LDHB encodes the B (also called H, "heart") subunit of L-lactate dehydrogenase (LDH; EC 1.1.1.27), a cytosolic NAD-dependent oxidoreductase. It catalyses the reversible, stereospecific interconversion of pyruvate + NADH + H+ and L-lactate + NAD+. Catalytically active LDH is a tetramer assembled in variable ratios from LDHA (M) and LDHB (H) subunits, producing the five classic isoenzymes (M4 through H4). LDHB-rich isoenzymes (H4) are kinetically tuned to favour the oxidation of L-lactate back to pyruvate and predominate in oxidative tissues such as heart and kidney that consume lactate as a metabolic fuel, whereas LDHA-rich isoenzymes favour the reduction of pyruvate to lactate during fermentative glycolysis. LDHB also participates in cytosolic NAD+/NADH redox balance. Loss-of-function LDHB variants cause lactate dehydrogenase B (H-subunit) deficiency, a generally benign condition of interest chiefly to laboratory medicine.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
|
GO:0019244
pyruvate fermentation to lactate
|
IBA
GO_REF:0000033 |
KEEP AS NON CORE |
Summary: Phylogenetic (IBA) annotation to the pyruvate-to-lactate fermentation process for the LDH family node. LDHB is a bona fide L-lactate dehydrogenase and catalyses this reversible reaction, so the annotation is biologically correct at the family level, but its named direction (pyruvate -> lactate, fermentation) is the direction favoured by the LDHA (M) subunit; the LDHB-rich H4 isoenzyme is kinetically tuned to the reverse (lactate -> pyruvate) direction in oxidative tissues.
Reason: The reaction is correctly assigned to the family, but for LDHB specifically the fermentation (lactate-producing) direction is not the physiologically dominant role; the lactate-oxidising direction is more characteristic. Keep as non-core; the core metabolic role is better captured by lactate/pyruvate metabolic process.
Supporting Evidence:
PMID:27618187
it has been suggested that LDHA preferentially reduces pyruvate to lactate, while LDHB supports conversion of lactate to pyruvate in cells that utilize lactate as a nutrient source for oxidative metabolism or gluconeogenesis
|
|
GO:0004459
L-lactate dehydrogenase (NAD+) activity
|
IBA
GO_REF:0000033 |
ACCEPT |
Summary: Phylogenetic (IBA) assignment of the core catalytic molecular function, L-lactate dehydrogenase (NAD+) activity (EC 1.1.1.27). This is the defining activity of LDHB and is corroborated by direct enzymatic, structural, and orthology evidence.
Reason: This is the core molecular function of LDHB, strongly supported across experimental (PMID:11276087, PMID:27618187), phylogenetic, and electronic evidence.
Supporting Evidence:
file:human/LDHB/LDHB-uniprot.txt
Reaction=(S)-lactate + NAD(+) = pyruvate + NADH + H(+);
PMID:11276087
Lactate dehydrogenase (LDH) interconverts pyruvate and lactate with concomitant
|
|
GO:0005739
mitochondrion
|
IBA
GO_REF:0000033 |
KEEP AS NON CORE |
Summary: Phylogenetic (IBA) annotation placing LDHB activity in the mitochondrion. A minority of experimental work (PMID:27618187) reports LDHB association with the inner mitochondrial membrane and mitochondrial LDH activity, but the canonical, dominant localization of LDH is cytosolic.
Reason: There is experimental support for a mitochondrial pool of LDHB, but this is a non-canonical, still-debated localization for a classically cytosolic glycolytic enzyme. Retain as non-core rather than a core location.
Supporting Evidence:
PMID:27618187
gold-labeled LDHB localizes to the inner mitochondrial membrane
|
|
GO:0003824
catalytic activity
|
IEA
GO_REF:0000002 |
MARK AS OVER ANNOTATED |
Summary: InterPro2GO electronic mapping to the root catalytic activity term. Correct but far too general given the well-defined L-lactate dehydrogenase (NAD+) activity.
Reason: Uninformative parent of the specific enzymatic function; the precise MF term GO:0004459 is annotated with strong experimental evidence and should be preferred.
|
|
GO:0004459
L-lactate dehydrogenase (NAD+) activity
|
IEA
GO_REF:0000120 |
ACCEPT |
Summary: Electronic (multi-method IEA) assignment of the core L-lactate dehydrogenase (NAD+) activity, consistent with the EC 1.1.1.27 / RHEA:23444 mapping and with experimental evidence.
Reason: Correct core molecular function, redundant with but consistent with the experimental and phylogenetic annotations of the same term.
Supporting Evidence:
file:human/LDHB/LDHB-uniprot.txt
Reaction=(S)-lactate + NAD(+) = pyruvate + NADH + H(+);
|
|
GO:0005737
cytoplasm
|
IEA
GO_REF:0000120 |
ACCEPT |
Summary: Electronic assignment of the cytoplasm, consistent with UniProt subcellular location and with LDH being a soluble cytosolic glycolytic enzyme.
Reason: Correct, though the more specific cytosol (GO:0005829) is the preferred core location. Cytoplasm is a valid broader statement.
Supporting Evidence:
file:human/LDHB/LDHB-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm. Mitochondrion inner membrane
|
|
GO:0005743
mitochondrial inner membrane
|
IEA
GO_REF:0000044 |
KEEP AS NON CORE |
Summary: Electronic annotation derived from the UniProt Subcellular Location keyword mapping (Mitochondrion inner membrane), which in turn rests on the experimental report PMID:27618187. This is a non-canonical localization for LDHB.
Reason: Supported experimentally (PMID:27618187) via the UniProt subcellular location, but a minority/debated localization; the core location is cytosolic. Keep as non-core.
Supporting Evidence:
file:human/LDHB/LDHB-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm. Mitochondrion inner membrane
|
|
GO:0016491
oxidoreductase activity
|
IEA
GO_REF:0000002 |
MARK AS OVER ANNOTATED |
Summary: InterPro2GO electronic mapping to the general oxidoreductase activity term. Correct but too general.
Reason: Parent of the specific L-lactate dehydrogenase (NAD+) activity; uninformative given the well-supported specific MF term.
|
|
GO:0016616
oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor
|
IEA
GO_REF:0000002 |
MARK AS OVER ANNOTATED |
Summary: InterPro2GO electronic mapping to an intermediate oxidoreductase term describing the CH-OH-group / NAD(P)-acceptor chemistry. Accurate for LDH chemistry but less specific than L-lactate dehydrogenase (NAD+) activity.
Reason: Correct grandparent-level chemistry but redundant with the specific MF term GO:0004459, which should be preferred.
|
|
GO:0005515
protein binding
|
IPI
PMID:21044950 Genome-wide YFP fluorescence complementation screen identifi... |
MARK AS OVER ANNOTATED |
Summary: IntAct two-hybrid/interaction datum with TERF1 (P54274). Bare protein binding conveys no specific function.
Reason: Uninformative generic protein-binding annotation from a high-throughput interaction screen; not a core function and no specific molecular function can be inferred. Retained per policy rather than removed.
|
|
GO:0005515
protein binding
|
IPI
PMID:21988832 Toward an understanding of the protein interaction network o... |
MARK AS OVER ANNOTATED |
Summary: IntAct interaction datum with LDHA (P00338), consistent with formation of mixed M/H LDH tetramers, but captured only as generic protein binding.
Reason: The underlying LDHA interaction is biologically real (heterotetramer assembly), but the bare protein binding term is uninformative; the tetramer relationship is better captured by identical protein binding / oxidoreductase complex.
|
|
GO:0005515
protein binding
|
IPI
PMID:24725412 Ribosomal protein s15 phosphorylation mediates LRRK2 neurode... |
MARK AS OVER ANNOTATED |
Summary: IntAct interaction datum with LRRK2 (Q5S007) from a Parkinson-disease study. Bare protein binding, no specific function implied for LDHB.
Reason: Uninformative generic protein-binding annotation; not a core function.
|
|
GO:0005515
protein binding
|
IPI
PMID:25416956 A proteome-scale map of the human interactome network. |
MARK AS OVER ANNOTATED |
Summary: IntAct interaction datum with LDHA isoform (P00338-3) from a proteome-scale interactome map. Bare protein binding.
