).
  • Predominantly expressed in anaerobic tissues (skeletal muscle, liver).

Disease

  • Deficiency causes Glycogen storage disease 11 (GSD11 / LDH-M deficiency, MIM:612933):
    exertional myoglobinuria, myopathy, cramps, easy fatigue [UniProt DISEASE; PMID:2334430,
    PMID:1953713 genetic characterization of LDH-A(M) deficiency mutations].

Regulation / interactions (mostly non-core, regulatory)

  • FLCN (folliculin) binds LDHA directly and is an uncompetitive inhibitor; regulates Warburg
    effect PMID:34381247. This paper's IMP for GO:0004459 (via R106 mutant) and IPI to FLCN
    (Q8NFG4) and self (identical protein binding) are supported.
  • MP31 micropeptide (from PTEN uORF; C0HLV8) competes with LDH for NAD+ PMID:33406399; IPI supported.
  • K5 acetylation inhibits LDHA and targets it for chaperone-mediated (HSC70) lysosomal degradation
    PMID:23523103; explains IntAct IPI with HSPA8/HSC70 (P11142).
  • CTLH E3 ligase ubiquitinates LDHA, inhibiting activity (Reactome R-HSA-9861563).

GOA review approach

  • Core MF: GO:0004459 L-lactate dehydrogenase (NAD+) activity (many redundant evidence lines: IBA,
    IEA, EXP PMID:11276087, IMP PMID:34381247, TAS, NAS) — ACCEPT the well-supported ones, the
    vaguer parents get MODIFY/MARK.
  • GO:0004457 lactate dehydrogenase activity (parent of 0004459) — ACCEPT (correct, slightly broader).
  • Core BP: pyruvate→lactate fermentation / lactate metabolic process / glycolytic process / pyruvate
    metabolism — all sound; keep the specific ones as core, broader/looser as non-core.
  • Core CC: cytosol/cytoplasm — ACCEPT.
  • GO:0005739 mitochondrion (IBA): LDHA is canonically cytosolic. A mitochondrial pool has been
    proposed (mLDH, e.g. PMID:33406399 "mitochondrial lactate dehydrogenase (mLDH)") but it is
    contested and not the core localization; the IBA is a projected/uncertain call. Mark as
    MARK_AS_OVER_ANNOTATED (non-core, contested) rather than accepting as a core location.
  • GO:0005515 protein binding (bare) IPIs: uninformative per curation policy → MARK_AS_OVER_ANNOTATED
    (NOT remove; these are experimental IntAct/UniProt IPIs).
  • GO:0042802 identical protein binding: informative (homotetramer self-association) → ACCEPT.
  • GO:0045296 cadherin binding (HDA, BioID proximity proteomics, PMID:25468996): proximity-labeling
    hit, not a demonstrated functional cadherin interaction → MARK_AS_OVER_ANNOTATED.
  • Exosome/membrane/nucleus/sperm-fibrous-sheath localizations: high-throughput proteomics
    (HDA/IEA-from-mouse ortholog) detecting abundant glycolytic enzyme in many fractions; not core
    → MARK_AS_OVER_ANNOTATED (keep as detected, not core; don't remove experimental HDA).
  • GO:1990204 oxidoreductase complex (ComplexPortal IPI, PMID:24816116): LDH tetramer is a bona fide
    oxidoreductase complex → ACCEPT.
  • IEA catalytic-activity/oxidoreductase parents (GO:0003824, GO:0016491, GO:0016616): correct but
    too general given the specific EC-level annotation exists → MODIFY to GO:0004459.

📄 View Raw YAML

 
id: P00338
gene_symbol: LDHA
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: LDHA encodes the L-lactate dehydrogenase A chain (LDH-A / LDH-M, the
  "muscle" subunit; EC 1.1.1.27), a cytosolic NAD+-dependent oxidoreductase that
  catalyses the reversible interconversion of pyruvate + NADH and L-lactate + NAD+.
  The A/M subunit kinetically favours the reduction of pyruvate to lactate, thereby
  regenerating cytosolic NAD+ so that glycolysis can continue under anaerobic or
  high-flux conditions; this is the terminal step of lactate fermentation and a
  hallmark of the Warburg effect in tumours. The catalytically active enzyme is a
  tetramer assembled from LDHA (A/M) and LDHB (B/H) subunits, giving five isoenzymes
  (A4 through B4); the LDHA homotetramer (M4, LDH-5) predominates in skeletal muscle
  and liver. Loss-of-function of LDHA causes glycogen storage disease type XI (LDH-M
  deficiency), characterized by exertional myopathy, myoglobinuria and cramps.
