LDHA

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.

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.

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. ORGANELLES check (2026-10-25), examined as a synthesis row. The IBA's WITH/FROM names LDHB (P07195) as the descendant evidence; LDHB's experimental mitochondrial annotation is an IDA to the inner membrane from immunogold TEM (PMID:27618187). That same paper tested LDHA and found it not at mitochondria, so the node's only seed shows the location is LDHB-specific and the projection to LDHA is contradicted by the source study. The current PAINT snapshot for PTN000899413 (interpro/panther/PTHR43128/PTHR43128-paint.tsv, 20260616) carries only the cytosol IBD, so the 2022 GOA row appears stale. LDHA has no transit peptide or TM segment and UniProt gives Cytoplasm only. The organelle claim is not supported for LDHA, so the row stays MARK_AS_OVER_ANNOTATED and no sub-compartment is added. The is_active_in qualifier is not supported either: the review shows no LDHA activity in the organelle.

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.

Proposed replacements: L-lactate dehydrogenase (NAD+) activity

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.

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

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.

Proposed replacements: L-lactate dehydrogenase (NAD+) activity

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.

Proposed replacements: L-lactate dehydrogenase (NAD+) activity

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.

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.

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).

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).

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.

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.

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.

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.

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.

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.

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.

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.

Summary: IntAct self-interaction (LDHA-LDHA), supporting homotetramer self-association.

Reason: Informative, core - consistent with the LDHA homotetramer required for catalytic activity.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Summary: Detected in an extracellular-vesicle proteome. The protein is plausible EV content, but this is not where it functions.

Reason: Cytoplasmic lactate dehydrogenase. Cytosolic protein (UniProt); cytosolic proteins, including abundant enzymes and cytoskeletal proteins, are expected and often promiscuous EV contents (MISEV2018 (PMID:30637094) category 2b). True, but not its core location. (Manual re-review for OMICS_EVIDENCE, 2026-10-10; previous action: MARK_AS_OVER_ANNOTATED.)

Summary: Detected in an extracellular-vesicle proteome. The protein is plausible EV content, but this is not where it functions.

Reason: Cytoplasmic lactate dehydrogenase. Cytosolic protein (UniProt); cytosolic proteins, including abundant enzymes and cytoskeletal proteins, are expected and often promiscuous EV contents (MISEV2018 (PMID:30637094) category 2b). True, but not its core location. (Manual re-review for OMICS_EVIDENCE, 2026-10-10; previous action: 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.

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.

Summary: Detected in an extracellular-vesicle proteome. The protein is plausible EV content, but this is not where it functions.

Reason: Cytoplasmic lactate dehydrogenase. Cytosolic protein (UniProt); cytosolic proteins, including abundant enzymes and cytoskeletal proteins, are expected and often promiscuous EV contents (MISEV2018 (PMID:30637094) category 2b). True, but not its core location. (Manual re-review for OMICS_EVIDENCE, 2026-10-10; previous action: MARK_AS_OVER_ANNOTATED.)

Summary: Detected in an extracellular-vesicle proteome. The protein is plausible EV content, but this is not where it functions.

Reason: Cytoplasmic lactate dehydrogenase. Cytosolic protein (UniProt); cytosolic proteins, including abundant enzymes and cytoskeletal proteins, are expected and often promiscuous EV contents (MISEV2018 (PMID:30637094) category 2b). True, but not its core location. (Manual re-review for OMICS_EVIDENCE, 2026-10-10; previous action: MARK_AS_OVER_ANNOTATED.)

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.

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.

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.

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.

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.

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.