GNE

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0008761 UDP-N-acetylglucosamine 2-epimerase activity	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic (IBA) assignment of the N-terminal epimerase catalytic activity. This is a core molecular function of GNE, extensively supported by direct experimental evidence (see the IDA/IMP annotations below). Accept as core. Supporting Evidence: file:human/GNE/GNE-uniprot.txt activities, and serves as the initiator of the biosynthetic pathway
GO:0009384 N-acylmannosamine kinase activity	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic (IBA) assignment of the C-terminal ManNAc kinase catalytic activity. Core molecular function, supported by direct experimental evidence (EXP PMID:16503651, IMP PMID:14707127). Accept as core. Supporting Evidence: file:human/GNE/GNE-uniprot.txt RecName: Full=N-acetylmannosamine kinase
GO:0004553 hydrolase activity, hydrolyzing O-glycosyl compounds	IEA GO_REF:0000002	MARK AS OVER ANNOTATED	Summary: InterPro2GO mapping from the UDP-GlcNAc 2-epimerase signature. GNE's epimerase is formally a hydrolyzing 2-epimerase (EC 3.2.1.183, releasing UDP), but this broad glycosidase term (the O-glycosidase parent) does not describe GNE's actual reaction and is misleading as a standalone molecular function. The specific and correct term GO:0008761 is separately annotated. Over-annotation.
GO:0005829 cytosol	IEA GO_REF:0000044	ACCEPT	Summary: Cytosol localization from UniProt Subcellular Location keyword mapping. Consistent with the curated location and with IDA/ISS/TAS annotations. Accept. Supporting Evidence: file:human/GNE/GNE-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol
GO:0006047 UDP-N-acetylglucosamine metabolic process	IEA GO_REF:0000002	KEEP AS NON CORE	Summary: InterPro-based process annotation. Accurate but general: GNE consumes UDP-GlcNAc as its epimerase substrate, so it participates in UDP-GlcNAc metabolism. Keep as a correct but non-core, higher-level process term; the specific pathway role is captured by N-acetylneuraminate biosynthetic process.
GO:0009384 N-acylmannosamine kinase activity	IEA GO_REF:0000120	ACCEPT	Summary: Electronic (ARBA/RHEA/EC:2.7.1.60) assignment of ManNAc kinase activity. Correct and redundant with the experimentally-supported core kinase annotation. Accept.
GO:0005515 protein binding	IPI PMID:18560563 UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kina...	MARK AS OVER ANNOTATED	Summary: IPI to alpha-actinin 1 (ACTN1, P12814). GNE binds alpha-actinin 1 in skeletal muscle, shown by SPR biosensor, in vitro binding and co-immunoprecipitation. This is a specific, biologically-motivated interaction (a search for muscle-specific GNE partners relevant to HIBM pathology), but the GO term used is the uninformative generic protein binding (GO:0005515) and no functional consequence for GNE's enzymatic role has been established. Keep per policy but mark as over-annotated; not a core function. Supporting Evidence: PMID:18560563 revealed alpha-actinin 1 as a potential interactor of GNE
GO:0005515 protein binding	IPI PMID:25416956 A proteome-scale map of the human interactome network.	MARK AS OVER ANNOTATED	Summary: IPI from a proteome-scale human interactome (Y2H) screen (Rolland et al.), producing generic protein binding annotations to many partners (keratins, keratin-associated proteins, SPRY2, GTPBP3, etc.). High-throughput binding with no established functional relevance to GNE's sialic-acid function. Uninformative term; over-annotation.
GO:0005515 protein binding	IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari...	MARK AS OVER ANNOTATED	Summary: IPI from a systematic interactome variant-disruption study (Fragoza et al.). Generic protein binding high-throughput annotation with no established functional consequence for GNE. Uninformative term; over-annotation.
