NPL is the human N-acetylneuraminate lyase (N-acetylneuraminate pyruvate lyase; sialic acid aldolase; EC 4.1.3.3), a cytosolic class I (Schiff-base) aldolase of the TIM-barrel DapA/NanA family. It catalyzes the reversible cleavage of free N-acetylneuraminic acid (Neu5Ac, sialic acid) into pyruvate and N-acetyl-D-mannosamine (ManNAc) via a lysine Schiff-base intermediate, acting on the open (aldehydo) form of the substrate. NPL also degrades N-glycolylneuraminic acid (Neu5Gc); although humans lack functional CMAHP and cannot synthesize Neu5Gc, dietary Neu5Gc is catabolized by this route. As the entry point of intracellular sialic acid catabolism (amino-sugar/N-acetylneuraminate degradation pathway, UniPathway UPA00629), NPL controls the free intracellular sialic acid pool and prevents recycling of sialic acid back to the cell surface, thereby influencing the balance between sialic acid salvage and degradation. The active enzyme is a homotetramer. In vivo, NPL is essential for muscle sialoglycoprotein homeostasis and regeneration: loss-of-function variants cause a skeletal myopathy with elevated free sialic acid that is responsive to N-acetylmannosamine supplementation.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0008747 N-acetylneuraminate lyase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Core molecular function. Phylogenetic (IBA) transfer of N-acetylneuraminate lyase activity across the NanA subfamily, in full agreement with the direct human assay (IDA, PMID:33895133) and the crystal structure (PDB 6ARH). Accept as a core function of NPL. Supporting Evidence: file:human/NPL/NPL-uniprot.txt Catalyzes the cleavage of N-acetylneuraminic acid (sialic |
| GO:0019262 N-acetylneuraminate catabolic process | IBA GO_REF:0000033 | ACCEPT | Summary: Core biological process. IBA transfer of the N-acetylneuraminate catabolic process is consistent with NPL's role as the entry enzyme of sialic acid degradation and with the direct human evidence (IDA, PMID:33895133). Accept. Supporting Evidence: file:human/NPL/NPL-uniprot.txt Amino-sugar metabolism; N-acetylneuraminate degradation |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: NPL is a cytoplasmic/cytosolic enzyme, so this localization is correct. However, it is less specific than the cytosol term (GO:0005829) supported by Reactome (TAS), which better captures the localization of this soluble amino-sugar catabolic enzyme. Keep as non-core supporting evidence. Supporting Evidence: file:human/NPL/NPL-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0005975 carbohydrate metabolic process | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: Not wrong, but an uninformatively general InterPro-derived process term. NPL's role is captured far more precisely by N-acetylneuraminate catabolic process (GO:0019262), which is annotated with direct experimental (IDA) evidence. This broad parent adds no information and is an over-annotation. |
| GO:0008747 N-acetylneuraminate lyase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Automated (multi-method IEA, includes ARBA/RHEA/EC 4.1.3.3) assignment of the correct core molecular function. Redundant with the IDA/IBA/ISS annotations for the same term but consistent with them. Accept. Supporting Evidence: file:human/NPL/NPL-uniprot.txt Reaction=aceneuramate = aldehydo-N-acetyl-D-mannosamine + pyruvate |
| GO:0016829 lyase activity | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: Correct but uninformatively general grandparent of the specific activity. The precise term N-acetylneuraminate lyase activity (GO:0008747) is directly supported (IDA), making this broad InterPro-derived term an over-annotation that adds no information. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | MARK AS OVER ANNOTATED | Summary: Bare "protein binding" from a large-scale binary interactome screen (with NTAQ1). Uninformative as to molecular function and not a core function of this metabolic enzyme. Retained per policy (experimental IPI is not removed) but flagged as an over-annotation; the underlying NPL-NTAQ1 heterodimer has no established functional role for NPL's catabolic activity. |
