PIGL is the N-acetylglucosaminyl-phosphatidylinositol de-N-acetylase (PIG-L, EC 3.5.1.89) that catalyzes the second step of glycosylphosphatidylinositol (GPI) anchor biosynthesis. It hydrolyzes N-acetylglucosaminyl-phosphatidylinositol (GlcNAc-PI) to glucosaminyl-phosphatidylinositol (GlcN-PI) plus acetate, a de-N-acetylation that is a prerequisite for the subsequent inositol acylation and mannosylation steps of GPI assembly. It is a single-pass type I endoplasmic reticulum membrane protein with a large cytoplasmic domain and belongs to the PIGL/LmbE-like deacetylase family. Biallelic loss-of-function or hypomorphic PIGL variants cause CHIME syndrome (Zeman-Sheard syndrome), an inherited GPI-deficiency disorder characterized by coloboma, congenital heart disease, ichthyosiform dermatosis, impaired intellectual development, and ear anomalies.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000225 N-acetylglucosaminylphosphatidylinositol deacetylase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (PAN-GO) inference of the core catalytic function, GlcNAc-PI de-N-acetylase activity. This is the correct and experimentally supported molecular function for PIGL and matches the enzyme identity (EC 3.5.1.89). Reason: The GlcNAc-PI de-N-acetylase activity is the defining function of PIGL and is directly supported by experimental work; the IBA inference across the conserved PIGL family (including yeast Gpi12p) is well founded. Supporting Evidence: PMID:10085243 The second step of GPI biosynthesis is PMID:14742432 catalyzed by N-acetylglucosaminylphosphatidylinositol deacetylase (PIG-L). |
| GO:0005783 endoplasmic reticulum | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Phylogenetic inference that PIGL is active in the endoplasmic reticulum. This is correct but is the broader compartment term; the more informative cellular component is the ER membrane (GO:0005789), where PIGL is experimentally localized. Reason: Correct localization but less specific than the experimentally supported ER membrane annotation. Retained as a valid, broader is_active_in statement while the ER membrane term captures the informative location. Supporting Evidence: PMID:14742432 activity is localized to the endoplasmic reticulum (ER) but enriched in a file:human/PIGL/PIGL-uniprot.txt Endoplasmic reticulum membrane |
| GO:0000225 N-acetylglucosaminylphosphatidylinositol deacetylase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic annotation of the deacetylase molecular function via UniRule/ARBA, RHEA:11660 and EC:3.5.1.89. Correct and consistent with the experimental evidence. Reason: The IEA mapping to GO:0000225 (EC 3.5.1.89 / RHEA:11660) is the correct catalytic term and agrees with experimental and phylogenetic evidence. Supporting Evidence: file:human/PIGL/PIGL-uniprot.txt Catalyzes the second step of glycosylphosphatidylinositol |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic annotation (ARBA / UniProtKB-SubCell SL-0097) placing PIGL in the ER membrane. Correct and matches the experimental IDA/EXP localization. Reason: The ER membrane location is experimentally established for human PIGL, a single-pass type I ER membrane protein; the IEA is consistent and correct. Supporting Evidence: file:human/PIGL/PIGL-uniprot.txt Endoplasmic reticulum membrane PMID:14742432 We show that human PIG-L is a type I membrane protein |
| GO:0006506 GPI anchor biosynthetic process | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic annotation (ARBA / UniPathway UPA00196) placing PIGL in GPI anchor biosynthesis. PIGL performs the second, obligatory step of this pathway. Reason: GPI anchor biosynthetic process is the core biological process for PIGL; the de-N-acetylation it catalyzes is a required step of GPI assembly. Supporting Evidence: file:human/PIGL/PIGL-uniprot.txt Glycolipid biosynthesis; glycosylphosphatidylinositol-anchor PMID:10085243 The second step of GPI biosynthesis is |
| GO:0006506 GPI anchor biosynthetic process | TAS Reactome:R-HSA-162710 | ACCEPT | Summary: Reactome traceable annotation to the overall GPI synthesis pathway. Correct; PIGL catalyzes the second reaction of this ER pathway. Reason: PIGL is a bona fide component of the GPI anchor biosynthetic pathway curated by Reactome (Synthesis of glycosylphosphatidylinositol). Supporting Evidence: Reactome:R-HSA-162710 GPI is synthesized in the endoplasmic reticulum. Reactome:R-HSA-162857 In the second step of GPI synthesis, N-acetylglucosaminyl-PI is hydrolyzed to yield glucosaminyl-PI and acetate. |
| GO:0000225 N-acetylglucosaminylphosphatidylinositol deacetylase activity | TAS Reactome:R-HSA-162857 | ACCEPT | Summary: Reactome traceable annotation of the second-step deacetylase reaction (N-acetylglucosaminyl-PI + H2O -> glucosaminyl-PI + acetate) catalyzed by PIG-L. Correct core molecular function. Reason: The Reactome reaction curation directly attributes the GlcNAc-PI de-N-acetylase activity to PIG-L, matching the experimental and phylogenetic evidence. Supporting Evidence: Reactome:R-HSA-162857 as is the PIG-L enzyme that catalyzes it |
