Post-translational modification: synthesis of GPI-anchored proteins (Homo sapiens)
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Description
Glycosylphosphatidyl inositol (GPI) acts as a membrane anchor for many cell surface proteins. GPI is synthesized in the endoplasmic reticulum. In humans, a single pathway consisting of eleven reactions appears to be responsible for the synthesis of the major GPI species involved in membrane protein anchoring.
As a nascent protein fated to become GPI-anchored moves into the lumen of the endoplasmic reticulum, it is attacked by a transamidase complex that cleaves it near its carboxy terminus and attaches an acylated GPI moiety. The GPI moiety is deacylated, yielding a protein-GPI conjugate that can be efficiently transported to the Golgi apparatus. Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=163125</div>
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- Taron BW, Colussi PA, Wiedman JM, Orlean P, Taron CH.; ''Human Smp3p adds a fourth mannose to yeast and human glycosylphosphatidylinositol precursors in vivo.''; PubMed Europe PMC Scholia
- Watanabe R, Kinoshita T, Masaki R, Yamamoto A, Takeda J, Inoue N.; ''PIG-A and PIG-H, which participate in glycosylphosphatidylinositol anchor biosynthesis, form a protein complex in the endoplasmic reticulum.''; PubMed Europe PMC Scholia
- Schofield JN, Rademacher TW.; ''Structure and expression of the human glycosylphosphatidylinositol phospholipase D1 (GPLD1) gene.''; PubMed Europe PMC Scholia
- Murakami Y, Siripanyaphinyo U, Hong Y, Tashima Y, Maeda Y, Kinoshita T.; ''The initial enzyme for glycosylphosphatidylinositol biosynthesis requires PIG-Y, a seventh component.''; PubMed Europe PMC Scholia
- Takahashi M, Inoue N, Ohishi K, Maeda Y, Nakamura N, Endo Y, Fujita T, Takeda J, Kinoshita T.; ''PIG-B, a membrane protein of the endoplasmic reticulum with a large lumenal domain, is involved in transferring the third mannose of the GPI anchor.''; PubMed Europe PMC Scholia
- Kang JY, Hong Y, Ashida H, Shishioh N, Murakami Y, Morita YS, Maeda Y, Kinoshita T.; ''PIG-V involved in transferring the second mannose in glycosylphosphatidylinositol.''; PubMed Europe PMC Scholia
- Maeda Y, Tanaka S, Hino J, Kangawa K, Kinoshita T.; ''Human dolichol-phosphate-mannose synthase consists of three subunits, DPM1, DPM2 and DPM3.''; PubMed Europe PMC Scholia
- Watanabe R, Murakami Y, Marmor MD, Inoue N, Maeda Y, Hino J, Kangawa K, Julius M, Kinoshita T.; ''Initial enzyme for glycosylphosphatidylinositol biosynthesis requires PIG-P and is regulated by DPM2.''; PubMed Europe PMC Scholia
- Pottekat A, Menon AK.; ''Subcellular localization and targeting of N-acetylglucosaminyl phosphatidylinositol de-N-acetylase, the second enzyme in the glycosylphosphatidylinositol biosynthetic pathway.''; PubMed Europe PMC Scholia
- Murakami Y, Siripanyapinyo U, Hong Y, Kang JY, Ishihara S, Nakakuma H, Maeda Y, Kinoshita T.; ''PIG-W is critical for inositol acylation but not for flipping of glycosylphosphatidylinositol-anchor.''; PubMed Europe PMC Scholia
- Davitz MA, Hereld D, Shak S, Krakow J, Englund PT, Nussenzweig V.; ''A glycan-phosphatidylinositol-specific phospholipase D in human serum.''; PubMed Europe PMC Scholia
- Fabre AL, Orlean P, Taron CH.; ''Saccharomyces cerevisiae Ybr004c and its human homologue are required for addition of the second mannose during glycosylphosphatidylinositol precursor assembly.''; PubMed Europe PMC Scholia
- Shishioh N, Hong Y, Ohishi K, Ashida H, Maeda Y, Kinoshita T.; ''GPI7 is the second partner of PIG-F and involved in modification of glycosylphosphatidylinositol.''; PubMed Europe PMC Scholia
- Low MG, Prasad AR.; ''A phospholipase D specific for the phosphatidylinositol anchor of cell-surface proteins is abundant in plasma.''; PubMed Europe PMC Scholia
- Hong Y, Ohishi K, Kang JY, Tanaka S, Inoue N, Nishimura J, Maeda Y, Kinoshita T.; ''Human PIG-U and yeast Cdc91p are the fifth subunit of GPI transamidase that attaches GPI-anchors to proteins.''; PubMed Europe PMC Scholia