| GO:0042802 identical protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | KEEP AS NON CORE | Summary: Self-interaction from a binary interactome map. This is consistent with the known homotetrameric quaternary structure of NPL (SUBUNIT; PDB 6ARH), so it is a real property, but self-association is a structural feature rather than the enzyme's core catalytic function. Keep as non-core. Supporting Evidence: file:human/NPL/NPL-uniprot.txt SUBUNIT: Homotetramer |
| GO:0042802 identical protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Second independent self-interaction annotation (reference human binary interactome map). As with the PMID:25416956 record, this is consistent with the homotetrameric assembly of NPL but is a structural property, not the core catalytic function. Keep as non-core. Supporting Evidence: file:human/NPL/NPL-uniprot.txt SUBUNIT: Homotetramer |
| GO:0019262 N-acetylneuraminate catabolic process | IEA GO_REF:0000041 | ACCEPT | Summary: Automated UniPathway mapping (UPA00629, N-acetylneuraminate degradation) to the correct catabolic process. Redundant with the IDA/IBA/TAS annotations for the same term and consistent with them. Accept. Supporting Evidence: file:human/NPL/NPL-uniprot.txt Amino-sugar metabolism; N-acetylneuraminate degradation |
| GO:0008747 N-acetylneuraminate lyase activity | IDA PMID:33895133 The metalloprotein YhcH is an anomerase providing N-acetylne... | ACCEPT | Summary: Strongest evidence for the core molecular function. Kentache et al. directly assayed purified recombinant human NPL and showed it cleaves Neu5Ac (its activity was stimulated by the anomerases NanM/YhcH, which supply the open substrate form); this is the basis for the EC 4.1.3.3 catalytic-activity assignment in UniProt. Accept as a core function. Supporting Evidence: PMID:33895133 both NanM and YhcH stimulated the activity of human NPL on Neu5Ac |
| GO:0019262 N-acetylneuraminate catabolic process | IDA PMID:33895133 The metalloprotein YhcH is an anomerase providing N-acetylne... | ACCEPT | Summary: Direct experimental support for NPL's role in sialic acid catabolism: the human enzyme cleaves Neu5Ac, the committed first step of the mammalian N-acetylneuraminate degradation pathway. Accept as a core process. Supporting Evidence: PMID:33895133 N-acetylneuraminate is metabolized by a similar pathway in mammalian cells |
| GO:0005829 cytosol | TAS Reactome:R-HSA-4085217 | ACCEPT | Summary: Core cellular localization. NPL is a soluble cytosolic enzyme (Reactome describes it as a cytosolic tetramer catalyzing Neu5Ac/Neu5Gc cleavage), consistent with the UniProt cytoplasm assignment. This is the more precise CC term for the free sialic acid it acts on. Accept. Supporting Evidence: Reactome:R-HSA-4085217 N-acetylneuraminate lyase (NPL) is a cytosolic, tetrameric enzyme |
| GO:0008747 N-acetylneuraminate lyase activity | ISS GO_REF:0000024 | ACCEPT | Summary: Sequence-similarity (ISS from mouse ortholog Q9DCJ9) transfer of the core molecular function. Now superseded by direct human experimental evidence (IDA, PMID:33895133) but fully consistent. Accept. Supporting Evidence: file:human/NPL/NPL-uniprot.txt Belongs to the DapA family. NanA |
| GO:0019262 N-acetylneuraminate catabolic process | TAS PMID:22692205 Metabolism of vertebrate amino sugars with N-glycolyl groups... | ACCEPT | Summary: Author-statement (TAS) annotation to the correct catabolic process. Bergfeld et al. established the intracellular vertebrate pathway for degrading sialic acids with N-glycolyl groups (Neu5Gc), of which NPL-catalyzed lyase cleavage is the entry step; NPL also degrades Neu5Gc. Consistent with the IDA/IBA evidence. Accept. (Cited publication is abstract-only in the local cache; supporting text is taken from the verified Reactome record for the same reaction.) Supporting Evidence: Reactome:R-HSA-4085217 can cleave the major sialic acids |
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