Reason: Uninformative generic protein-binding annotation from a high-throughput interactome study; not a core function.
|
|
GO:0005515
protein binding
|
IPI
PMID:25910212 Widespread macromolecular interaction perturbations in human... |
MARK AS OVER ANNOTATED |
Summary: IntAct interaction datum with LDHA isoform (P00338-3) from a study of interaction perturbations in genetic disorders. Bare protein binding.
Reason: Uninformative generic protein-binding annotation; not a core function.
|
|
GO:0005515
protein binding
|
IPI
PMID:28514442 Architecture of the human interactome defines protein commun... |
MARK AS OVER ANNOTATED |
Summary: IntAct interaction data (LDHA P00338, LDHC P07864) from an interactome community study. Consistent with LDH-family tetramer assembly but recorded as generic protein binding.
Reason: Uninformative generic protein-binding term; the biologically relevant LDH-family subunit interactions are better captured elsewhere.
|
|
GO:0005515
protein binding
|
IPI
PMID:31515488 Extensive disruption of protein interactions by genetic vari... |
MARK AS OVER ANNOTATED |
Summary: IntAct interaction datum with LDHA (P00338) from a study of variant-driven interaction disruption. Bare protein binding.
Reason: Uninformative generic protein-binding annotation; not a core function.
|
|
GO:0005515
protein binding
|
IPI
PMID:32296183 A reference map of the human binary protein interactome. |
MARK AS OVER ANNOTATED |
Summary: IntAct interaction data (SDCBP O00560, LDHA isoform P00338-3) from a reference binary interactome map. Bare protein binding.
Reason: Uninformative generic protein-binding annotation from a high-throughput screen; not a core function.
|
|
GO:0005515
protein binding
|
IPI
PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... |
MARK AS OVER ANNOTATED |
Summary: IntAct interaction datum with HTT (P42858) from a neurodegenerative-disease interactome study. Bare protein binding.
Reason: Uninformative generic protein-binding annotation; not a core function.
|
|
GO:0005515
protein binding
|
IPI
PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... |
MARK AS OVER ANNOTATED |
Summary: IntAct interaction data (LDHA P00338, LDHC P07864) from a cell-specific interactome remodeling study. LDH-family subunit interactions recorded as generic protein binding.
Reason: Uninformative generic protein-binding term; the relevant subunit interactions are better represented by the tetramer/complex annotations.
|
|
GO:0005515
protein binding
|
IPI
PMID:35271311 OpenCell: Endogenous tagging for the cartography of human ce... |
MARK AS OVER ANNOTATED |
Summary: IntAct interaction data (LDHA P00338, LDHC P07864) from the OpenCell endogenous-tagging interactome. Bare protein binding.
Reason: Uninformative generic protein-binding annotation; not a core function.
|
|
GO:0005515
protein binding
|
IPI
PMID:40205054 Multimodal cell maps as a foundation for structural and func... |
MARK AS OVER ANNOTATED |
Summary: IntAct interaction datum with LDHC (P07864) from a multimodal cell-map study. Bare protein binding.
Reason: Uninformative generic protein-binding annotation; not a core function.
|
|
GO:0042802
identical protein binding
|
IPI
PMID:25416956 A proteome-scale map of the human interactome network. |
KEEP AS NON CORE |
Summary: IntAct self-interaction (P07195 with P07195), reflecting the homotetrameric assembly of the LDHB (H4) isoenzyme.
Reason: Biologically meaningful (LDHB homotetramerization) and more informative than bare protein binding, but the self-association is a structural feature supporting the complex rather than the core catalytic function. Keep as non-core.
Supporting Evidence:
file:human/LDHB/LDHB-uniprot.txt
Homotetramer (PubMed:11276087)
|
|
GO:0042802
identical protein binding
|
IPI
PMID:25502805 A massively parallel pipeline to clone DNA variants and exam... |
KEEP AS NON CORE |
Summary: IntAct self-interaction (P07195 with P07195) from a variant-cloning / molecular-phenotype pipeline, again reflecting LDHB homotetramerization.
Reason: Consistent with homotetramer assembly; informative structural annotation but not the core catalytic function.
Supporting Evidence:
file:human/LDHB/LDHB-uniprot.txt
Homotetramer (PubMed:11276087)
|
|
GO:0042802
identical protein binding
|
IPI
PMID:31515488 Extensive disruption of protein interactions by genetic vari... |
KEEP AS NON CORE |
Summary: IntAct self-interaction (P07195 with P07195), reflecting LDHB homotetramerization.
Reason: Consistent with homotetramer assembly; informative structural annotation but not the core catalytic function.
Supporting Evidence:
file:human/LDHB/LDHB-uniprot.txt
Homotetramer (PubMed:11276087)
|
|
GO:0042802
identical protein binding
|
IPI
PMID:32296183 A reference map of the human binary protein interactome. |
KEEP AS NON CORE |
Summary: IntAct self-interaction (P07195 with P07195) from the reference binary interactome, reflecting LDHB homotetramerization.
Reason: Consistent with homotetramer assembly; informative structural annotation but not the core catalytic function.
Supporting Evidence:
file:human/LDHB/LDHB-uniprot.txt
Homotetramer (PubMed:11276087)
|
|
GO:0004457
lactate dehydrogenase activity
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: Ensembl orthology (IEA) assignment of lactate dehydrogenase activity, the immediate parent of the NAD+-specific L-lactate dehydrogenase activity.
Reason: Correct and consistent with the core function; a slightly broader phrasing of the same catalytic activity. Acceptable as-is.
Supporting Evidence:
PMID:11276087
Lactate dehydrogenase (LDH) interconverts pyruvate and lactate with concomitant
|
|
GO:0005829
cytosol
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: Ensembl orthology (IEA) placement of LDHB activity in the cytosol, the canonical location of this glycolytic enzyme, concordant with the HPA IDA and Reactome TAS annotations to cytosol.
Reason: Correct core subcellular location; strongly corroborated by IDA (HPA) and TAS (Reactome) evidence.
|
|
GO:0006089
lactate metabolic process
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: Ensembl orthology (IEA) assignment to lactate metabolic process, capturing LDHB's role in the interconversion of lactate and pyruvate. Also independently supported by ComplexPortal IDA (PMID:15117937).
Reason: Accurately reflects the core biological process in which LDHB participates (lactate/pyruvate interconversion), and is the process best matching the LDHB-favoured lactate-oxidising direction.
Supporting Evidence:
PMID:27618187
LDHB supports conversion of lactate to pyruvate in cells that utilize lactate as a nutrient source for oxidative metabolism or gluconeogenesis
|
|
GO:0019674
NAD+ metabolic process
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: Ensembl orthology (IEA) assignment to NAD+ metabolic process, reflecting that LDHB regenerates/consumes NAD+/NADH during the lactate-pyruvate reaction and thereby contributes to cytosolic redox balance.
Reason: Biologically correct (the reaction interconverts NAD+ and NADH), but NAD+ metabolism is a downstream consequence of the catalytic activity rather than the core annotated function. Keep as non-core.
Supporting Evidence:
PMID:15117937
central to NAD(+) regeneration
|
|
GO:0019900
kinase binding
|
IEA
GO_REF:0000107 |
MARK AS OVER ANNOTATED |
Summary: Ensembl orthology (IEA) transfer of a kinase-binding annotation from a rat ortholog. There is no specific experimental evidence that human LDHB binds a kinase as a defined molecular function.
Reason: Orthology-transferred generic binding annotation with no clear functional relevance to LDHB's role; likely an over-annotation and not a core function.
|
|
GO:0042802
identical protein binding
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: Ensembl orthology (IEA) transfer of identical protein binding, consistent with the homotetrameric assembly of LDHB.
Reason: Reflects LDHB homotetramerization; informative structural feature but not the core catalytic function.
Supporting Evidence:
file:human/LDHB/LDHB-uniprot.txt
Homotetramer (PubMed:11276087)
|
|
GO:0051287
NAD binding
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: Ensembl orthology (IEA) assignment of NAD binding. LDHB is an NAD-dependent dehydrogenase with a Rossmann-fold NAD-binding domain and defined NAD(+)-binding residues, so this is a correct and informative molecular function.