alternative_products:
- name: '1'
  id: P00338-1
- name: '2'
  id: P00338-2
  sequence_note: VSP_014261, VSP_042787
- name: '3'
  id: P00338-3
  sequence_note: VSP_042206
- name: '4'
  id: P00338-4
  sequence_note: VSP_042786
- name: '5'
  id: P00338-5
  sequence_note: VSP_042788, VSP_042789
existing_annotations:
- term:
    id: GO:0019244
    label: pyruvate fermentation to lactate
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Phylogenetic (IBA) annotation to the specific process that LDHA
      terminates - reduction of pyruvate to lactate as the final step of lactate
      fermentation, regenerating NAD+ for glycolysis. This is a core biological
      process for the A/M subunit.
    action: ACCEPT
    reason: LDHA catalyses exactly this reaction, and the A/M subunit kinetically
      favours the pyruvate-to-lactate direction, which is the defining role of this
      isoform. UniProt assigns the pathway "pyruvate fermentation to lactate" to
      LDHA. Well-supported core BP.
    supported_by:
    - reference_id: PMID:24816116
      supporting_text: predominantly found in skeletal muscle and catalyses the reversible conversion
    - reference_id: file:human/LDHA/LDHA-uniprot.txt
      supporting_text: pyruvate fermentation to lactate
- term:
    id: GO:0004459
    label: L-lactate dehydrogenase (NAD+) activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: Phylogenetic (IBA) annotation to the precise EC 1.1.1.27 molecular
      function of LDHA. This is the core molecular function of the gene product.
    action: ACCEPT
    reason: Directly supported by structural/enzymatic work on human LDH-A and by
      the UniProt catalytic-activity statement (RHEA:23444, EC 1.1.1.27). The IBA
      is at exactly the right level of specificity.
    supported_by:
    - reference_id: PMID:11276087
      supporting_text: interconverts pyruvate and lactate with concomitant
    - reference_id: file:human/LDHA/LDHA-uniprot.txt
      supporting_text: Interconverts simultaneously and stereospecifically pyruvate
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: Phylogenetic (IBA) annotation placing LDHA activity in the
      mitochondrion. LDHA is canonically a cytosolic enzyme; a mitochondrial LDH
      pool ("mLDH") has been proposed but remains contested and is not the core
      localization of the human A/M subunit.
    action: MARK_AS_OVER_ANNOTATED
    reason: UniProt records LDHA subcellular location as Cytoplasm, and the
      experimental/HPA/Reactome annotations consistently place it in the cytosol.
      Although some literature invokes a mitochondrial lactate-oxidation pool, this
      is disputed and not established for human LDHA; the IBA projection should not
      be treated as a core location. Retained as a possible non-core pool rather
      than removed, since it is a reviewed phylogenetic call.
    propagation_review:
      root_cause: PROPAGATION_BAD
      failure_modes:
        - COMPARTMENT_OR_COMPLEX_MISMATCH
    supported_by:
    - reference_id: PMID:33406399
      supporting_text: competing with mitochondrial lactate dehydrogenase (mLDH) for nicotinamide
    - reference_id: file:human/LDHA/LDHA-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0003824
    label: catalytic activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: InterPro2GO electronic annotation to the root catalytic-activity term.
      Correct but far too general given that LDHA has a precisely defined EC-level
      function.
    action: MODIFY
    reason: LDHA is a well-characterized oxidoreductase with a specific NAD+-dependent
      lactate dehydrogenase activity; the generic "catalytic activity" term is
      uninformative and should be replaced by the specific function.
    proposed_replacement_terms:
    - id: GO:0004459
      label: L-lactate dehydrogenase (NAD+) activity
    supported_by:
    - reference_id: file:human/LDHA/LDHA-uniprot.txt
      supporting_text: Interconverts simultaneously and stereospecifically pyruvate
- term:
    id: GO:0004459
    label: L-lactate dehydrogenase (NAD+) activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: Electronic (UniProt IEA, GO_REF:0000120) annotation to the precise
      EC 1.1.1.27 function, mapped via RHEA:23444/EC:1.1.1.27. Core molecular
      function; consistent with the experimental annotations.
    action: ACCEPT
    reason: Correct, specific MF supported by UniProt catalytic-activity data and
      experimental enzymology.
    supported_by:
    - reference_id: file:human/LDHA/LDHA-uniprot.txt
      supporting_text: EC=1.1.1.27
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: Electronic (UniProt IEA) annotation to cytoplasm, matching the UniProt
      subcellular-location statement. Correct but less precise than the cytosol
      annotations.
    action: MODIFY
    reason: LDHA is a soluble cytosolic enzyme; the more specific term GO:0005829
      cytosol (supported experimentally by HPA and Reactome) is preferable to the
      broad "cytoplasm".
    proposed_replacement_terms:
    - id: GO:0005829
      label: cytosol
    supported_by:
    - reference_id: file:human/LDHA/LDHA-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0016491
    label: oxidoreductase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: InterPro2GO annotation to the broad oxidoreductase parent. Correct in
      class but too general.
    action: MODIFY
    reason: LDHA's oxidoreductase activity is specifically NAD+-dependent L-lactate
      dehydrogenase; replace the generic parent with the specific function.
