PKLR

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0004743 pyruvate kinase activity	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetically inferred pyruvate kinase activity, the defining molecular function of PKLR and the entire pyruvate kinase family. Reason: This is the core molecular function of the gene product, catalysing PEP + ADP -> pyruvate + ATP (EC 2.7.1.40). It is directly supported by biochemical and structural characterization of human RPK and by the UniProt catalytic-activity annotation, and is consistent across the pyruvate kinase phylogeny. Supporting Evidence: file:human/PKLR/PKLR-uniprot.txt Pyruvate kinase that catalyzes the conversion of
GO:0005737 cytoplasm	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Phylogenetic assignment of cytoplasmic localization; correct but less informative than the specific cytosol term. Reason: PKLR is a soluble glycolytic enzyme active in the cytosol. Cytoplasm is correct but is subsumed by the more informative GO:0005829 cytosol annotation (TAS, Reactome), so it is retained as a non-core, general localization statement.
GO:0006096 glycolytic process	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetically inferred participation in glycolysis; PKLR catalyses the final ATP-generating step of the pathway. Reason: Pyruvate kinase catalyses glycolysis step 5/5 (pyruvate from D-glyceraldehyde 3-phosphate), the committed, essentially irreversible PEP -> pyruvate reaction that generates ATP. This is a core biological process for the gene product. Supporting Evidence: file:human/PKLR/PKLR-uniprot.txt PATHWAY: Carbohydrate degradation; glycolysis; pyruvate from D-
GO:0032869 cellular response to insulin stimulus	IBA GO_REF:0000033	MARK AS OVER ANNOTATED	Summary: Phylogenetically projected involvement in the cellular insulin response, reflecting hormonal regulation of the liver isoform rather than PKLR's own molecular function. Reason: The liver (L) isoform's expression and phosphorylation state are modulated by insulin/glucagon signalling, but this describes upstream regulation of the enzyme, not a process PKLR itself carries out. The phylogenetic support is thin (only two source annotations, PANTHER + rat RGD) and the term over-states PKLR's role in insulin signalling; it is retained but flagged as an over-annotation. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION CONTEXT OR TISSUE MISMATCH Sources checked: RGD:3336 · Pklr (rat) SUPPORTS SOURCE BUT NOT TARGET Rat ortholog regulatory/physiological context; captures hormonal regulation of the hepatic enzyme, not a molecular process PKLR itself performs. PANTHER:PTN000212861 · pyruvate kinase family node SUPPORTS SOURCE BUT NOT TARGET Family-node projection of a regulatory biological process, thinly supported (two source annotations only).
GO:0000287 magnesium ion binding	IEA GO_REF:0000002	ACCEPT	Summary: InterPro-based assignment of magnesium ion binding, the catalytic divalent metal cofactor of pyruvate kinase. Reason: Pyruvate kinase requires a divalent metal cofactor (Mg2+, or Mn2+ in vitro) for catalysis; UniProt lists Mg(2+) and Mn(2+) as cofactors and the human RPK crystal structure resolves the catalytic divalent-metal site. The InterPro mapping is structurally supported. Supporting Evidence: file:human/PKLR/PKLR-uniprot.txt Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
GO:0004743 pyruvate kinase activity	IEA GO_REF:0000120	ACCEPT	Summary: Automated multi-method assignment of pyruvate kinase activity (EC 2.7.1.40, RHEA:18157), the core catalytic function. Reason: Redundant electronic support (mapping via EC 2.7.1.40, RHEA:18157 and PK InterPro domains) for the experimentally established pyruvate kinase activity; correct and consistent with the EXP/TAS/IBA evidence. Supporting Evidence: file:human/PKLR/PKLR-uniprot.txt EC=2.7.1.40 {ECO:0000269\|PubMed:11960989}
GO:0006096 glycolytic process	IEA GO_REF:0000120	ACCEPT	Summary: Automated multi-method assignment (via UniPathway glycolysis) of participation in the glycolytic process. Reason: Redundant electronic support for PKLR's role in glycolysis, consistent with the UniProt pathway annotation and the IBA glycolytic process annotation. Supporting Evidence: file:human/PKLR/PKLR-uniprot.txt PATHWAY: Carbohydrate degradation; glycolysis; pyruvate from D-