| GO:0000225 N-acetylglucosaminylphosphatidylinositol deacetylase activity | EXP PMID:14742432 Subcellular localization and targeting of N-acetylglucosamin... | ACCEPT | Summary: Experimental demonstration of GlcNAc-PI de-N-acetylase activity for human PIG-L (Pottekat & Menon 2004), which characterized the activity and its ER localization. This is the strongest, experiment-based support for the core molecular function. Reason: Direct experimental evidence in human cells that PIG-L catalyzes GlcNAc-PI de-N-acetylation; represents the core catalytic function. Supporting Evidence: PMID:14742432 catalyzed by N-acetylglucosaminylphosphatidylinositol deacetylase (PIG-L). |
| GO:0005789 endoplasmic reticulum membrane | EXP PMID:10085243 Mammalian PIG-L and its yeast homologue Gpi12p are N-acetylg... | ACCEPT | Summary: ER membrane localization supported in the original PIG-L characterization; the de-N-acetylation step and its enzyme are components of the ER GPI machinery. Reason: ER membrane localization is correct and independently confirmed by the experimental study of Pottekat & Menon (PMID:14742432); PIGL is a single-pass ER membrane protein. Supporting Evidence: PMID:14742432 We show that human PIG-L is a type I membrane protein file:human/PIGL/PIGL-uniprot.txt Endoplasmic reticulum membrane |
| GO:0000225 N-acetylglucosaminylphosphatidylinositol deacetylase activity | ISS GO_REF:0000024 | ACCEPT | Summary: Sequence-similarity transfer (from mouse ortholog O35790) of the deacetylase molecular function. Correct and redundant with the experimental evidence. Reason: The ISS transfer of GO:0000225 from the conserved rodent ortholog is correct and matches the experimentally established human activity. Supporting Evidence: PMID:10085243 has GlcNAc-PI de-N-acetylase activity in vitro |
| GO:0005789 endoplasmic reticulum membrane | IDA PMID:14742432 Subcellular localization and targeting of N-acetylglucosamin... | ACCEPT | Summary: Direct assay localizing human PIG-L and its GlcNAc-PI de-N-acetylase activity to the ER membrane (Pottekat & Menon 2004), including identification of ER retention signals. Core cellular component. Reason: Direct experimental evidence that PIG-L is an ER membrane protein; the most informative and best-supported cellular component annotation. Supporting Evidence: PMID:14742432 activity is localized to the endoplasmic reticulum (ER) but enriched in a PMID:14742432 We show that human PIG-L is a type I membrane protein |
| GO:0006506 GPI anchor biosynthetic process | IMP PMID:10085243 Mammalian PIG-L and its yeast homologue Gpi12p are N-acetylg... | ACCEPT | Summary: Functional/complementation evidence (Watanabe et al. 1999) that PIG-L is required for GPI biosynthesis - the rat gene was cloned by complementing a CHO mutant defective in the second step, and its yeast homologue Gpi12p is essential for GPI and cell viability. Core biological process. Reason: Loss/restoration of GlcNAc-PI de-N-acetylase activity and cell-surface GPI-anchored protein expression on manipulating PIG-L/Gpi12p demonstrates PIGL's required role in GPI anchor biosynthesis. Supporting Evidence: PMID:10085243 the cell-surface expression of GPI-anchored proteins and GlcNAc-PI PMID:10085243 indispensable in yeasts |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-162857 | ACCEPT | Summary: Reactome traceable annotation placing the PIG-L enzyme and its substrates in the ER membrane for the second-step reaction. Correct. Reason: Consistent with the experimental ER membrane localization; Reactome curates the reaction as occurring in the ER membrane with PIG-L as the catalyst. Supporting Evidence: Reactome:R-HSA-162857 as is the PIG-L enzyme that catalyzes it |
| GO:0000225 N-acetylglucosaminylphosphatidylinositol deacetylase activity | NAS PMID:10085243 Mammalian PIG-L and its yeast homologue Gpi12p are N-acetylg... | ACCEPT | Summary: Non-traceable/author-statement annotation of the deacetylase molecular function from the original PIG-L paper (Watanabe et al. 1999), which established GlcNAc-PI de-N-acetylase activity for recombinant PIG-L. Correct core function. Reason: The molecular function is correct and is directly supported by the enzymatic assays in this reference and by later human EXP evidence (PMID:14742432). Supporting Evidence: PMID:10085243 has GlcNAc-PI de-N-acetylase activity in vitro |
| GO:0006506 GPI anchor biosynthetic process | NAS PMID:10085243 Mammalian PIG-L and its yeast homologue Gpi12p are N-acetylg... | ACCEPT | Summary: Author-statement annotation of involvement in GPI biosynthesis from the original PIG-L characterization. Correct core biological process. Reason: PIG-L catalyzes the essential second step of GPI biosynthesis; the process annotation is well supported by the same reference and by disease genetics (CHIME/GPI-deficiency). Supporting Evidence: PMID:10085243 The second step of GPI biosynthesis is PMID:10085243 indispensable in yeasts |
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