    proposed_replacement_terms:
    - id: GO:0004459
      label: L-lactate dehydrogenase (NAD+) activity
    supported_by:
    - reference_id: file:human/LDHA/LDHA-uniprot.txt
      supporting_text: EC=1.1.1.27
- term:
    id: GO:0016616
    label: oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP
      as acceptor
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: InterPro2GO annotation to the CH-OH/NAD(P) oxidoreductase parent. This
      is the correct branch (LDHA acts on the CH-OH group of lactate using NAD+),
      but a level too general.
    action: MODIFY
    reason: The specific child term GO:0004459 L-lactate dehydrogenase (NAD+)
      activity is the appropriate function and is already supported experimentally.
    proposed_replacement_terms:
    - id: GO:0004459
      label: L-lactate dehydrogenase (NAD+) activity
    supported_by:
    - reference_id: file:human/LDHA/LDHA-uniprot.txt
      supporting_text: EC=1.1.1.27
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21988832
  qualifier: enables
  review:
    summary: IntAct-curated binary interaction (LDHA-LDHB, P07195) from a large-scale
      liver interactome study, annotated to the uninformative "protein binding" term.
    action: MARK_AS_OVER_ANNOTATED
    reason: Per curation guidelines, bare "protein binding" is uninformative and is
      not retained as a core function. The interaction itself (LDHA-LDHB) is real
      and biologically meaningful (A/B heterotetramer isoenzymes), but the generic
      MF term adds nothing beyond what identical/heterosubunit association already
      captures. Retained (not removed) as an experimental IPI.
    supported_by:
    - reference_id: PMID:21988832
      supporting_text: Toward an understanding of the protein interaction network of the human liver
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23523103
  qualifier: enables
  review:
    summary: IntAct interaction with HSPA8/HSC70 (P11142). HSC70 recognizes
      K5-acetylated LDHA and delivers it to lysosomes for chaperone-mediated
      degradation, a regulatory (turnover) interaction.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare "protein binding" is uninformative and non-core; retained as an
      experimental IPI. The underlying biology (acetylation-triggered HSC70-mediated
      degradation) is a regulatory mechanism, not the enzyme's molecular function.
    supported_by:
    - reference_id: PMID:23523103
      supporting_text: LDH-A is recognized by the HSC70 chaperone and delivered to lysosomes for
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  qualifier: enables
  review:
    summary: IntAct interaction (LDHA-LDHB, P07195) from a large-scale human
      interactome mapping study, annotated to the generic "protein binding" term.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative bare "protein binding"; non-core. Retained as an
      experimental IPI (LDHA-LDHB subunit association).
    supported_by:
    - reference_id: PMID:28514442
      supporting_text: Architecture of the human interactome defines protein communities and disease
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  qualifier: enables
  review:
    summary: IntAct interaction with LDHC (P07864) from the same human interactome
      study, annotated to the generic "protein binding" term.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative bare "protein binding"; non-core. Retained as an
      experimental IPI (LDHA-LDHC subunit association).
    supported_by:
    - reference_id: PMID:28514442
      supporting_text: Architecture of the human interactome defines protein communities and disease
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:31515488
  qualifier: enables
  review:
    summary: IntAct interaction (LDHA-LDHB, P07195) from a variant-effect
      interactome study, annotated to the generic "protein binding" term.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative bare "protein binding"; non-core. Retained as an
      experimental IPI.
    supported_by:
    - reference_id: PMID:31515488
      supporting_text: Extensive disruption of protein interactions by genetic variants
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: IntAct interaction (LDHA-LDHB, P07195) from a proteome-scale
      interactome network study, annotated to the generic "protein binding" term.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative bare "protein binding"; non-core. Retained as an
      experimental IPI.
    supported_by:
    - reference_id: PMID:33961781
      supporting_text: Dual proteome-scale networks reveal cell-specific remodeling of the human
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: IntAct interaction with LDHC (P07864) from the same proteome-scale
      study, annotated to the generic "protein binding" term.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative bare "protein binding"; non-core. Retained as an
      experimental IPI.
    supported_by:
    - reference_id: PMID:33961781
      supporting_text: Dual proteome-scale networks reveal cell-specific remodeling of the human
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:35271311
  qualifier: enables
  review:
    summary: IntAct interaction (LDHA-LDHB, P07195) from the OpenCell endogenous
      tagging study, annotated to the generic "protein binding" term.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative bare "protein binding"; non-core. Retained as an
      experimental IPI.
    supported_by:
    - reference_id: PMID:35271311
      supporting_text: 'OpenCell: Endogenous tagging for the cartography of human cellular organization'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:35271311
  qualifier: enables
  review:
    summary: IntAct interaction with LDHC (P07864) from the OpenCell study,
      annotated to the generic "protein binding" term.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative bare "protein binding"; non-core. Retained as an
      experimental IPI.