GO:0030955 potassium ion binding	IEA GO_REF:0000002	ACCEPT	Summary: InterPro-based assignment of potassium ion binding, the required monovalent cation cofactor of pyruvate kinase. Reason: Pyruvate kinase activity requires K+; the human RPK structure resolves the K+ site (binding residues 118, 120, 156, 157) and UniProt lists K(+) as a cofactor. The InterPro mapping is structurally supported. Supporting Evidence: file:human/PKLR/PKLR-uniprot.txt Name=K(+); Xref=ChEBI:CHEBI:29103;
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	MARK AS OVER ANNOTATED	Summary: Single high-throughput yeast two-hybrid interaction (with CPNE7, UniProt Q9UBL6-2) from the HuRI reference interactome; uninformative bare protein-binding term. Reason: GO:0005515 protein binding conveys no specific molecular function and derives from a single systematic Y2H screen (HuRI) reporting a PKLR-CPNE7 interaction with no functional characterization or independent orthogonal validation for PKLR. Per curation guidance this bare protein-binding IPI is retained but flagged as an over-annotation rather than treated as a core function. Supporting Evidence: PMID:32296183 With approximately 53,000 protein-protein interactions, HuRI has approximately four times as many such interactions as there are high-quality curated interactions from small-scale studies.
GO:0001666 response to hypoxia	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Response to hypoxia projected electronically from the rat ortholog (P12928) via Ensembl Compara orthology. Reason: This is an orthology-transferred physiological/regulatory context (glycolytic flux is modulated under hypoxia), not PKLR's own molecular function. Biologically plausible for a glycolytic enzyme but peripheral to the core catalytic role, so retained as non-core.
GO:0007584 response to nutrient	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Response to nutrient projected electronically from the rat ortholog (P12928) via Ensembl Compara orthology. Reason: Reflects nutritional/dietary regulation of the hepatic pyruvate kinase isoform's expression rather than PKLR's molecular function. Retained as a non-core, orthology-inferred regulatory context.
GO:0009749 response to glucose	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Response to glucose projected electronically from the rat ortholog (P12928) via Ensembl Compara orthology. Reason: Hepatic pyruvate kinase (L isoform) transcription is induced by dietary glucose/carbohydrate; this is a regulatory context transferred from the rat ortholog, not PKLR's molecular activity. Retained as non-core.
GO:0010038 response to metal ion	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Response to metal ion projected electronically from the rat ortholog (P12928) via Ensembl Compara orthology. Reason: Pyruvate kinase depends on Mg2+/Mn2+ and K+ as catalytic cofactors, so metal-ion sensitivity is biologically plausible, but this orthology-transferred biological-process term overlaps with the more precise metal-ion-binding molecular-function annotations and is peripheral to the core function. Retained as non-core.
GO:0032869 cellular response to insulin stimulus	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Cellular insulin response projected electronically from the rat ortholog (P12928); reflects hormonal regulation of the liver isoform, not PKLR's molecular function. Reason: Duplicates the IBA cellular-response-to-insulin annotation via orthology transfer. It captures upstream insulin/glucagon regulation of hepatic pyruvate kinase expression and phosphorylation rather than a process PKLR itself performs; retained but flagged as an over-annotation.
GO:0033198 response to ATP	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Response to ATP projected electronically from the rat ortholog (P12928) via Ensembl Compara orthology. Reason: ATP is both a product of the pyruvate kinase reaction and a classic allosteric inhibitor of the enzyme, so ATP-sensitivity is biologically real, but this orthology-transferred biological-process term is peripheral to the core catalytic function. Retained as non-core.
