PMM2 encodes phosphomannomutase 2 (EC 5.4.2.8), a cytosolic, Mg2+-dependent enzyme of the eukaryotic phosphomannomutase family within the haloacid dehalogenase (HAD) superfamily. It catalyzes the reversible isomerization of mannose 6-phosphate to mannose 1-phosphate, the committed second step in the conversion of fructose 6-phosphate to GDP-mannose. The mannose 1-phosphate produced is the precursor of GDP-mannose and dolichol-phosphate-mannose, the activated mannose donors used by the N-linked glycosylation (lipid-linked oligosaccharide/dolichol) pathway and other mannosyl-transfer reactions. PMM2 functions as a homodimer using an aspartate nucleophile and divalent magnesium for phosphoryl transfer, and is a soluble, ubiquitously expressed housekeeping enzyme. Because it supplies a key nucleotide-sugar precursor rather than acting directly on glycoprotein substrates, its loss disrupts glycosylation indirectly. Biallelic loss-of-function variants cause PMM2-CDG (congenital disorder of glycosylation type Ia, Jaeken syndrome), the most common congenital disorder of glycosylation, characterized by underglycosylation of serum glycoproteins and a multisystem, predominantly neurological, phenotype.
Definition: Any phosphomannomutase activity (EC 5.4.2.8; interconversion of D-mannose 6-phosphate and alpha-D-mannose 1-phosphate) that is a step in the GDP-mannose biosynthetic process. Captures the precursor-supply role of phosphomannomutase 2 (PMM2) and its orthologs within nucleotide-sugar biosynthesis, distinguishing the committed mutase step from downstream mannosyl-transfer functions.
Justification: Existing annotations conflate the direct molecular function (phosphomannomutase activity) with downstream processes (N-linked glycosylation, glycoprotein biosynthesis). A function-in-process term would let curators record PMM2's role with the correct granularity and avoid substrate guilt-by-association over-annotation.
Parent term: phosphomannomutase activity
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004615 phosphomannomutase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetically inferred molecular function that exactly matches the experimentally established catalytic activity of PMM2 (EC 5.4.2.8, Man6P <-> Man1P). This is the core molecular function of the gene product. Reason: Core, well-supported molecular function; concordant with experimental (EXP/TAS) annotations and UniProt catalytic-activity curation. Supporting Evidence: file:human/PMM2/PMM2-uniprot.txt Reaction=alpha-D-mannose 1-phosphate = D-mannose 6-phosphate |
| GO:0006013 mannose metabolic process | IBA GO_REF:0000033 | ACCEPT | Summary: Correct, parent-level biological-process annotation. PMM2 acts on mannose phosphosugars, so participation in mannose metabolism is accurate, though the more informative process term is GDP-mannose biosynthetic process. Reason: Accurate process annotation directly describing the metabolite class the enzyme acts on; retained as core (parent of the GDP-mannose biosynthetic term). |
| GO:0005829 cytosol | IBA GO_REF:0000033 | ACCEPT | Summary: PMM2 is a soluble cytosolic enzyme; the Man6P<->Man1P reaction occurs in the cytosol. Consistent with UniProt (Cytoplasm), HPA IDA, and Reactome. Reason: Core localization, supported by direct (IDA) and multiple inferred annotations. Supporting Evidence: file:human/PMM2/PMM2-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0006487 protein N-linked glycosylation | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: PMM2 only supplies GDP-mannose, a nucleotide-sugar precursor used many steps upstream of N-glycosylation; it is not a glycosyltransferase and does not act on protein substrates. The 'involved_in' relationship is defensible because biallelic PMM2 loss causes protein hypoglycosylation (the basis of PMM2-CDG), but this is a downstream consequence (substrate guilt-by-association), not the enzyme's molecular role. Keep as a non-core process annotation. Independently corroborated in a yeast SEC53/PMM2 disease model, where PMM2 mutations are described as affecting protein N-linked glycosylation (PMID:36214454). Reason: Downstream pathway annotation reflecting precursor supply, not the direct catalytic function; retained because loss-of-function disrupts N-glycosylation, but it is not a core function of this metabolic enzyme. Supporting Evidence: PMID:36214454 mutations in the phosphomannomutase gene PMM2, which affect protein N-linked |
| GO:0004615 phosphomannomutase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic assertion of the core catalytic activity, consistent with the EC 5.4.2.8 / Rhea mapping and InterPro PMM family signature. Redundant with the experimental and IBA annotations of the same term. Reason: Correct core molecular function via independent electronic methods. |
| GO:0005737 cytoplasm | IEA GO_REF:0000120 | MODIFY | Summary: Correct but less specific parent of cytosol. The cytosol (GO:0005829) annotation is the more informative and directly supported localization. Reason: Generalizes the supported cytosol localization; replace with the more specific term. Proposed replacements: cytosol |