    supported_by:
    - reference_id: PMID:35271311
      supporting_text: 'OpenCell: Endogenous tagging for the cartography of human cellular organization'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:40205054
  qualifier: enables
  review:
    summary: IntAct interaction with LDHC (P07864) from a multimodal cell-map study,
      annotated to the generic "protein binding" term.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative bare "protein binding"; non-core. Retained as an
      experimental IPI.
    supported_by:
    - reference_id: PMID:40205054
      supporting_text: Multimodal cell maps as a foundation for structural and functional genomics
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:21988832
  qualifier: enables
  review:
    summary: IntAct self-interaction (LDHA-LDHA, P00338). Reflects the homotypic
      subunit association that builds the active LDHA homotetramer (M4/LDH-5).
    action: ACCEPT
    reason: Informative and biologically core - LDHA self-associates into a
      homotetramer, which is required for catalytic activity. Directly corroborated
      by crystallography showing homotetramerization.
    supported_by:
    - reference_id: PMID:11276087
      supporting_text: the M form, predominantly found in
    - reference_id: file:human/LDHA/LDHA-uniprot.txt
      supporting_text: Homotetramer
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:25502805
  qualifier: enables
  review:
    summary: IntAct self-interaction (LDHA-LDHA) from a massively parallel
      variant-phenotyping pipeline, supporting homotetramer self-association.
    action: ACCEPT
    reason: Informative, core - consistent with the LDHA homotetramer required for
      function.
    supported_by:
    - reference_id: PMID:25502805
      supporting_text: A massively parallel pipeline to clone DNA variants
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:31515488
  qualifier: enables
  review:
    summary: IntAct self-interaction (LDHA-LDHA), supporting homotetramer
      self-association.
    action: ACCEPT
    reason: Informative, core - consistent with the LDHA homotetramer required for
      catalytic activity.
    supported_by:
    - reference_id: PMID:31515488
      supporting_text: Extensive disruption of protein interactions by genetic variants
- term:
    id: GO:0004457
    label: lactate dehydrogenase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: Ensembl-Compara orthology (IEA) transfer of lactate dehydrogenase
      activity from the mouse ortholog. Correct; a slightly broader parent of the
      NAD+-specific term.
    action: ACCEPT
    reason: Accurately captures LDHA's function; retained even though it is one level
      broader than GO:0004459, as it is not incorrect and is well-supported.
    supported_by:
    - reference_id: file:human/LDHA/LDHA-uniprot.txt
      supporting_text: EC=1.1.1.27
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: Ensembl-Compara orthology (IEA) transfer of cytosolic localization.
      Matches the experimental cytosol annotations.
    action: ACCEPT
    reason: LDHA is a soluble cytosolic glycolytic enzyme; localization is correct
      and core.
    supported_by:
    - reference_id: file:human/LDHA/LDHA-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0035686
    label: sperm fibrous sheath
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: Ensembl-Compara orthology (IEA) transfer of a sperm fibrous sheath
      localization from the mouse ortholog. This is a specialized germ-cell
      localization more characteristic of the testis-specific paralog LDHC, not a
      core localization of somatic LDHA.
    action: MARK_AS_OVER_ANNOTATED
    reason: LDHA is predominantly a cytosolic enzyme of muscle and liver; a sperm
      fibrous sheath localization is peripheral/germ-cell-specific and is not part
      of the core function. Retained as a possible non-core localization from
      orthology transfer rather than removed.
    supported_by:
    - reference_id: file:human/LDHA/LDHA-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0042867
    label: pyruvate catabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Ensembl-Compara orthology (IEA) transfer of pyruvate catabolic process.
      LDHA consumes pyruvate (reducing it to lactate), so this is a correct process
      annotation.
    action: ACCEPT
    reason: LDHA catalyses pyruvate reduction to lactate, a catabolic fate of
      pyruvate that regenerates NAD+. Correct, though the more specific fermentation
      term is the primary process.
    supported_by:
    - reference_id: PMID:24816116
      supporting_text: predominantly found in skeletal muscle and catalyses the reversible conversion
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: HPA immunofluorescence (IDA) localization of LDHA to the cytosol.
      Direct experimental support for the core cytosolic localization.
    action: ACCEPT
    reason: Direct experimental evidence for cytosolic localization, consistent with
      LDHA being a soluble glycolytic enzyme.
    supported_by:
    - reference_id: file:human/LDHA/LDHA-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0004459
    label: L-lactate dehydrogenase (NAD+) activity
  evidence_type: EXP
  original_reference_id: PMID:11276087
  qualifier: enables
  review:
    summary: Experimental (crystallography + enzymology) demonstration of the
      NAD+-dependent lactate dehydrogenase activity of human LDH-M (LDHA). Core
      molecular function.
    action: ACCEPT
    reason: Definitive experimental support - the study determined the crystal
      structure of the human M (LDHA) isoform as a ternary complex with NADH and
      the substrate analog oxamate and characterized its catalytic activity.