GO:0008761 UDP-N-acetylglucosamine 2-epimerase activity	IEA GO_REF:0000120	ACCEPT	Summary: Electronic (ARBA / mouse ortholog Q91WG8) assignment of the epimerase activity. Correct and redundant with the experimentally-supported core epimerase annotation. Accept.
GO:0046380 N-acetylneuraminate biosynthetic process	IEA GO_REF:0000107	ACCEPT	Summary: Orthology-based (Ensembl Compara, mouse Q91WG8) assignment of the sialic acid biosynthetic process. This is the core biological process of GNE, also supported by IMP (PMID:14707127, PMID:31121216). Accept as core. Supporting Evidence: file:human/GNE/GNE-uniprot.txt PATHWAY: Amino-sugar metabolism; N-acetylneuraminate biosynthesis.
GO:0006045 N-acetylglucosamine biosynthetic process	IEA GO_REF:0000041	MARK AS OVER ANNOTATED	Summary: UniPathway (UPA00630) mapping. This term is the wrong direction for GNE: the epimerase consumes UDP-GlcNAc, it does not biosynthesize N-acetylglucosamine. The mapping reflects the amino-sugar pathway container rather than GNE's actual role, which is ManNAc/Neu5Ac production. Over-annotation / misleading.
GO:0008761 UDP-N-acetylglucosamine 2-epimerase activity	TAS Reactome:R-HSA-4088338	ACCEPT	Summary: Reactome TAS for the epimerase activity (reaction "Defective GNE does not hydrolyse UDP-GlcNAc"). Corroborates the core epimerase function. Accept.
GO:0009384 N-acylmannosamine kinase activity	TAS Reactome:R-HSA-4088322	ACCEPT	Summary: Reactome TAS for the ManNAc kinase activity (reaction "Defective GNE does not phosphorylate ManNAc to ManNAc-6-P"). Corroborates the core kinase function. Accept.
GO:0005829 cytosol	IDA GO_REF:0000052	ACCEPT	Summary: Direct immunofluorescence localization (HPA) to cytosol. Consistent with the curated subcellular location. Accept as the supported location. Supporting Evidence: file:human/GNE/GNE-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol
GO:0009384 N-acylmannosamine kinase activity	EXP PMID:16503651 Influence of UDP-GlcNAc 2-epimerase/ManNAc kinase mutant pro...	ACCEPT	Summary: Experimental characterization of ManNAc kinase activity: recombinant GNE (and HIBM mutants) assayed for both activities in insect cells, each mutant showing reduced kinase and epimerase activity. Direct support for the core ManNAc kinase function. Accept as core. Supporting Evidence: PMID:16503651 Each of the mutants that was analyzed displayed a reduction in the two known GNE activities
GO:0006055 CMP-N-acetylneuraminate biosynthetic process	IMP PMID:31121216 Activity of N-acylneuraminate-9-phosphatase (NANP) is not es...	KEEP AS NON CORE	Summary: GNE knockout dramatically reduced cellular CMP-sialic acid, placing GNE in CMP-Neu5Ac biosynthesis. This is a step downstream of GNE's direct reactions (CMP-Neu5Ac is made by CMAS), but GNE is required for it as the pathway-initiating enzyme. Correct and supported; keep as a non-core process framing (the direct process is N-acetylneuraminate biosynthesis). Supporting Evidence: PMID:31121216 CMP-sialic acid was dramatically reduced in GNE and NANS KO cells
GO:0046380 N-acetylneuraminate biosynthetic process	IMP PMID:31121216 Activity of N-acylneuraminate-9-phosphatase (NANP) is not es...	ACCEPT	Summary: GNE knockout reduced cell-surface sialylation and CMP-sialic acid, directly demonstrating GNE's requirement for de novo sialic acid (N-acetylneuraminate) biosynthesis. Direct support for the core biological process. Accept as core. Supporting Evidence: PMID:31121216 Sialylation of cell surface glycans was reduced by KO of GNE
GO:0008761 UDP-N-acetylglucosamine 2-epimerase activity	IDA PMID:26980148 Mechanism and inhibition of human UDP-GlcNAc 2-epimerase, th...	ACCEPT	Summary: Direct biochemical/structural characterization of the human UDP-GlcNAc 2-epimerase domain, including catalytic-residue mutagenesis (D112A, R113A, S302A) confirming the epimerase mechanism, and CMP-Neu5Ac feedback inhibition. Strong direct support for the core epimerase function. Accept as core. Supporting Evidence: PMID:26980148 The bifunctional enzyme UDP-GlcNAc 2-epimerase/ManNAc kinase (GNE) plays a key role in sialic acid production.