| GO:0006013 mannose metabolic process | IEA GO_REF:0000117 | ACCEPT | Summary: Electronic duplicate of the IBA mannose metabolic process annotation; correct. Reason: Accurate process annotation via ARBA model; concordant with the IBA annotation. |
| GO:0009298 GDP-mannose biosynthetic process | IEA GO_REF:0000120 | ACCEPT | Summary: Core biological process: the PMM step (Man6P->Man1P) is step 2/2 in the UniPathway route from fructose 6-phosphate to Man1P feeding GDP-mannose synthesis. Concordant with experimental, TAS, and IMP annotations. Functionally corroborated by metabolic tracer work showing PMM2 deficiency depletes GDP-mannose (PMID:37257447) and by structural work noting that Man-1-P formation is a pivotal step in GDP-mannose and dolichol-phosphate-mannose biosynthesis (PMID:40572562). Reason: Core process directly describing the metabolic pathway the enzyme commits to. Supporting Evidence: file:human/PMM2/PMM2-uniprot.txt GDP-alpha-D-mannose PMID:37257447 caused by PMM2 deficiency, presents with depleted GDP-mannose and abnormal PMID:40572562 The formation of Man-1-P is a pivotal step in the biosynthesis of GDP-mannose |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | MARK AS OVER ANNOTATED | Summary: Generic 'protein binding' from a proteome-scale binary (Y2H) interactome map. The interaction was experimentally detected (IPI), so it is real, but the generic GO:0005515 term carries no specific functional meaning for a cytosolic metabolic enzyme and does not identify an adapter/scaffold function. This is an uninformative over-annotation, not an incorrect one. Reason: Experimentally detected but uninformative high-throughput 'protein binding' annotation; the interaction is real but the generic term provides no functional information about PMM2. |
| GO:0005515 protein binding | IPI PMID:26871637 Widespread Expansion of Protein Interaction Capabilities by ... | MARK AS OVER ANNOTATED | Summary: Generic 'protein binding' from a high-throughput alternative-splicing interactome study. The interaction was experimentally detected (IPI) and is real, but as above the generic term is uninformative for this metabolic enzyme and not a core function. Reason: Experimentally detected but uninformative high-throughput 'protein binding' annotation; real interaction but no specific function established. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: Generic 'protein binding' from the HuRI reference binary interactome. The recorded partners (e.g. ACY3, MEOX2, SGK2 isoform) were experimentally detected (IPI) and are real interactions, but they are not connected to PMM2's catalytic role and the generic term provides no functional insight. Uninformative over-annotation rather than incorrect. Reason: Experimentally detected but uninformative high-throughput 'protein binding' annotation; real interactions but no specific function established for a cytosolic phosphomannomutase. |
| GO:0005829 cytosol | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic duplicate of the well-supported cytosol localization. Correct. Reason: Core localization confirmed by multiple independent lines of evidence. |
| GO:0043025 neuronal cell body | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Single Ensembl-orthology electronic annotation transferred from mouse. PMM2 is a ubiquitously expressed soluble cytosolic housekeeping enzyme (HPA: low tissue specificity); detection in a neuronal cell body reflects where the cytosol of that cell is, not a neuron-specific function or a distinct localization. Over-annotation for a soluble metabolic enzyme. Reason: Orthology-transferred, cell-type-specific component annotation that adds no functional information beyond the general cytosolic localization and risks implying a neuron-restricted role. |
| GO:0009298 GDP-mannose biosynthetic process | TAS Reactome:R-HSA-446205 | ACCEPT | Summary: Reactome-curated involvement in GDP-mannose synthesis, matching the enzyme's committed pathway step. Core process annotation. Reason: Author-curated (TAS) support for the core GDP-mannose biosynthetic process role. Supporting Evidence: Reactome:R-HSA-446205 GDP-mannose is the mannose donor for the first 5 mannose addition reactions |
| GO:0004615 phosphomannomutase activity | EXP PMID:16540464 The X-ray crystal structures of human alpha-phosphomannomuta... | ACCEPT | Summary: Experimental support for phosphomannomutase activity. Although the abstract foregrounds the PMM1 crystal structures, the study explicitly compares both isozymes and shows alpha-PMM1 and alpha-PMM2 have a conserved active site and similar kinetic properties; UniProt assigns the EC 5.4.2.8 catalytic-activity ECO:0000269 evidence to this paper for PMM2. This is the primary experimental anchor of the core molecular function. Reason: Direct experimental evidence for the core catalytic activity; the defining function of the gene product. Supporting Evidence: PMID:16540464 are shown to have a conserved active-site structure and to display similar kinetic properties |
| GO:0004615 phosphomannomutase activity | TAS Reactome:R-HSA-3781926 | ACCEPT | Summary: Reactome-curated phosphomannomutase activity (Man6P->Man1P) for PMM2. Concordant with the experimental and IBA/IEA annotations of the same term. Reason: Author-curated support for the core molecular function. Supporting Evidence: Reactome:R-HSA-3781926 PMM2) catalyses the isomerisation of mannose 6-phosphate (Man6P) to mannose 1-phosphate (Man1P) |