    supported_by:
    - reference_id: PMID:11276087
      supporting_text: interconverts pyruvate and lactate with concomitant
- term:
    id: GO:0006089
    label: lactate metabolic process
  evidence_type: IDA
  original_reference_id: PMID:24816116
  qualifier: involved_in
  review:
    summary: ComplexPortal IDA linking the LDH complex to lactate metabolism, based
      on the structural/enzymatic characterization of human LDH-A. Core biological
      process.
    action: ACCEPT
    reason: LDHA directly interconverts pyruvate and lactate; participation in
      lactate metabolic process is well-supported experimentally.
    supported_by:
    - reference_id: PMID:24816116
      supporting_text: predominantly found in skeletal muscle and catalyses the reversible conversion
- term:
    id: GO:1990204
    label: oxidoreductase complex
  evidence_type: IPI
  original_reference_id: PMID:24816116
  qualifier: part_of
  review:
    summary: ComplexPortal annotation that LDHA is part of an oxidoreductase complex
      (the LDH tetramer). The active enzyme is an oligomeric oxidoreductase.
    action: ACCEPT
    reason: The functional LDH enzyme is a homo/heterotetramer that is a bona fide
      oxidoreductase complex; this correctly captures LDHA's participation in an
      oligomeric enzyme.
    supported_by:
    - reference_id: PMID:24816116
      supporting_text: assemble to form hLDH-1 (B4), hLDH-2 (AB3), hLDH-3 (A2B2), hLDH-4 (A3B) and hLDH-5 (A4)
- term:
    id: GO:0006089
    label: lactate metabolic process
  evidence_type: IDA
  original_reference_id: PMID:34381247
  qualifier: involved_in
  review:
    summary: UniProt IDA linking LDHA to lactate metabolic process, based on the
      FLCN study demonstrating that LDHA activity (lactate production) is directly
      regulated. Core process.
    action: ACCEPT
    reason: This study experimentally established LDHA as the enzyme driving lactate
      production (Warburg effect), directly supporting its role in lactate
      metabolism.
    supported_by:
    - reference_id: PMID:34381247
      supporting_text: we identify the human tumor suppressor folliculin (FLCN) as a binding partner and uncompetitive inhibitor of LDHA
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9861563
  qualifier: located_in
  review:
    summary: Reactome TAS cytosolic localization (from the CTLH-ligase ubiquitination
      reaction). Consistent with the core cytosolic location.
    action: ACCEPT
    reason: Cytosolic localization is well-established for LDHA and supported by
      multiple independent sources.
    supported_by:
    - reference_id: file:human/LDHA/LDHA-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0004459
    label: L-lactate dehydrogenase (NAD+) activity
  evidence_type: IMP
  original_reference_id: PMID:34381247
  qualifier: enables
  review:
    summary: IMP annotation of the L-lactate dehydrogenase activity, from the FLCN
      study using the LDHA R106 mutant to probe activity regulation. Core molecular
      function.
    action: ACCEPT
    reason: The study functionally assayed LDHA enzymatic activity (including a
      mutagenesis of Arg-106 affecting FLCN binding), directly supporting the MF
      annotation.
    supported_by:
    - reference_id: PMID:34381247
      supporting_text: we identify the human tumor suppressor folliculin (FLCN) as a binding partner and uncompetitive inhibitor of LDHA
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:34381247
  qualifier: enables
  review:
    summary: UniProt IPI for the direct LDHA-FLCN (folliculin, Q8NFG4) interaction.
      FLCN is a direct, uncompetitive inhibitor of LDHA - a physiologically
      important regulatory interaction, but annotated to the uninformative "protein
      binding" term.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare "protein binding" is uninformative per curation policy and is not
      retained as a core MF. The interaction itself is real, direct and functionally
      important (activity regulation), and is retained as an experimental IPI rather
      than removed.
    supported_by:
    - reference_id: PMID:34381247
      supporting_text: we identify the human tumor suppressor folliculin (FLCN) as a binding partner and uncompetitive inhibitor of LDHA
    - reference_id: file:human/LDHA/LDHA-uniprot.txt
      supporting_text: the interaction is direct and inhibits enzymatic activity
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:34381247
  qualifier: enables
  review:
    summary: UniProt IPI self-interaction (LDHA-LDHA) reported in the FLCN study,
      consistent with the LDHA homotetramer / dimer-tetramer equilibrium described
      there.
    action: ACCEPT
    reason: Informative and core - LDHA self-association underlies the active
      tetramer; the FLCN study explicitly discusses the LDHA dimer/tetramer states.
    supported_by:
    - reference_id: PMID:34381247
      supporting_text: FLCN prefers binding to the less active LDHA dimer, compared to the hyperactive LDHA tetramer
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33406399
  qualifier: enables
  review:
    summary: UniProt IPI for the LDHA-MP31 (C0HLV8) interaction. MP31, a micropeptide
      from the PTEN uORF, competes with LDH for NAD+ and limits lactate-pyruvate
      conversion; annotated to the uninformative "protein binding" term.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare "protein binding" is uninformative and non-core. The MP31
      interaction is real (mutagenesis of Asp-56 and Arg-99 abolishes it) and
      regulatory, retained as an experimental IPI rather than removed.