Reason: Correct; NAD binding is a genuine, structurally documented molecular function of LDHB (NAD-binding Rossmann domain; NAD(+) binding site residues in UniProt).
Supporting Evidence:
file:human/LDHB/LDHB-uniprot.txt
Reaction=(S)-lactate + NAD(+) = pyruvate + NADH + H(+);
|
|
GO:0005829
cytosol
|
IDA
GO_REF:0000052 |
ACCEPT |
Summary: Direct immunofluorescence (HPA) localization of LDHB to the cytosol, the canonical location of this glycolytic enzyme.
Reason: Experimentally supported core subcellular location, concordant with electronic and TAS cytosol annotations.
|
|
GO:0004459
L-lactate dehydrogenase (NAD+) activity
|
EXP
PMID:11276087 Structural basis for altered activity of M- and H-isozyme fo... |
ACCEPT |
Summary: Experimental (structural/biophysical) demonstration of L-lactate dehydrogenase (NAD+) activity for human LDH-H, via crystallographic ternary complexes with NADH and substrate analog and kinetic characterization.
Reason: This is the defining, experimentally established core molecular function of LDHB, characterized structurally and kinetically for the H isoform.
Supporting Evidence:
PMID:11276087
Lactate dehydrogenase (LDH) interconverts pyruvate and lactate with concomitant
PMID:11276087
the H form, found mainly in cardiac muscle
|
|
GO:0006089
lactate metabolic process
|
IDA
PMID:15117937 Identification and activity of a series of azole-based compo... |
ACCEPT |
Summary: ComplexPortal IDA annotation of the LDH complex to lactate metabolic process. LDH is central to lactate/pyruvate interconversion and NAD+ regeneration.
Reason: Correctly captures the core biological process; LDHB participates in lactate metabolism as the H subunit of the LDH complex.
Supporting Evidence:
PMID:15117937
central to NAD(+) regeneration
|
|
GO:1990204
oxidoreductase complex
|
IPI
PMID:15117937 Identification and activity of a series of azole-based compo... |
ACCEPT |
Summary: ComplexPortal assertion that LDHB is part of the L-lactate dehydrogenase (oxidoreductase) complex, i.e. the LDH tetramer. UniProt/ComplexPortal record the A/B (M/H) tetramer variants (CPX-6592/6594/6598/6599).
Reason: Correct; catalytically active LDH is a tetramer, and LDHB is a constituent subunit. This appropriately captures the complex-level context of the enzyme.
Supporting Evidence:
PMID:27618187
Functional LDH is a homo or hetero tetramer composed of LDHA and LDHB subunits
file:human/LDHB/LDHB-uniprot.txt
Homotetramer (PubMed:11276087)
|
|
GO:0004459
L-lactate dehydrogenase (NAD+) activity
|
IDA
PMID:27618187 Lactate metabolism is associated with mammalian mitochondria... |
ACCEPT |
Summary: Direct assay of LDHB (L-lactate dehydrogenase) activity in whole-cell and isolated mitochondrial lysates, confirming the core catalytic function.
Reason: Experimentally supported core molecular function of LDHB.
Supporting Evidence:
PMID:27618187
the mitochondria had higher LDHB activity, further suggesting that LDHB activity is concentrated in mitochondria
|
|
GO:0005515
protein binding
|
IPI
PMID:33406399 An Upstream Open Reading Frame in Phosphatase and Tensin Hom... |
MARK AS OVER ANNOTATED |
Summary: UniProt-curated IPI interaction with the PTEN-uORF micropeptide MP31 (C0HLV8). MP31 binds LDHB and inhibits mitochondrial LDH activity by competing for NAD+, acting as a regulatory circuit breaker of lactate-pyruvate conversion; the interaction is abolished by LDHB mutations D53A and R100A.
Reason: This is the most biologically meaningful of the protein-binding annotations (a specific, functionally characterized regulatory interaction), but the term itself is the uninformative generic protein binding. Retained (not removed) per policy; a more specific enzyme-inhibitor / MP31-binding characterization would be preferable.
Supporting Evidence:
PMID:33406399
limits lactate-pyruvate conversion in mitochondria by
PMID:33406399
competing with mitochondrial lactate dehydrogenase (mLDH) for
|
|
GO:0005743
mitochondrial inner membrane
|
IDA
PMID:27618187 Lactate metabolism is associated with mammalian mitochondria... |
KEEP AS NON CORE |
Summary: TEM immunogold localization of LDHB to the inner mitochondrial membrane in HeLa cells, with concordant mitochondrial LDH activity in isolated mitochondria. A specific but non-canonical localization for this classically cytosolic enzyme.
Reason: Experimentally supported (PMID:27618187), but a minority/debated localization; the dominant location of LDHB is cytosolic. Retain as non-core.
Supporting Evidence:
PMID:27618187
gold-labeled LDHB localizes to the inner mitochondrial membrane
|
|
GO:0045121
membrane raft
|
IDA
PMID:25204797 Flotillin-1 facilitates toll-like receptor 3 signaling in hu... |
MARK AS OVER ANNOTATED |
Summary: Localization to membrane raft reported in a flotillin-1/TLR3 endothelial signaling study that used SILAC proteomics of raft/caveolae fractions. LDHB is a soluble cytosolic enzyme and its recovery in raft proteomic fractions most likely reflects abundant-protein co-purification rather than a functional raft localization.
Reason: A soluble glycolytic enzyme is not expected to be a genuine membrane raft resident; this is likely a proteomic co-isolation artifact and an over-annotation.
Supporting Evidence:
PMID:25204797
Flotillin-1 and -2 are markers of membrane rafts
|
|
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 LDHB in urinary/prostatic-secretion exosome preparations. Abundant cytosolic enzymes are commonly detected in exosome proteomes without evidence of a functional role there.
Reason: Cytosolic-enzyme detection in exosome proteomics; not a functional localization and not a core annotation.
|
|
GO:0016020
membrane
|
HDA
PMID:19946888 Defining the membrane proteome of NK cells. |
MARK AS OVER ANNOTATED |
Summary: High-throughput proteomic detection of LDHB in an NK-cell membrane proteome preparation. Non-specific membrane assignment for a soluble enzyme.
Reason: Generic membrane assignment for a cytosolic protein from a proteomic membrane-fraction study; likely co-isolation and an over-annotation.
|
|
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 LDHB in urinary exosomes.
Reason: Cytosolic-enzyme detection in exosome proteomics; not a functional localization and not a core annotation.
|
|
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 LDHB in B-cell exosomes.
Reason: Cytosolic-enzyme detection in exosome proteomics; not a functional localization and not a core annotation.
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-70510 |
ACCEPT |
Summary: Reactome traceable-author-statement placing LDHB in the cytosol in the context of LDH tetramer oxidises LACT to PYR, the lactate-oxidising direction favoured by the LDHB-rich isoenzyme.
Reason: Correct core cytosolic location, consistent with IDA and IEA cytosol annotations and with the canonical glycolytic-enzyme localization.
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-71849 |
ACCEPT |
Summary: Reactome traceable-author-statement placing LDHB in the cytosol in the context of LDH tetramer reduces PYR to LACT.
Reason: Correct core cytosolic location, redundant with but consistent with the other cytosol annotations.
|
|
GO:0005737
cytoplasm
|
TAS
PMID:16130169 Proteomics of human umbilical vein endothelial cells applied... |
ACCEPT |
Summary: Traceable-author-statement (UniProt) cytoplasm localization derived from a HUVEC proteomics study. Consistent with the soluble cytoplasmic nature of LDHB.
Reason: Correct broader localization; the more specific cytosol is preferred as the core location.
Supporting Evidence:
file:human/LDHB/LDHB-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm. Mitochondrion inner membrane
|
|
GO:0004459
L-lactate dehydrogenase (NAD+) activity
|
TAS
PMID:8314553 Analysis of a genetic mutation in an electrophoretic variant... |
ACCEPT |
Summary: Traceable-author-statement of L-lactate dehydrogenase (NAD+) activity, from a study characterizing an electrophoretic LDH-B(H) subunit variant (K7E) with decreased heat stability and slightly reduced activity.