GO:0042866 pyruvate biosynthetic process	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Pyruvate biosynthesis projected electronically from the rat ortholog (P12928); an alternative process framing of the pyruvate kinase reaction, whose product is pyruvate. Reason: Pyruvate is the direct product of the pyruvate kinase reaction, so this is a correct but redundant restatement of the glycolytic function. It duplicates the Reactome TAS pyruvate-biosynthetic-process annotation and is subsumed by the glycolytic-process core annotation; retained as non-core.
GO:0048029 monosaccharide binding	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Monosaccharide binding projected electronically from the rat ortholog (P12928); likely a misleading generalization of fructose 1,6-bisphosphate allosteric binding. Reason: PKLR is allosterically activated by fructose 1,6-bisphosphate, a bisphosphorylated hexose, via a dedicated allosteric site. Generalizing this to broad monosaccharide binding is misleading (FBP is a phosphorylated sugar bisphosphate, not a free monosaccharide) and adds no informative molecular function. Retained but flagged as an over-annotation.
GO:0051591 response to cAMP	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Response to cAMP projected electronically from the rat ortholog (P12928) via Ensembl Compara orthology. Reason: Glucagon raises hepatic cAMP, activating PKA, which phosphorylates and inhibits the liver pyruvate kinase isoform; cAMP-responsiveness is therefore biologically plausible but represents upstream regulation rather than PKLR's molecular function. Retained as non-core.
GO:0071872 cellular response to epinephrine stimulus	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Cellular epinephrine response projected electronically from the rat ortholog (P12928) via Ensembl Compara orthology. Reason: Epinephrine, like glucagon, elevates cAMP/PKA signalling that regulates hepatic pyruvate kinase activity by phosphorylation; this is an orthology-transferred regulatory context peripheral to PKLR's core catalytic function. Retained as non-core.
GO:0042866 pyruvate biosynthetic process	TAS Reactome:R-HSA-70268	KEEP AS NON CORE	Summary: Reactome-asserted involvement in pyruvate biosynthesis, reflecting that pyruvate is the product of the pyruvate kinase reaction. Reason: Correct product-oriented framing of the same PEP -> pyruvate reaction that is captured more informatively by the glycolytic-process and pyruvate-kinase-activity core annotations. Retained as non-core to avoid redundancy with the core function.
GO:0061621 canonical glycolysis	TAS Reactome:R-HSA-70171	ACCEPT	Summary: Reactome-asserted participation in canonical glycolysis (Embden-Meyerhof-Parnas pathway), the final ATP-generating step of which PKLR catalyses. Reason: Canonical glycolysis is a precise subtype of glycolytic process describing the classic glucose-to-pyruvate EMP pathway, of which pyruvate kinase catalyses the terminal committed step. This accurately captures PKLR's biological process role.
GO:0004743 pyruvate kinase activity	EXP PMID:11960989 Structure and function of human erythrocyte pyruvate kinase....	ACCEPT	Summary: Experimentally demonstrated pyruvate kinase activity of human erythrocyte RPK, characterized structurally and kinetically together with disease mutants. Reason: This study solved the crystal structure of human RPK in complex with fructose 1,6-bisphosphate and a substrate analogue and functionally characterized wild-type and mutant enzymes, directly establishing the pyruvate kinase catalytic activity that is the core molecular function of PKLR. Supporting Evidence: PMID:11960989 we have solved the 2.7 A resolution crystal structure of human RPK in complex with fructose 1,6-bisphosphate, the allosteric activator, and phosphoglycolate, a substrate analogue