    supported_by:
    - reference_id: PMID:33406399
      supporting_text: competing with mitochondrial lactate dehydrogenase (mLDH) for nicotinamide
- term:
    id: GO:0045296
    label: cadherin binding
  evidence_type: HDA
  original_reference_id: PMID:25468996
  qualifier: enables
  review:
    summary: High-throughput BioID proximity-biotinylation proteomics detected LDHA
      in the vicinity of the E-cadherin cytoplasmic tail. This is a proximity hit,
      not a demonstrated direct/functional cadherin interaction.
    action: MARK_AS_OVER_ANNOTATED
    reason: BioID labels proteins within ~20-30 nm of the bait and captures many
      abundant cytosolic proteins; the authors note most identified proteins are not
      junctional. LDHA is an abundant glycolytic enzyme with no established cadherin
      adhesion role, so this is an over-annotation. Retained (not removed) as an
      experimental high-throughput observation.
    supported_by:
    - reference_id: PMID:25468996
      supporting_text: we employed proximity biotinylation and quantitative proteomics to isolate and identify 612 proteins in the vicinity of E-cadherin
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:11487543
  qualifier: located_in
  review:
    summary: High-throughput proteomic detection of LDHA in secreted exosome-like
      vesicles. LDHA is an abundant cytosolic protein commonly detected in exosome
      preparations.
    action: MARK_AS_OVER_ANNOTATED
    reason: Detection of a highly abundant cytosolic glycolytic enzyme in exosome
      proteomes does not establish exosome localization as a core function; likely
      reflects passive incorporation/contamination. Retained as a high-throughput
      observation, not core.
    supported_by:
    - reference_id: PMID:11487543
      supporting_text: exosome-like vesicles
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:23533145
  qualifier: located_in
  review:
    summary: High-throughput proteomic detection of LDHA in prostatic-secretion
      exosomes.
    action: MARK_AS_OVER_ANNOTATED
    reason: As with other exosome-proteomics hits, this reflects the abundance of
      the cytosolic enzyme rather than a dedicated exosomal function; non-core,
      retained as an observation.
    supported_by:
    - reference_id: PMID:23533145
      supporting_text: exosomes isolated from expressed prostatic secretions
- term:
    id: GO:0016020
    label: membrane
  evidence_type: HDA
  original_reference_id: PMID:19946888
  qualifier: located_in
  review:
    summary: High-throughput membrane-proteome (NK cell) detection of LDHA. LDHA is
      a soluble cytosolic enzyme; membrane co-fractionation is likely peripheral
      association or contamination of the membrane fraction.
    action: MARK_AS_OVER_ANNOTATED
    reason: No evidence that LDHA is an integral or functionally membrane-associated
      protein; this large-scale fractionation hit is non-core. Retained as an
      observation rather than removed.
    supported_by:
    - reference_id: PMID:19946888
      supporting_text: membrane proteome of NK cells
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: HDA
  original_reference_id: PMID:21630459
  qualifier: located_in
  review:
    summary: High-throughput proteomic detection of LDHA in the human sperm nucleus
      fraction. A nuclear pool of LDHA has been reported in some contexts, but this
      HDA hit does not establish a core nuclear function.
    action: MARK_AS_OVER_ANNOTATED
    reason: LDHA is predominantly cytosolic; nuclear detection in a sperm-nucleus
      proteome is peripheral/context-specific and non-core. Retained as a
      high-throughput observation.
    supported_by:
    - reference_id: PMID:21630459
      supporting_text: sperm nucleus
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:19056867
  qualifier: located_in
  review:
    summary: High-throughput proteomic detection of LDHA in urinary exosomes.
    action: MARK_AS_OVER_ANNOTATED
    reason: Abundant cytosolic enzyme detected in exosome proteomics; non-core.
      Retained as a high-throughput observation.
    supported_by:
    - reference_id: PMID:19056867
      supporting_text: proteomics and phosphoproteomics of urinary exosomes
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:20458337
  qualifier: located_in
  review:
    summary: High-throughput proteomic detection of LDHA in B-cell exosomes.
    action: MARK_AS_OVER_ANNOTATED
    reason: As with other exosome-proteomics hits, non-core; reflects abundance
      rather than dedicated exosomal function. Retained as an observation.
    supported_by:
    - reference_id: PMID:20458337
      supporting_text: exosomes and potential functional
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-70510
  qualifier: located_in
  review:
    summary: Reactome TAS cytosolic localization (LDH tetramer oxidises lactate to
      pyruvate reaction). Consistent with core cytosolic location.
    action: ACCEPT
    reason: Well-established cytosolic localization for the glycolytic LDH enzyme.
    supported_by:
    - reference_id: file:human/LDHA/LDHA-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-71849
  qualifier: located_in
  review:
    summary: Reactome TAS cytosolic localization (LDH tetramer reduces pyruvate to
      lactate reaction). Consistent with core cytosolic location.