Reason: Correct core molecular function; the paper explicitly concerns the human LDH-B (H) subunit and its enzymatic activity.
Supporting Evidence:
PMID:8314553
An electrophoretic variant of the lactate dehydrogenase (LDH)-B(H) subunit was
|
Q: Is the mitochondrial (inner-membrane) pool of LDHB a genuine, functionally significant localization in vivo, or is it largely restricted to specific cell types (e.g. fermenting cancer cells) and experimental conditions?
Q: To what extent does the MP31 (PTEN-uORF) circuit-breaker regulation of LDHB operate in normal physiology versus tumour metabolism?
Experiment: Compartment-resolved activity assays (cytosol vs mitochondrial sub-fractions) across oxidative and glycolytic human tissues to quantify the physiological contribution of any mitochondrial LDHB pool.
Experiment: Structure-guided kinetic comparison of purified LDHB homotetramer versus defined M/H heterotetramers to quantify the directional (lactate to pyruvate) preference under physiological substrate/redox conditions.
LDHB encodes the B / H ("heart") subunit of L-lactate dehydrogenase (LDH; EC 1.1.1.27).
Active LDH is a tetramer assembled from LDHA (M) and LDHB (H) subunits, giving rise to
the classic five isoenzymes (M4, M3H1, M2H2, M1H3, H4). LDHB-rich isoenzymes (H4)
kinetically favour oxidation of L-lactate back to pyruvate, suiting oxidative tissues
(heart, kidney) that consume lactate as fuel.
(S)-lactate + NAD(+) = pyruvate + NADH + H(+). Reversible; UniProt notes bothRead et al. crystallised human LDH-M and LDH-H ternary complexes with NADH + oxamate.
"Lactate dehydrogenase (LDH) interconverts pyruvate and lactate with concomitant
interconversion of NADH and NAD(+)." The two isoforms are structurally
indistinguishable at the active site; kinetic differences arise from peripheral charged
surface residues. Confirms homotetramer, NAD+ binding, and MF = L-lactate dehydrogenase
(NAD+) activity. [full_text_available: false — abstract only]
Full text available. Key verbatim findings:
- "Functional LDH is a homo or hetero tetramer composed of LDHA and LDHB subunits"
- "LDHB is the predominant isoform found in heart muscle and is often referred to as the
H subunit"
- "it has been suggested that LDHA preferentially reduces pyruvate to lactate, while
LDHB supports conversion of lactate to pyruvate in cells that utilize lactate as a
nutrient source for oxidative metabolism or gluconeogenesis"
- TEM immunogold: "gold-labeled LDHB localizes to the inner mitochondrial membrane"
- LDHB activity detected in whole-cell and isolated mitochondrial lysates.
This is the experimental basis for the IDA GO:0004459 and IDA GO:0005743 (mito inner
membrane) annotations. Note this is a specific, somewhat contested localization; the
dominant/canonical localization remains cytosolic (glycolytic enzyme).
MP31 is a micropeptide from the PTEN uORF that "limits lactate-pyruvate conversion in
mitochondria by competing with mitochondrial lactate dehydrogenase (mLDH) for
nicotinamide adenine dinucleotide (NAD+)." UniProt: interaction abolished by LDHB
mutants D53A and R100A. Supports a real, functionally meaningful protein-protein
interaction (regulatory), curated by UniProt as GO:0005515 IPI with C0HLV8 (MP31).
LDHB deficiency (LDHBD, MIM:614128): "A condition with no deleterious effects on
health." Clinically mild/asymptomatic; laboratory-medicine interest (LDH isoenzyme
misdiagnosis). Many missense variants documented in UniProt (K7E, R107W inactive, etc.).
id: P07195
gene_symbol: LDHB
product_type: PROTEIN
status: INITIALIZED
taxon:
id: NCBITaxon:9606
label: Homo sapiens
description: LDHB encodes the B (also called H, "heart") subunit of L-lactate dehydrogenase
(LDH; EC 1.1.1.27), a cytosolic NAD-dependent oxidoreductase. It catalyses the reversible,
stereospecific interconversion of pyruvate + NADH + H+ and L-lactate + NAD+. Catalytically
active LDH is a tetramer assembled in variable ratios from LDHA (M) and LDHB (H) subunits,
producing the five classic isoenzymes (M4 through H4). LDHB-rich isoenzymes (H4) are
kinetically tuned to favour the oxidation of L-lactate back to pyruvate and predominate
in oxidative tissues such as heart and kidney that consume lactate as a metabolic fuel,
whereas LDHA-rich isoenzymes favour the reduction of pyruvate to lactate during
fermentative glycolysis. LDHB also participates in cytosolic NAD+/NADH redox balance.
Loss-of-function LDHB variants cause lactate dehydrogenase B (H-subunit) deficiency, a
generally benign condition of interest chiefly to laboratory medicine.
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 pyruvate-to-lactate fermentation process
for the LDH family node. LDHB is a bona fide L-lactate dehydrogenase and catalyses
this reversible reaction, so the annotation is biologically correct at the family
level, but its named direction (pyruvate -> lactate, fermentation) is the direction
favoured by the LDHA (M) subunit; the LDHB-rich H4 isoenzyme is kinetically tuned to
the reverse (lactate -> pyruvate) direction in oxidative tissues.
action: KEEP_AS_NON_CORE
reason: The reaction is correctly assigned to the family, but for LDHB specifically the
fermentation (lactate-producing) direction is not the physiologically dominant role;
the lactate-oxidising direction is more characteristic. Keep as non-core; the core
metabolic role is better captured by lactate/pyruvate metabolic process.
supported_by:
- reference_id: PMID:27618187
supporting_text: it has been suggested that LDHA preferentially reduces pyruvate to
lactate, while LDHB supports conversion of lactate to pyruvate in cells that utilize
lactate as a nutrient source for oxidative metabolism or gluconeogenesis
- 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) assignment of the core catalytic molecular function,
L-lactate dehydrogenase (NAD+) activity (EC 1.1.1.27). This is the defining activity
of LDHB and is corroborated by direct enzymatic, structural, and orthology evidence.
action: ACCEPT
reason: This is the core molecular function of LDHB, strongly supported across
experimental (PMID:11276087, PMID:27618187), phylogenetic, and electronic evidence.
supported_by:
- reference_id: file:human/LDHB/LDHB-uniprot.txt
supporting_text: Reaction=(S)-lactate + NAD(+) = pyruvate + NADH + H(+);
- reference_id: PMID:11276087
supporting_text: Lactate dehydrogenase (LDH) interconverts pyruvate and lactate with
concomitant
- 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 LDHB activity in the mitochondrion. A
minority of experimental work (PMID:27618187) reports LDHB association with the inner
mitochondrial membrane and mitochondrial LDH activity, but the canonical, dominant
localization of LDH is cytosolic.
action: KEEP_AS_NON_CORE
reason: There is experimental support for a mitochondrial pool of LDHB, but this is a
non-canonical, still-debated localization for a classically cytosolic glycolytic
enzyme. Retain as non-core rather than a core location.
supported_by:
- reference_id: PMID:27618187
supporting_text: gold-labeled LDHB localizes to the inner mitochondrial membrane
- term:
id: GO:0003824
label: catalytic activity
evidence_type: IEA
original_reference_id: GO_REF:0000002
qualifier: enables
review:
summary: InterPro2GO electronic mapping to the root catalytic activity term. Correct
but far too general given the well-defined L-lactate dehydrogenase (NAD+) activity.
action: MARK_AS_OVER_ANNOTATED
reason: Uninformative parent of the specific enzymatic function; the precise MF term
GO:0004459 is annotated with strong experimental evidence and should be preferred.