- Ohishi K, Inoue N, Kinoshita T.; ''PIG-S and PIG-T, essential for GPI anchor attachment to proteins, form a complex with GAA1 and GPI8.''; PubMed Europe PMC Scholia
- Ashida H, Hong Y, Murakami Y, Shishioh N, Sugimoto N, Kim YU, Maeda Y, Kinoshita T.; ''Mammalian PIG-X and yeast Pbn1p are the essential components of glycosylphosphatidylinositol-mannosyltransferase I.''; PubMed Europe PMC Scholia
- Sharma DK, Smith TK, Weller CT, Crossman A, Brimacombe JS, Ferguson MA.; ''Differences between the trypanosomal and human GlcNAc-PI de-N-acetylases of glycosylphosphatidylinositol membrane anchor biosynthesis.''; PubMed Europe PMC Scholia
- Kinoshita T, Inoue N.; ''Dissecting and manipulating the pathway for glycosylphos-phatidylinositol-anchor biosynthesis.''; PubMed Europe PMC Scholia
- Watanabe R, Inoue N, Westfall B, Taron CH, Orlean P, Takeda J, Kinoshita T.; ''The first step of glycosylphosphatidylinositol biosynthesis is mediated by a complex of PIG-A, PIG-H, PIG-C and GPI1.''; PubMed Europe PMC Scholia
- Maeda Y, Watanabe R, Harris CL, Hong Y, Ohishi K, Kinoshita K, Kinoshita T.; ''PIG-M transfers the first mannose to glycosylphosphatidylinositol on the lumenal side of the ER.''; PubMed Europe PMC Scholia
- Yu J, Nagarajan S, Knez JJ, Udenfriend S, Chen R, Medof ME.; ''The affected gene underlying the class K glycosylphosphatidylinositol (GPI) surface protein defect codes for the GPI transamidase.''; PubMed Europe PMC Scholia
- Gaynor EC, Mondésert G, Grimme SJ, Reed SI, Orlean P, Emr SD.; ''MCD4 encodes a conserved endoplasmic reticulum membrane protein essential for glycosylphosphatidylinositol anchor synthesis in yeast.''; PubMed Europe PMC Scholia
History
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DataNodes
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Annotated Interactions
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| Source | Target | Type | Database reference | Comment |
|---|---|---|---|---|
| 1,2-Diacylglyceroll | Arrow | REACT_2043 (Reactome)  | ||
| 1,2-Diacylglyceroll | Arrow | REACT_464 (Reactome) | ||
| Arrow | REACT_2043 (Reactome) | |||
| Arrow | REACT_464 (Reactome) | |||
| CH3COO- | Arrow | REACT_779 (Reactome) | ||
| CoA-SH | Arrow | REACT_1049 (Reactome) | ||
| DOLP | REACT_2036 (Reactome) | |||
| DOLPman | REACT_1018 (Reactome) | |||
| DOLPman | REACT_1308 (Reactome) | |||
| DOLPman | REACT_1848 (Reactome) | |||
| DOLPman | REACT_2179 (Reactome) | |||
| DPM1,2,3 | mim-catalysis | REACT_2036 (Reactome) | ||
| Fatty acyl CoA | REACT_1049 (Reactome) | |||
| GDP-Man | REACT_2036 (Reactome) | |||
| GPI mannosyltransferase I | mim-catalysis | REACT_1018 (Reactome) | ||
| GPI transamidase | mim-catalysis | REACT_1777 (Reactome) | ||
| GPI-N-acetylglucosaminyltransferase | mim-catalysis | REACT_1240 (Reactome) | ||
| H2O | REACT_1978 (Reactome) | |||
| H2O | REACT_779 (Reactome) | |||
| Long-chain fatty acid | Arrow | REACT_1978 (Reactome) | ||
| N-acetylglucosaminyl-PI | Arrow | REACT_1240 (Reactome) | ||
| N-acetylglucosaminyl-PI | REACT_779 (Reactome) | |||
| N-glycyl-glycosylphosphatidylinositolethanolamine-PLAUR | Arrow | REACT_1777 (Reactome) | ||
| N-glycyl-glycosylphosphatidylinositolethanolamine-PLAUR | REACT_1978 (Reactome) | |||
| PE | REACT_2043 (Reactome) | |||
| PE | REACT_464 (Reactome) | |||
| PGAP1 | mim-catalysis | REACT_1978 (Reactome) | ||
| PIG-F GPI7 complex | mim-catalysis | REACT_155 (Reactome) | ||
| PIG-F PIG-O complex | mim-catalysis | REACT_2043 (Reactome) | ||
| PIGB | mim-catalysis | REACT_1308 (Reactome) | ||
| PIGL | mim-catalysis | REACT_779 (Reactome) | ||
| PIGN | mim-catalysis | REACT_464 (Reactome) | ||
| PIGV | mim-catalysis | REACT_1848 (Reactome) | ||
| PIGW | mim-catalysis | REACT_1049 (Reactome) | ||
| PLAUR | Arrow | REACT_1777 (Reactome) | ||
| PLAUR | Arrow | REACT_1978 (Reactome) | ||
| PLAUR | REACT_1777 (Reactome) | |||