| GO:0005829 cytosol | IDA GO_REF:0000052 | ACCEPT | Summary: Direct immunofluorescence localization (HPA) to the cytosol. Strongest evidence for the core cytosolic localization. Reason: Direct experimental localization supporting the core cytosolic component annotation. |
| GO:0009298 GDP-mannose biosynthetic process | IMP PMID:9525984 Carbohydrate-deficient glycoprotein syndrome type Ib. Phosph... | ACCEPT | Summary: The GO term (GDP-mannose biosynthetic process) is biologically correct for PMM2 and is independently and strongly supported (EXP PMID:16540464; TAS PMID:9140401 and Reactome; IEA pathway). However, the cited reference PMID:9525984 is about phosphomannose ISOMERASE (PMI/MPI) deficiency causing CDG type Ib and mannose therapy - a different enzyme (F6P<->Man6P) and a different gene - and does not study PMM2's mutase step. The annotation is therefore kept (the term is right and is a core process) but the citation appears mis-attributed; this is recorded in the reference review rather than removing an experimental-coded annotation. Reason: Core process annotation; term is correct and well supported by other evidence. The specific PMID:9525984 citation is flagged as likely mis-attributed (PMI/CDG-Ib paper) in reference_review, but the GO term itself is retained. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-3781926 | ACCEPT | Summary: Reactome-curated cytosolic localization. Concordant with IDA/IBA/IEA evidence. Reason: Author-curated support for the core cytosolic localization. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-446201 | ACCEPT | Summary: Reactome-curated cytosolic localization (PMM1,2 isomerise Man6P to Man1P). Concordant with all other localization evidence. Reason: Author-curated support for the core cytosolic localization. Supporting Evidence: Reactome:R-HSA-446201 Cytosolic phosphomannomutases 1 and 2 (PMM1 and PMM2) catalyse the isomerisation of mannose 6-phosphate (Man6P) to mannose 1-phosphate (Man1P) |
| GO:0004615 phosphomannomutase activity | TAS PMID:9140401 Mutations in PMM2, a phosphomannomutase gene on chromosome 1... | ACCEPT | Summary: The original cloning paper identifies PMM2 as a phosphomannomutase whose deficiency underlies CDG1. Author-stated (TAS) support for the core catalytic activity. Reason: Foundational TAS support for the core molecular function. Supporting Evidence: PMID:9140401 phosphomannomutase (PMM)8, an enzyme necessary for |
| GO:0009101 glycoprotein biosynthetic process | TAS PMID:9140401 Mutations in PMM2, a phosphomannomutase gene on chromosome 1... | KEEP AS NON CORE | Summary: Broad downstream process. PMM2 contributes to glycoprotein biosynthesis only by supplying GDP-mannose; it is not itself a glycosyltransferase. This is the most general of the downstream-glycosylation annotations and reflects the disease phenotype (CDG) rather than the enzyme's molecular role. Keep as non-core. Reason: General downstream-pathway annotation by precursor supply; true at the organismal/disease level but not a core function of this metabolic enzyme. |
| GO:0009298 GDP-mannose biosynthetic process | TAS PMID:9140401 Mutations in PMM2, a phosphomannomutase gene on chromosome 1... | ACCEPT | Summary: Author-stated (TAS) support for the core GDP-mannose biosynthetic process role, from the gene's foundational characterization paper. Reason: Core process annotation supported by the original characterization of PMM2. Supporting Evidence: PMID:9140401 phosphomannomutase (PMM)8, an enzyme necessary for |
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Download this section (compressed HTML)Q: Beyond supplying GDP-mannose, does PMM2 have any moonlighting or regulatory role (e.g. metabolite sensing, complex membership) that would justify any of its high-throughput binary protein-interaction hits?
Q: Does PMM2 contribute to the cytosolic pool balance between mannose-1-phosphate and glucose-1-phosphate handling in vivo, given its measurable activity on glucose 1-phosphate, and does this affect interpretation of residual-activity CDG genotypes?
Experiment: Perform affinity-purification mass spectrometry (AP-MS) on endogenously tagged PMM2 in human cells under native conditions and compare to the binary Y2H hits; test whether candidate partners (ACY3, MEOX2, SGK2) co-purify and whether their knockdown alters PMM2 activity or GDP-mannose levels.
Hypothesis: PMM2's only biologically relevant function is to supply Man1P/GDP-mannose; its reported binary protein interactions are not functionally meaningful.
Type: AP-MS / interaction validation
Experiment: Reconstitute patient PMM2 missense variants in PMM2-null cells and measure enzyme kinetics, steady-state GDP-mannose and Dol-P-Man pools, and lipid-linked oligosaccharide profiles; correlate with clinical severity to test the flux-limitation model.
Hypothesis: CDG-Ia phenotype severity tracks quantitatively with residual cytosolic GDP-mannose flux through the PMM2 step rather than with any non-catalytic property.
Type: variant reconstitution / metabolic flux analysis
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