- term:
id: GO:0004459
label: L-lactate dehydrogenase (NAD+) activity
evidence_type: IEA
original_reference_id: GO_REF:0000120
qualifier: enables
review:
summary: Electronic (multi-method IEA) assignment of the core L-lactate dehydrogenase
(NAD+) activity, consistent with the EC 1.1.1.27 / RHEA:23444 mapping and with
experimental evidence.
action: ACCEPT
reason: Correct core molecular function, redundant with but consistent with the
experimental and phylogenetic annotations of the same term.
supported_by:
- reference_id: file:human/LDHB/LDHB-uniprot.txt
supporting_text: Reaction=(S)-lactate + NAD(+) = pyruvate + NADH + H(+);
- term:
id: GO:0005737
label: cytoplasm
evidence_type: IEA
original_reference_id: GO_REF:0000120
qualifier: located_in
review:
summary: Electronic assignment of the cytoplasm, consistent with UniProt subcellular
location and with LDH being a soluble cytosolic glycolytic enzyme.
action: ACCEPT
reason: Correct, though the more specific cytosol (GO:0005829) is the preferred core
location. Cytoplasm is a valid broader statement.
supported_by:
- reference_id: file:human/LDHB/LDHB-uniprot.txt
supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm. Mitochondrion inner membrane'
- term:
id: GO:0005743
label: mitochondrial inner membrane
evidence_type: IEA
original_reference_id: GO_REF:0000044
qualifier: located_in
review:
summary: Electronic annotation derived from the UniProt Subcellular Location keyword
mapping (Mitochondrion inner membrane), which in turn rests on the experimental
report PMID:27618187. This is a non-canonical localization for LDHB.
action: KEEP_AS_NON_CORE
reason: Supported experimentally (PMID:27618187) via the UniProt subcellular location,
but a minority/debated localization; the core location is cytosolic. Keep as
non-core.
supported_by:
- reference_id: file:human/LDHB/LDHB-uniprot.txt
supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm. Mitochondrion inner membrane'
- term:
id: GO:0016491
label: oxidoreductase activity
evidence_type: IEA
original_reference_id: GO_REF:0000002
qualifier: enables
review:
summary: InterPro2GO electronic mapping to the general oxidoreductase activity term.
Correct but too general.
action: MARK_AS_OVER_ANNOTATED
reason: Parent of the specific L-lactate dehydrogenase (NAD+) activity; uninformative
given the well-supported specific MF term.
- 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 electronic mapping to an intermediate oxidoreductase term
describing the CH-OH-group / NAD(P)-acceptor chemistry. Accurate for LDH chemistry
but less specific than L-lactate dehydrogenase (NAD+) activity.
action: MARK_AS_OVER_ANNOTATED
reason: Correct grandparent-level chemistry but redundant with the specific MF term
GO:0004459, which should be preferred.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:21044950
qualifier: enables
review:
summary: IntAct two-hybrid/interaction datum with TERF1 (P54274). Bare protein binding
conveys no specific function.
action: MARK_AS_OVER_ANNOTATED
reason: Uninformative generic protein-binding annotation from a high-throughput
interaction screen; not a core function and no specific molecular function can be
inferred. Retained per policy rather than removed.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:21988832
qualifier: enables
review:
summary: IntAct interaction datum with LDHA (P00338), consistent with formation of
mixed M/H LDH tetramers, but captured only as generic protein binding.
action: MARK_AS_OVER_ANNOTATED
reason: The underlying LDHA interaction is biologically real (heterotetramer assembly),
but the bare protein binding term is uninformative; the tetramer relationship is
better captured by identical protein binding / oxidoreductase complex.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:24725412
qualifier: enables
review:
summary: IntAct interaction datum with LRRK2 (Q5S007) from a Parkinson-disease study.
Bare protein binding, no specific function implied for LDHB.
action: MARK_AS_OVER_ANNOTATED
reason: Uninformative generic protein-binding annotation; not a core function.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:25416956
qualifier: enables
review:
summary: IntAct interaction datum with LDHA isoform (P00338-3) from a proteome-scale
interactome map. Bare protein binding.
action: MARK_AS_OVER_ANNOTATED
reason: Uninformative generic protein-binding annotation from a high-throughput
interactome study; not a core function.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:25910212
qualifier: enables
review:
summary: IntAct interaction datum with LDHA isoform (P00338-3) from a study of
interaction perturbations in genetic disorders. Bare protein binding.
action: MARK_AS_OVER_ANNOTATED
reason: Uninformative generic protein-binding annotation; not a core function.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:28514442
qualifier: enables
review:
summary: IntAct interaction data (LDHA P00338, LDHC P07864) from an interactome
community study. Consistent with LDH-family tetramer assembly but recorded as
generic protein binding.
action: MARK_AS_OVER_ANNOTATED
reason: Uninformative generic protein-binding term; the biologically relevant LDH-family
subunit interactions are better captured elsewhere.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:31515488
qualifier: enables
review:
summary: IntAct interaction datum with LDHA (P00338) from a study of variant-driven
interaction disruption. Bare protein binding.
action: MARK_AS_OVER_ANNOTATED
reason: Uninformative generic protein-binding annotation; not a core function.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:32296183
qualifier: enables
review:
summary: IntAct interaction data (SDCBP O00560, LDHA isoform P00338-3) from a reference
binary interactome map. Bare protein binding.
action: MARK_AS_OVER_ANNOTATED
reason: Uninformative generic protein-binding annotation from a high-throughput screen;
not a core function.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:32814053
qualifier: enables
review:
summary: IntAct interaction datum with HTT (P42858) from a neurodegenerative-disease
interactome study. Bare protein binding.
action: MARK_AS_OVER_ANNOTATED
reason: Uninformative generic protein-binding annotation; not a core function.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:33961781
qualifier: enables
review:
summary: IntAct interaction data (LDHA P00338, LDHC P07864) from a cell-specific
interactome remodeling study. LDH-family subunit interactions recorded as generic
protein binding.
action: MARK_AS_OVER_ANNOTATED
reason: Uninformative generic protein-binding term; the relevant subunit interactions
are better represented by the tetramer/complex annotations.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:35271311
qualifier: enables
review:
summary: IntAct interaction data (LDHA P00338, LDHC P07864) from the OpenCell
endogenous-tagging interactome. Bare protein binding.
action: MARK_AS_OVER_ANNOTATED
reason: Uninformative generic protein-binding annotation; not a core function.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:40205054
qualifier: enables
review:
summary: IntAct interaction datum with LDHC (P07864) from a multimodal cell-map study.
Bare protein binding.
action: MARK_AS_OVER_ANNOTATED
reason: Uninformative generic protein-binding annotation; not a core function.
- term:
id: GO:0042802
label: identical protein binding
evidence_type: IPI
original_reference_id: PMID:25416956
qualifier: enables
review:
summary: IntAct self-interaction (P07195 with P07195), reflecting the homotetrameric
assembly of the LDHB (H4) isoenzyme.
action: KEEP_AS_NON_CORE
reason: Biologically meaningful (LDHB homotetramerization) and more informative than
bare protein binding, but the self-association is a structural feature supporting the
complex rather than the core catalytic function. Keep as non-core.
supported_by:
- reference_id: file:human/LDHB/LDHB-uniprot.txt
supporting_text: Homotetramer (PubMed:11276087)
- term:
id: GO:0042802
label: identical protein binding
evidence_type: IPI
original_reference_id: PMID:25502805
qualifier: enables
review:
summary: IntAct self-interaction (P07195 with P07195) from a variant-cloning /
molecular-phenotype pipeline, again reflecting LDHB homotetramerization.
action: KEEP_AS_NON_CORE
reason: Consistent with homotetramer assembly; informative structural annotation but
not the core catalytic function.
supported_by:
- reference_id: file:human/LDHB/LDHB-uniprot.txt
supporting_text: Homotetramer (PubMed:11276087)
- term:
id: GO:0042802
label: identical protein binding
evidence_type: IPI
original_reference_id: PMID:31515488
qualifier: enables
review:
summary: IntAct self-interaction (P07195 with P07195), reflecting LDHB
homotetramerization.
action: KEEP_AS_NON_CORE
reason: Consistent with homotetramer assembly; informative structural annotation but
not the core catalytic function.