    action: ACCEPT
    reason: Well-established cytosolic localization for the glycolytic LDH enzyme.
    supported_by:
    - reference_id: file:human/LDHA/LDHA-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0004459
    label: L-lactate dehydrogenase (NAD+) activity
  evidence_type: TAS
  original_reference_id: PMID:2334430
  qualifier: enables
  review:
    summary: Traceable-author-statement MF annotation from the molecular
      characterization of human LDH-A(M) deficiency. Core molecular function.
    action: ACCEPT
    reason: This genetics paper characterizes the LDH-A (Muscle) subunit and its
      deficiency, treating the L-lactate dehydrogenase activity of LDHA as
      established. Core MF, consistent with all other evidence.
    supported_by:
    - reference_id: PMID:2334430
      supporting_text: deficient in LDH-A (Muscle) subunit
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: PMID:2434947
  qualifier: located_in
  review:
    summary: Traceable-author-statement cytosolic localization from an older study.
      Consistent with the core cytosolic location.
    action: ACCEPT
    reason: Cytosolic localization is robustly established for LDHA across many
      sources.
    supported_by:
    - reference_id: file:human/LDHA/LDHA-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0004459
    label: L-lactate dehydrogenase (NAD+) activity
  evidence_type: NAS
  original_reference_id: PMID:1953713
  qualifier: enables
  review:
    summary: Non-traceable-author-statement MF annotation from a study of LDH-A(M)
      deficiency mutations. Core molecular function.
    action: ACCEPT
    reason: The paper analyzes disease-causing mutations in the human LDH-A gene,
      treating the lactate dehydrogenase activity of LDHA as established. Core MF,
      concordant with the experimental annotations.
    supported_by:
    - reference_id: PMID:1953713
      supporting_text: Human lactate dehydrogenase (LDH)-A mutant gene was analyzed
- term:
    id: GO:0006096
    label: glycolytic process
  evidence_type: NAS
  original_reference_id: PMID:1953713
  qualifier: involved_in
  review:
    summary: Author-stated involvement of LDHA in the glycolytic process. LDHA
      regenerates cytosolic NAD+ (by reducing pyruvate to lactate) required to
      sustain glycolytic flux; a core process for the A/M subunit under anaerobic /
      high-flux conditions.
    action: ACCEPT
    reason: LDHA is a canonical glycolysis-associated enzyme - its lactate-forming
      reaction recycles NAD+ that keeps glycolysis (specifically GAPDH) running.
      Correct core process annotation.
    supported_by:
    - reference_id: PMID:1953713
      supporting_text: Human lactate dehydrogenase (LDH)-A mutant gene was analyzed
core_functions:
- description: NAD+-dependent L-lactate dehydrogenase - reversibly interconverts
    pyruvate + NADH and L-lactate + NAD+, with the A/M subunit favouring reduction
    of pyruvate to lactate to regenerate cytosolic NAD+
  molecular_function:
    id: GO:0004459
    label: L-lactate dehydrogenase (NAD+) activity
  directly_involved_in:
  - id: GO:0019244
    label: pyruvate fermentation to lactate
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: PMID:11276087
    supporting_text: interconverts pyruvate and lactate with concomitant
  - reference_id: file:human/LDHA/LDHA-uniprot.txt
    supporting_text: Interconverts simultaneously and stereospecifically pyruvate
- description: Lactate/NAD+ recycling supporting glycolytic flux - reducing pyruvate
    to lactate regenerates NAD+ so that glycolysis can continue under anaerobic or
    high-flux (e.g. Warburg-effect) conditions
  molecular_function:
    id: GO:0004459
    label: L-lactate dehydrogenase (NAD+) activity
  directly_involved_in:
  - id: GO:0006089
    label: lactate metabolic process
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: PMID:24816116
    supporting_text: predominantly found in skeletal muscle and catalyses the reversible conversion
  - reference_id: PMID:34381247
    supporting_text: we identify the human tumor suppressor folliculin (FLCN) as a binding partner and uncompetitive inhibitor of LDHA
- description: Homotetramer assembly - LDHA self-associates (and heteroassociates
    with LDHB/LDHC) into the catalytically active tetrameric oxidoreductase complex
    (M4/LDH-5 and A/B isoenzymes)
  molecular_function:
    id: GO:0042802
    label: identical protein binding
  directly_involved_in:
  - id: GO:0019244
    label: pyruvate fermentation to lactate
  in_complex:
    id: GO:1990204
    label: oxidoreductase complex
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: PMID:11276087
    supporting_text: the M form, predominantly found in
  - reference_id: PMID:24816116
    supporting_text: assemble to form hLDH-1 (B4), hLDH-2 (AB3), hLDH-3 (A2B2), hLDH-4 (A3B) and hLDH-5 (A4)
proposed_new_terms: []
suggested_questions:
- question: Is there a genuine, functionally significant mitochondrial pool of human
    LDHA ("mLDH"), or is the mitochondrial IBA annotation an over-projection?