GO:0005829 cytosol	ISS GO_REF:0000024	ACCEPT	Summary: Cytosol (is_active_in) inferred by sequence similarity from the mouse ortholog (O35826). Consistent with all other localization evidence and with GNE acting on cytosolic nucleotide-sugar substrates. Accept. Supporting Evidence: file:human/GNE/GNE-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol
GO:0008761 UDP-N-acetylglucosamine 2-epimerase activity	IDA PMID:2808337 Identification of the metabolic defect in sialuria.	ACCEPT	Summary: Direct assay of the rate-limiting UDP-GlcNAc 2-epimerase activity in cell lysates, which identified the sialuria defect as loss of CMP-Neu5Ac feedback inhibition of this enzyme. Direct support for the core epimerase function (and its feedback regulation). Accept as core. Supporting Evidence: PMID:2808337 the activity of the rate-limiting enzyme in the biosynthesis of sialic acid has been measured directly in whole cell lysates
GO:0008761 UDP-N-acetylglucosamine 2-epimerase activity	IMP PMID:14707127 Reduction of UDP-N-acetylglucosamine 2-epimerase/N-acetylman...	ACCEPT	Summary: Mutational analysis (DMRV/HIBM patient variants) showing reduced epimerase activity in an in vitro expression assay. Supports the core epimerase function. Accept as core. Supporting Evidence: PMID:14707127 the bifunctional enzyme UDP-GlcNAc 2-epimerase/ManNAc kinase, which
GO:0009384 N-acylmannosamine kinase activity	IMP PMID:14707127 Reduction of UDP-N-acetylglucosamine 2-epimerase/N-acetylman...	ACCEPT	Summary: Mutational analysis showing reduced ManNAc kinase activity for patient variants in an in vitro expression assay. Supports the core kinase function. Accept as core. Supporting Evidence: PMID:14707127 which catalyzes the initial two steps in the biosynthesis of sialic acid
GO:0046380 N-acetylneuraminate biosynthetic process	IMP PMID:14707127 Reduction of UDP-N-acetylglucosamine 2-epimerase/N-acetylman...	ACCEPT	Summary: Reduced GNE enzymatic activity in DMRV patients was accompanied by reduced muscle sialylation, linking GNE to sialic acid (N-acetylneuraminate) biosynthesis in vivo. Direct support for the core biological process. Accept as core. Supporting Evidence: PMID:14707127 the levels of sialic acid in muscle and primary cultured cells from DMRV patients were reduced to 60-75% of control
GO:0005829 cytosol	TAS Reactome:R-HSA-4088322	ACCEPT	Summary: Reactome TAS cytosol location, associated with the ManNAc kinase reaction. Consistent with the curated location. Accept.
GO:0005829 cytosol	TAS Reactome:R-HSA-4088338	ACCEPT	Summary: Reactome TAS cytosol location, associated with the epimerase reaction. Consistent with the curated location. Accept.
GO:0005829 cytosol	TAS Reactome:R-HSA-4085021	ACCEPT	Summary: Reactome TAS cytosol location (reaction: GNE hydrolyzes and epimerises UDP-GlcNAc to ManNAc and UDP). Consistent with the curated location. Accept. Supporting Evidence: Reactome:R-HSA-4085021 (GNE) is a bifunctional enzyme in the cytosol
GO:0005829 cytosol	TAS Reactome:R-HSA-4085028	ACCEPT	Summary: Reactome TAS cytosol location (reaction: GNE phosphorylates ManNAc to ManNAc-6-P). Consistent with the curated location. Accept. Supporting Evidence: Reactome:R-HSA-4085028 (GNE) is a bifunctional enzyme in the cytosol

Gene Description

Existing Annotations Review

Core Functions

N-acetylmannosamine kinase activity of the C-terminal ROK-family domain, phosphorylating N-acetyl-D-mannosamine (ManNAc) with ATP to ManNAc-6-phosphate (EC 2.7.1.60); the second committed step of sialic acid biosynthesis, requiring a divalent metal ion.

References

📚 Additional Documentation

Notes

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