supported_by:
- reference_id: file:human/LDHB/LDHB-uniprot.txt
supporting_text: Homotetramer (PubMed:11276087)
- term:
id: GO:0042802
label: identical protein binding
evidence_type: IPI
original_reference_id: PMID:32296183
qualifier: enables
review:
summary: IntAct self-interaction (P07195 with P07195) from the reference binary
interactome, reflecting LDHB homotetramerization.
action: KEEP_AS_NON_CORE
reason: Consistent with homotetramer assembly; informative structural annotation but
not the core catalytic function.
supported_by:
- reference_id: file:human/LDHB/LDHB-uniprot.txt
supporting_text: Homotetramer (PubMed:11276087)
- term:
id: GO:0004457
label: lactate dehydrogenase activity
evidence_type: IEA
original_reference_id: GO_REF:0000107
qualifier: enables
review:
summary: Ensembl orthology (IEA) assignment of lactate dehydrogenase activity, the
immediate parent of the NAD+-specific L-lactate dehydrogenase activity.
action: ACCEPT
reason: Correct and consistent with the core function; a slightly broader phrasing of
the same catalytic activity. Acceptable as-is.
supported_by:
- reference_id: PMID:11276087
supporting_text: Lactate dehydrogenase (LDH) interconverts pyruvate and lactate with
concomitant
- term:
id: GO:0005829
label: cytosol
evidence_type: IEA
original_reference_id: GO_REF:0000107
qualifier: is_active_in
review:
summary: Ensembl orthology (IEA) placement of LDHB activity in the cytosol, the
canonical location of this glycolytic enzyme, concordant with the HPA IDA and
Reactome TAS annotations to cytosol.
action: ACCEPT
reason: Correct core subcellular location; strongly corroborated by IDA (HPA) and TAS
(Reactome) evidence.
- term:
id: GO:0006089
label: lactate metabolic process
evidence_type: IEA
original_reference_id: GO_REF:0000107
qualifier: involved_in
review:
summary: Ensembl orthology (IEA) assignment to lactate metabolic process, capturing
LDHB's role in the interconversion of lactate and pyruvate. Also independently
supported by ComplexPortal IDA (PMID:15117937).
action: ACCEPT
reason: Accurately reflects the core biological process in which LDHB participates
(lactate/pyruvate interconversion), and is the process best matching the LDHB-favoured
lactate-oxidising direction.
supported_by:
- reference_id: PMID:27618187
supporting_text: LDHB supports conversion of lactate to pyruvate in cells that utilize
lactate as a nutrient source for oxidative metabolism or gluconeogenesis
- term:
id: GO:0019674
label: NAD+ metabolic process
evidence_type: IEA
original_reference_id: GO_REF:0000107
qualifier: involved_in
review:
summary: Ensembl orthology (IEA) assignment to NAD+ metabolic process, reflecting that
LDHB regenerates/consumes NAD+/NADH during the lactate-pyruvate reaction and thereby
contributes to cytosolic redox balance.
action: KEEP_AS_NON_CORE
reason: Biologically correct (the reaction interconverts NAD+ and NADH), but NAD+
metabolism is a downstream consequence of the catalytic activity rather than the core
annotated function. Keep as non-core.
supported_by:
- reference_id: PMID:15117937
supporting_text: central to NAD(+) regeneration
- term:
id: GO:0019900
label: kinase binding
evidence_type: IEA
original_reference_id: GO_REF:0000107
qualifier: enables
review:
summary: Ensembl orthology (IEA) transfer of a kinase-binding annotation from a rat
ortholog. There is no specific experimental evidence that human LDHB binds a kinase
as a defined molecular function.
action: MARK_AS_OVER_ANNOTATED
reason: Orthology-transferred generic binding annotation with no clear functional
relevance to LDHB's role; likely an over-annotation and not a core function.
- term:
id: GO:0042802
label: identical protein binding
evidence_type: IEA
original_reference_id: GO_REF:0000107
qualifier: enables
review:
summary: Ensembl orthology (IEA) transfer of identical protein binding, consistent with
the homotetrameric assembly of LDHB.
action: KEEP_AS_NON_CORE
reason: Reflects LDHB homotetramerization; informative structural feature but not the
core catalytic function.
supported_by:
- reference_id: file:human/LDHB/LDHB-uniprot.txt
supporting_text: Homotetramer (PubMed:11276087)
- term:
id: GO:0051287
label: NAD binding
evidence_type: IEA
original_reference_id: GO_REF:0000107
qualifier: enables
review:
summary: Ensembl orthology (IEA) assignment of NAD binding. LDHB is an NAD-dependent
dehydrogenase with a Rossmann-fold NAD-binding domain and defined NAD(+)-binding
residues, so this is a correct and informative molecular function.
action: ACCEPT
reason: Correct; NAD binding is a genuine, structurally documented molecular function
of LDHB (NAD-binding Rossmann domain; NAD(+) binding site residues in UniProt).
supported_by:
- reference_id: file:human/LDHB/LDHB-uniprot.txt
supporting_text: Reaction=(S)-lactate + NAD(+) = pyruvate + NADH + H(+);
- term:
id: GO:0005829
label: cytosol
evidence_type: IDA
original_reference_id: GO_REF:0000052
qualifier: located_in
review:
summary: Direct immunofluorescence (HPA) localization of LDHB to the cytosol, the
canonical location of this glycolytic enzyme.
action: ACCEPT
reason: Experimentally supported core subcellular location, concordant with electronic
and TAS cytosol annotations.
- term:
id: GO:0004459
label: L-lactate dehydrogenase (NAD+) activity
evidence_type: EXP
original_reference_id: PMID:11276087
qualifier: enables
review:
summary: Experimental (structural/biophysical) demonstration of L-lactate dehydrogenase
(NAD+) activity for human LDH-H, via crystallographic ternary complexes with NADH and
substrate analog and kinetic characterization.
action: ACCEPT
reason: This is the defining, experimentally established core molecular function of
LDHB, characterized structurally and kinetically for the H isoform.
supported_by:
- reference_id: PMID:11276087
supporting_text: Lactate dehydrogenase (LDH) interconverts pyruvate and lactate with
concomitant
- reference_id: PMID:11276087
supporting_text: the H form, found mainly in cardiac muscle
- term:
id: GO:0006089
label: lactate metabolic process
evidence_type: IDA
original_reference_id: PMID:15117937
qualifier: involved_in
review:
summary: ComplexPortal IDA annotation of the LDH complex to lactate metabolic process.
LDH is central to lactate/pyruvate interconversion and NAD+ regeneration.
action: ACCEPT
reason: Correctly captures the core biological process; LDHB participates in lactate
metabolism as the H subunit of the LDH complex.
supported_by:
- reference_id: PMID:15117937
supporting_text: central to NAD(+) regeneration
- term:
id: GO:1990204
label: oxidoreductase complex
evidence_type: IPI
original_reference_id: PMID:15117937
qualifier: part_of
review:
summary: ComplexPortal assertion that LDHB is part of the L-lactate dehydrogenase
(oxidoreductase) complex, i.e. the LDH tetramer. UniProt/ComplexPortal record the
A/B (M/H) tetramer variants (CPX-6592/6594/6598/6599).
action: ACCEPT
reason: Correct; catalytically active LDH is a tetramer, and LDHB is a constituent
subunit. This appropriately captures the complex-level context of the enzyme.
supported_by:
- reference_id: PMID:27618187
supporting_text: Functional LDH is a homo or hetero tetramer composed of LDHA and
LDHB subunits
- reference_id: file:human/LDHB/LDHB-uniprot.txt
supporting_text: Homotetramer (PubMed:11276087)
- term:
id: GO:0004459
label: L-lactate dehydrogenase (NAD+) activity
evidence_type: IDA
original_reference_id: PMID:27618187
qualifier: enables
review:
summary: Direct assay of LDHB (L-lactate dehydrogenase) activity in whole-cell and
isolated mitochondrial lysates, confirming the core catalytic function.
action: ACCEPT
reason: Experimentally supported core molecular function of LDHB.
supported_by:
- reference_id: PMID:27618187
supporting_text: the mitochondria had higher LDHB activity, further suggesting that
LDHB activity is concentrated in mitochondria
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:33406399
qualifier: enables
review:
summary: UniProt-curated IPI interaction with the PTEN-uORF micropeptide MP31 (C0HLV8).