- question: To what extent do the reported nuclear and cadherin-proximal localizations
    of LDHA reflect moonlighting functions versus abundance-driven proteomics artifacts?
suggested_experiments:
- description: Quantitative subcellular fractionation with activity assays to test
    whether a catalytically active mitochondrial LDHA pool exists in human cells.
- description: Structure-guided mutagenesis of the FLCN- and MP31-interaction
    interfaces to define how these regulators modulate LDHA activity and oligomeric
    state in vivo.
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:11276087
  title: Structural basis for altered activity of M- and H-isozyme forms of human
    lactate dehydrogenase.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified; crystal structures of human M (LDHA) and H (LDHB)
      isoforms as NADH/oxamate ternary complexes; establishes catalytic activity and
      homotetramerization. Abstract-only in cache but directly on-target.
- id: PMID:11487543
  title: Intestinal epithelial cells secrete exosome-like vesicles.
  findings: []
- id: PMID:19056867
  title: Large-scale proteomics and phosphoproteomics of urinary exosomes.
  findings: []
- id: PMID:1953713
  title: Analysis of genetic mutations in human lactate dehydrogenase-A(M) deficiency
    using DNA conformation polymorphism in combination with polyacrylamide gradient
    gel and silver staining.
  findings: []
- id: PMID:19946888
  title: Defining the membrane proteome of NK cells.
  findings: []
- id: PMID:20458337
  title: MHC class II-associated proteins in B-cell exosomes and potential functional
    implications for exosome biogenesis.
  findings: []
- id: PMID:21630459
  title: Proteomic characterization of the human sperm nucleus.
  findings: []
- id: PMID:21988832
  title: Toward an understanding of the protein interaction network of the human liver.
  findings: []
- id: PMID:2334430
  title: Molecular characterization of genetic mutation in human lactate dehydrogenase-A
    (M) deficiency.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified; characterizes a frameshift mutation causing human
      LDH-A(M) deficiency (GSD11). Directly relevant to LDHA function and disease.
- id: PMID:23523103
  title: Lysine-5 acetylation negatively regulates lactate dehydrogenase A and is
    decreased in pancreatic cancer.
  findings: []
- id: PMID:23533145
  title: In-depth proteomic analyses of exosomes isolated from expressed prostatic
    secretions in urine.
  findings: []
- id: PMID:2434947
  title: Centrosomal proteins and lactate dehydrogenase possess a common epitope in
    human cell lines.
  findings: []
- id: PMID:24816116
  title: Structural characterization of the apo form and NADH binary complex of human
    lactate dehydrogenase.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified; apo and NADH-bound crystal structures of human
      LDH-A; describes A vs B subunit kinetics and the five A/B tetramer isoenzymes.
- id: PMID:25468996
  title: E-cadherin interactome complexity and robustness resolved by quantitative
    proteomics.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: BioID proximity-proteomics study; LDHA is a proximity hit near the
      E-cadherin tail, not a demonstrated functional cadherin interactor.
- id: PMID:25502805
  title: A massively parallel pipeline to clone DNA variants and examine molecular
    phenotypes of human disease mutations.
  findings: []
- id: PMID:28514442
  title: Architecture of the human interactome defines protein communities and disease
    networks.
  findings: []
- id: PMID:31515488
  title: Extensive disruption of protein interactions by genetic variants across the
    allele frequency spectrum in human populations.
  findings: []
- id: PMID:33406399
  title: An Upstream Open Reading Frame in Phosphatase and Tensin Homolog Encodes
    a Circuit Breaker of Lactate Metabolism.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: PubMed-verified; identifies MP31 micropeptide that competes with
      LDH for NAD+; supports the LDHA-MP31 IPI. Regulatory context, not core enzyme
      function.
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human
    interactome.
  findings: []
- id: PMID:34381247
  title: The tumor suppressor folliculin inhibits lactate dehydrogenase A and regulates
    the Warburg effect.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified; FLCN is a direct uncompetitive inhibitor of LDHA;
      functional activity assays and dimer/tetramer state analysis support the MF
      (IMP) and interaction (IPI) annotations.
- id: PMID:35271311
  title: 'OpenCell: Endogenous tagging for the cartography of human cellular organization.'
  findings: []
- id: PMID:40205054
  title: Multimodal cell maps as a foundation for structural and functional genomics.
  findings: []
- id: Reactome:R-HSA-70510
  title: LDH tetramer oxidises LACT to PYR
  findings: []
- id: Reactome:R-HSA-71849
  title: LDH tetramer reduces PYR to LACT
  findings: []
- id: Reactome:R-HSA-9861563
  title: CTLH E3 ligase ubiquitinates LDHA
  findings: []
- id: file:human/LDHA/LDHA-uniprot.txt
  title: UniProtKB entry P00338 (LDHA_HUMAN)
  findings: []