GO:0004743 pyruvate kinase activity	EXP PMID:15996096 Structural basis for tumor pyruvate kinase M2 allosteric reg...	ACCEPT	Summary: Pyruvate kinase activity supported by a structural/mechanistic study; the cited paper characterizes the human M2 isozyme (PKM gene), applied to PKLR by isozyme analogy via Reactome. Reason: The pyruvate kinase catalytic activity assignment is correct for PKLR and independently established by human RPK biochemistry (PMID:11960989). This particular Reactome-sourced EXP citation is the PKM2 crystallography paper (a paralog); the catalytic mechanism, cofactor (Mg2+/K+) and FBP allostery are conserved across the L/R/M1/M2 isozymes, so it does not conflict with the annotation. Per curation policy the experimental annotation is retained rather than removed; reference relevance is flagged as MEDIUM (paralog-derived). Supporting Evidence: PMID:15996096 The X-ray structure of human hPKM2 complexed with Mg(2+), K(+), the inhibitor oxalate, and the allosteric activator fructose 1,6-bisphosphate
GO:0070062 extracellular exosome	HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos...	KEEP AS NON CORE	Summary: High-throughput proteomic detection of PKLR in urinary exosomes; a common MS finding for abundant cytosolic enzymes rather than a functional location. Reason: Detection in an exosome/extracellular-vesicle proteome is a frequent incidental finding for highly abundant soluble glycolytic enzymes and does not reflect where PKLR performs its catalytic function (the cytosol). Retained as a non-core localization observation. Supporting Evidence: PMID:19056867 we used LC-MS/MS to profile the proteome of human urinary exosomes
GO:0005829 cytosol	TAS Reactome:R-HSA-71670	ACCEPT	Summary: Reactome-asserted cytosolic localization, the compartment where PKLR catalyses the glycolytic pyruvate kinase reaction. Reason: PKLR is a soluble cytosolic enzyme; glycolysis occurs in the cytosol and the pyruvate kinase step is cytosolic. This is the informative subcellular location and represents the core cellular component for the gene product.
GO:0005829 cytosol	TAS Reactome:R-HSA-9727857	ACCEPT	Summary: Reactome-asserted cytosolic localization (from a SARS-CoV-1 host-interaction model), consistent with PKLR being a soluble cytosolic enzyme. Reason: Duplicate cytosol localization from a different Reactome reaction; correct and consistent with the primary glycolysis-based cytosol annotation. Cytosol is the core cellular component for PKLR.
GO:0004743 pyruvate kinase activity	TAS PMID:3126495 Human liver type pyruvate kinase: complete amino acid sequen...	ACCEPT	Summary: Author-stated pyruvate kinase activity from the study that cloned and expressed human liver (L)-type PK, detecting enzymatic activity in transfected cells. Reason: This paper determined the full-length human L-type PK cDNA and expressed it in COS cells, where L-type PK activity was detected, corroborating the core pyruvate kinase molecular function of PKLR. Supporting Evidence: PMID:3126495 Human L-type PK activity was detected in the extract of COS cells by the classical PK electrophoresis method.
GO:0004743 pyruvate kinase activity	NAS PMID:1445295 Structural analysis of human pyruvate kinase L-gene and iden...	ACCEPT	Summary: Non-traceable author statement of pyruvate kinase identity from a study of the human PK L-gene structure and its erythroid promoter. Reason: This paper characterizes the human pyruvate kinase L-gene (12 exons, R- and L-type transcripts from alternative first exons) and its promoter; the pyruvate kinase activity assignment is correct for the gene, though the evidence here is genomic/promoter rather than a direct activity assay. Consistent with the stronger EXP/TAS evidence, so accepted. Supporting Evidence: PMID:1445295 The human pyruvate kinase (PK) L-gene is organized in 12 exons over 9.5

Gene Description

Existing Annotations Review

Core Functions

Catalyses the final, committed, essentially irreversible ATP-generating step of glycolysis, transferring phosphate from phosphoenolpyruvate to ADP to form pyruvate and ATP (EC 2.7.1.40), requiring Mg2+/Mn2+ and K+ as cofactors and allosterically activated by fructose 1,6-bisphosphate.

References

📚 Additional Documentation

Notes

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