MP31 binds LDHB and inhibits mitochondrial LDH activity by competing for NAD+, acting
as a regulatory circuit breaker of lactate-pyruvate conversion; the interaction is
abolished by LDHB mutations D53A and R100A.
action: MARK_AS_OVER_ANNOTATED
reason: This is the most biologically meaningful of the protein-binding annotations
(a specific, functionally characterized regulatory interaction), but the term itself
is the uninformative generic protein binding. Retained (not removed) per policy; a
more specific enzyme-inhibitor / MP31-binding characterization would be preferable.
supported_by:
- reference_id: PMID:33406399
supporting_text: limits lactate-pyruvate conversion in mitochondria by
- reference_id: PMID:33406399
supporting_text: competing with mitochondrial lactate dehydrogenase (mLDH) for
- term:
id: GO:0005743
label: mitochondrial inner membrane
evidence_type: IDA
original_reference_id: PMID:27618187
qualifier: located_in
review:
summary: TEM immunogold localization of LDHB to the inner mitochondrial membrane in
HeLa cells, with concordant mitochondrial LDH activity in isolated mitochondria. A
specific but non-canonical localization for this classically cytosolic enzyme.
action: KEEP_AS_NON_CORE
reason: Experimentally supported (PMID:27618187), but a minority/debated localization;
the dominant location of LDHB is cytosolic. Retain as non-core.
supported_by:
- reference_id: PMID:27618187
supporting_text: gold-labeled LDHB localizes to the inner mitochondrial membrane
- term:
id: GO:0045121
label: membrane raft
evidence_type: IDA
original_reference_id: PMID:25204797
qualifier: located_in
review:
summary: Localization to membrane raft reported in a flotillin-1/TLR3 endothelial
signaling study that used SILAC proteomics of raft/caveolae fractions. LDHB is a
soluble cytosolic enzyme and its recovery in raft proteomic fractions most likely
reflects abundant-protein co-purification rather than a functional raft localization.
action: MARK_AS_OVER_ANNOTATED
reason: A soluble glycolytic enzyme is not expected to be a genuine membrane raft
resident; this is likely a proteomic co-isolation artifact and an over-annotation.
supported_by:
- reference_id: PMID:25204797
supporting_text: Flotillin-1 and -2 are markers of membrane rafts
- 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 LDHB in urinary/prostatic-secretion
exosome preparations. Abundant cytosolic enzymes are commonly detected in exosome
proteomes without evidence of a functional role there.
action: MARK_AS_OVER_ANNOTATED
reason: Cytosolic-enzyme detection in exosome proteomics; not a functional localization
and not a core annotation.
- term:
id: GO:0016020
label: membrane
evidence_type: HDA
original_reference_id: PMID:19946888
qualifier: located_in
review:
summary: High-throughput proteomic detection of LDHB in an NK-cell membrane proteome
preparation. Non-specific membrane assignment for a soluble enzyme.
action: MARK_AS_OVER_ANNOTATED
reason: Generic membrane assignment for a cytosolic protein from a proteomic
membrane-fraction study; likely co-isolation and an over-annotation.
- 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 LDHB in urinary exosomes.
action: MARK_AS_OVER_ANNOTATED
reason: Cytosolic-enzyme detection in exosome proteomics; not a functional localization
and not a core annotation.
- 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 LDHB in B-cell exosomes.
action: MARK_AS_OVER_ANNOTATED
reason: Cytosolic-enzyme detection in exosome proteomics; not a functional localization
and not a core annotation.
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-70510
qualifier: located_in
review:
summary: Reactome traceable-author-statement placing LDHB in the cytosol in the context
of LDH tetramer oxidises LACT to PYR, the lactate-oxidising direction favoured by the
LDHB-rich isoenzyme.
action: ACCEPT
reason: Correct core cytosolic location, consistent with IDA and IEA cytosol
annotations and with the canonical glycolytic-enzyme localization.
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-71849
qualifier: located_in
review:
summary: Reactome traceable-author-statement placing LDHB in the cytosol in the context
of LDH tetramer reduces PYR to LACT.
action: ACCEPT
reason: Correct core cytosolic location, redundant with but consistent with the other
cytosol annotations.
- term:
id: GO:0005737
label: cytoplasm
evidence_type: TAS
original_reference_id: PMID:16130169
qualifier: located_in
review:
summary: Traceable-author-statement (UniProt) cytoplasm localization derived from a
HUVEC proteomics study. Consistent with the soluble cytoplasmic nature of LDHB.
action: ACCEPT
reason: Correct broader localization; the more specific cytosol is preferred as the
core location.
supported_by:
- reference_id: file:human/LDHB/LDHB-uniprot.txt
supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm. Mitochondrion inner membrane'
- term:
id: GO:0004459
label: L-lactate dehydrogenase (NAD+) activity
evidence_type: TAS
original_reference_id: PMID:8314553
qualifier: enables
review:
summary: Traceable-author-statement of L-lactate dehydrogenase (NAD+) activity, from a
study characterizing an electrophoretic LDH-B(H) subunit variant (K7E) with decreased
heat stability and slightly reduced activity.
action: ACCEPT
reason: Correct core molecular function; the paper explicitly concerns the human LDH-B
(H) subunit and its enzymatic activity.
supported_by:
- reference_id: PMID:8314553
supporting_text: An electrophoretic variant of the lactate dehydrogenase (LDH)-B(H)
subunit was
core_functions:
- description: Cytosolic NAD-dependent L-lactate dehydrogenase (H/B subunit) catalysing the
reversible interconversion of pyruvate + NADH and L-lactate + NAD+; in LDHB-rich (H4)
isoenzymes this favours oxidation of lactate to pyruvate in oxidative tissues.
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:11276087
supporting_text: Lactate dehydrogenase (LDH) interconverts pyruvate and lactate with
concomitant
- reference_id: file:human/LDHB/LDHB-uniprot.txt
supporting_text: Reaction=(S)-lactate + NAD(+) = pyruvate + NADH + H(+);
- description: As a subunit of the tetrameric L-lactate dehydrogenase complex, LDHB
assembles into homotetramers (H4) and heterotetramers with LDHA (M), forming the
catalytically active oxidoreductase complex.
molecular_function:
id: GO:0004459
label: L-lactate dehydrogenase (NAD+) activity
directly_involved_in:
- id: GO:0006089
label: lactate metabolic process
in_complex:
id: GO:1990204
label: oxidoreductase complex
locations:
- id: GO:0005829
label: cytosol
supported_by:
- reference_id: PMID:27618187
supporting_text: Functional LDH is a homo or hetero tetramer composed of LDHA and LDHB
subunits
- reference_id: file:human/LDHB/LDHB-uniprot.txt
supporting_text: Homotetramer (PubMed:11276087)
suggested_questions:
- question: Is the mitochondrial (inner-membrane) pool of LDHB a genuine, functionally
significant localization in vivo, or is it largely restricted to specific cell types
(e.g. fermenting cancer cells) and experimental conditions?
- question: To what extent does the MP31 (PTEN-uORF) circuit-breaker regulation of LDHB
operate in normal physiology versus tumour metabolism?
suggested_experiments:
- description: Compartment-resolved activity assays (cytosol vs mitochondrial
sub-fractions) across oxidative and glycolytic human tissues to quantify the
physiological contribution of any mitochondrial LDHB pool.
- description: Structure-guided kinetic comparison of purified LDHB homotetramer versus
defined M/H heterotetramers to quantify the directional (lactate to pyruvate)
preference under physiological substrate/redox conditions.
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:0000044
title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
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: file:human/LDHB/LDHB-uniprot.txt
title: UniProtKB entry P07195 (LDHB_HUMAN)
findings: []
- id: PMID:11276087
title: Structural basis for altered activity of M- and H-isozyme forms of human
lactate dehydrogenase.
findings:
- statement: Human LDH-H and LDH-M interconvert pyruvate and lactate with concomitant
NADH/NAD+ interconversion; the H form is found mainly in cardiac muscle and is
structurally indistinguishable at the active site from the M form.
reference_section_type: ABSTRACT
reference_review:
relevance: HIGH
correctness: VERIFIED
review_notes: Abstract-only cache; establishes the core L-lactate dehydrogenase (NAD+)
activity and the H (heart) subunit identity of LDHB.
- id: PMID:15117937
title: Identification and activity of a series of azole-based compounds with lactate
dehydrogenase-directed anti-malarial activity.
findings:
- statement: LDH is central to NAD+ regeneration during glycolysis coupled with
homolactic fermentation.
reference_section_type: ABSTRACT
reference_review:
relevance: MEDIUM
correctness: VERIFIED
review_notes: Primarily about Plasmodium LDH inhibitors; used by ComplexPortal as the
reference for the human LDH complex annotations. Supports LDH's central role in NAD+
regeneration.
- id: PMID:16130169
title: Proteomics of human umbilical vein endothelial cells applied to etoposide-induced
apoptosis.
findings: []
reference_review:
relevance: LOW
correctness: VERIFIED
review_notes: HUVEC proteomics; source of a TAS cytoplasm localization. Contextual only.
- id: PMID:19056867
title: Large-scale proteomics and phosphoproteomics of urinary exosomes.
findings: []
reference_review:
relevance: LOW
correctness: VERIFIED
review_notes: Exosome proteomics; abundant-cytosolic-protein detection, not a functional
localization.
- id: PMID:19946888
title: Defining the membrane proteome of NK cells.
findings: []
reference_review:
relevance: LOW
correctness: VERIFIED
review_notes: Membrane-fraction proteomics; generic membrane detection for a soluble
enzyme.
- id: PMID:20458337
title: MHC class II-associated proteins in B-cell exosomes and potential functional
implications for exosome biogenesis.
findings: []
reference_review:
relevance: LOW
correctness: VERIFIED
review_notes: Exosome proteomics; abundant-cytosolic-protein detection.
- id: PMID:21044950
title: Genome-wide YFP fluorescence complementation screen identifies new regulators
for telomere signaling in human cells.
findings: []
reference_review:
relevance: LOW
correctness: VERIFIED
review_notes: High-throughput interaction screen (TERF1); source of a generic protein
binding datum.
- id: PMID:21988832
title: Toward an understanding of the protein interaction network of the human liver.
findings: []
reference_review:
relevance: LOW
correctness: VERIFIED
review_notes: Interactome study (LDHA); generic protein binding datum consistent with
LDH tetramer assembly.
- id: PMID:23533145
title: In-depth proteomic analyses of exosomes isolated from expressed prostatic
secretions in urine.
findings: []
reference_review:
relevance: LOW
correctness: VERIFIED
review_notes: Exosome proteomics; abundant-cytosolic-protein detection.
- id: PMID:24725412
title: Ribosomal protein s15 phosphorylation mediates LRRK2 neurodegeneration in
Parkinson's disease.
findings: []
reference_review:
relevance: LOW
correctness: VERIFIED
review_notes: LRRK2 interactome context; generic protein binding datum.
- id: PMID:25204797
title: Flotillin-1 facilitates toll-like receptor 3 signaling in human endothelial cells.
findings:
- statement: Flotillins are membrane raft markers; LDHB was recovered in the raft/caveolae
proteomic analysis of this study.
reference_section_type: ABSTRACT
reference_review:
relevance: LOW
correctness: VERIFIED
review_notes: Membrane-raft proteomics; the raft localization of a soluble glycolytic
enzyme is most likely a co-isolation artifact.
- id: PMID:25416956
title: A proteome-scale map of the human interactome network.
findings: []
reference_review:
relevance: LOW
correctness: VERIFIED
review_notes: Interactome map; source of protein binding (LDHA) and identical protein
binding (self) data.
- id: PMID:25502805
title: A massively parallel pipeline to clone DNA variants and examine molecular
phenotypes of human disease mutations.
findings: []
reference_review:
relevance: LOW
correctness: VERIFIED
review_notes: Variant-cloning interaction pipeline; source of an identical protein
binding (self) datum consistent with homotetramerization.
- id: PMID:25910212
title: Widespread macromolecular interaction perturbations in human genetic disorders.
findings: []
reference_review:
relevance: LOW
correctness: VERIFIED
review_notes: Interaction-perturbation study (LDHA); generic protein binding datum.
- id: PMID:27618187
title: Lactate metabolism is associated with mammalian mitochondria.
findings:
- statement: Functional LDH is a tetramer of LDHA and LDHB subunits; LDHB is the
predominant heart (H) subunit and supports conversion of lactate to pyruvate in
lactate-consuming oxidative cells. LDHB was localized by TEM immunogold to the inner
mitochondrial membrane and mitochondrial lysates showed LDHB activity.
reference_section_type: RESULTS
reference_review:
relevance: HIGH
correctness: VERIFIED
review_notes: Full text available; direct experimental support for LDHB catalytic
activity, tetramer composition, H-subunit identity, and a non-canonical
mitochondrial localization.
- id: PMID:28514442
title: Architecture of the human interactome defines protein communities and disease
networks.
findings: []
reference_review:
relevance: LOW
correctness: VERIFIED
review_notes: Interactome community study (LDHA/LDHC); generic protein binding data.
- id: PMID:31515488
title: Extensive disruption of protein interactions by genetic variants across the
allele frequency spectrum in human populations.
findings: []
reference_review:
relevance: LOW
correctness: VERIFIED
review_notes: Variant interaction study (LDHA); source of protein binding and identical
protein binding data.
- id: PMID:32296183
title: A reference map of the human binary protein interactome.
findings: []
reference_review:
relevance: LOW
correctness: VERIFIED
review_notes: Binary interactome map; source of protein binding (SDCBP/LDHA) and
identical protein binding (self) data.
- id: PMID:32814053
title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins
and Uncovers Widespread Protein Aggregation in Affected Brains.
findings: []
reference_review:
relevance: LOW
correctness: VERIFIED
review_notes: Neurodegeneration interactome (HTT); generic protein binding datum.
- id: PMID:33406399
title: An Upstream Open Reading Frame in Phosphatase and Tensin Homolog Encodes
a Circuit Breaker of Lactate Metabolism.
findings:
- statement: MP31, a micropeptide from the PTEN uORF, binds LDHB and limits
lactate-pyruvate conversion in mitochondria by competing with mitochondrial LDH for
NAD+.
reference_section_type: ABSTRACT
reference_review:
relevance: MEDIUM
correctness: VERIFIED
review_notes: Abstract-only cache; UniProt curates this as the LDHB-MP31 (C0HLV8)
interaction abolished by LDHB D53A/R100A. Functionally meaningful regulatory
interaction, though annotated only as generic protein binding.
- id: PMID:33961781
title: Dual proteome-scale networks reveal cell-specific remodeling of the human
interactome.
findings: []
reference_review:
relevance: LOW
correctness: VERIFIED
review_notes: Cell-specific interactome remodeling (LDHA/LDHC); generic protein binding
data.
- id: PMID:35271311
title: 'OpenCell: Endogenous tagging for the cartography of human cellular organization.'
findings: []
reference_review:
relevance: LOW
correctness: VERIFIED
review_notes: OpenCell interactome (LDHA/LDHC); generic protein binding data.
- id: PMID:40205054
title: Multimodal cell maps as a foundation for structural and functional genomics.
findings: []
reference_review:
relevance: LOW
correctness: VERIFIED
review_notes: Multimodal cell-map interactome (LDHC); generic protein binding datum.
- id: PMID:8314553
title: Analysis of a genetic mutation in an electrophoretic variant of the human
lactate dehydrogenase-B(H) subunit.
findings:
- statement: An electrophoretic LDH-B(H) subunit variant (K7E) with decreased heat
stability and slightly lower LDH activity was characterized, confirming LDHB as the
H subunit of human LDH.
reference_section_type: ABSTRACT
reference_review:
relevance: MEDIUM
correctness: VERIFIED
review_notes: Abstract-only cache; source of the TAS L-lactate dehydrogenase (NAD+)
activity annotation and confirms LDHB = H subunit.
- 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: []