| REACT_1018 (Reactome) | In the fifth step of GPI synthesis, a mannose residue is added to glucosaminyl-acyl-PI. The reaction takes place at the lumenal surface of the endoplasmic reticulum membrane. It is catalyzed by a complex of at least two components, PIG-M and PIG-X (Maeda et al. 2001; Ashida et al. 2005). | |||
| REACT_1049 (Reactome) | In the fourth step of GPI synthesis, an acyl group (typically palmitate) is transferred from acyl CoA to glucosaminyl-PI. Mutagenesis and cloning studies suggest that a single protein, PIG-W, catalyzes this reaction (Murakami et al. 2003). | |||
| REACT_1240 (Reactome) | The first step of GPI synthesis is the transfer of N-acetylglucosamine from cytosolic UDP-N-acetylglucosamine to phosphatidyl inositol (PI) in the endoplasmic reticulum membrane. The reaction is catalyzed by a multimeric enzyme, also localized to the endoplasmic reticulum membrane, six components of which have been identified to date by mutagenesis studies in cultured cells and by co-recipitation studies in vitro (Watanabe et al. 1996, 1998, 2000). | |||
| REACT_1308 (Reactome) | In the eighth reaction of GPI synthesis, a third mannose residue is added, catalyzed by PIG-B (Takahashi et al. 1996). | |||
| REACT_1526 (Reactome) | GPI moieties are synthesized anchored to dolichol phosphate in the membrane of the endoplasmic reticulum. The first two steps of the synthetic pathway, leading to the production of glucosaminyl-PI, occur on the cytosolic face of the membrane, while addition of an acyl group (step 4) and all subsequent steps occur on the lumenal face (Murakami et al. 2003). No mutant cell lines defective in the reorientation step have been identified, and the mechanism by which it occurs is unknown. | |||
| REACT_155 (Reactome) | Most human GPI anchors have ethanolamine phosphate groups attached to their first and third mannose residues, but GPI anchors with ethanolamine phosphates attached to all three mannose residues have also been identified. Addition of the third ethanolamine phosphate can be catalyzed by a complex of PIG-F and a newly described human protein, GPI7. The donor of the ethanolamine phosphate for this reaction is unknown (Shishioh et al. 2005). | |||
| REACT_1777 (Reactome) | ||||
| REACT_1848 (Reactome) | ||||
| REACT_1978 (Reactome) | The fatty acid group added to inositol in the fourth step of GPI biosynthsis is removed from GPI-conjugated uPAR. This hydrolysis event occurs in the endoplasmic reticulum and appears to be associated with efficient transport of the conjugated protein from the endoplasmic reticulum to the Golgi apparatus (Tanaka et al. 2004). | |||
| REACT_2036 (Reactome) | Cytosolic GDP-mannose reacts with dolichyl phosphate in the endoplasmic reticulum membrane to form dolichyl phosphate D-mannose. The reaction is catalyzed by dolichyl-phosphate mannosyltransferase, a heterotrimeric protein embedded in the endoplasmic reticulum membrane. The first subunit of the heterotrimer appears to be the actual catalyst, and the other two subunits appear to stabilize it (Maeda et al. 2000). | |||
| REACT_2043 (Reactome) | The final step in the main pathway for the synthesis of GPI moieties in human cells is the addition of an ethanolamine phosphate to the third mannose residue of the glycolipid, donated by phosphatidylethanolamine. This reaction has been experimentally characterized in the mouse, where studies with mutated cell lines defective in GPI biosynthesis have established the role of two proteins, PIG-F and PIG-O, in this reaction (Hong et al. 2000). While a human PIG-F protein has been identified and shown to be involved in this event (Inoue et al. 1993), the human event has not been fully characterized and is therefore annotated here as inferred from studies of the mouse event. | |||
| REACT_2179 (Reactome) | Most human GPI anchors are thought to contain three mannose residues, while most yeast GPI anchors contain four. Recently, a human homologue of the yeast enzyme responsible for addition of the fourth mannose residue to GPI molecules was identified and shown to mediate synthesis of human GPI molecules with four mannose residues. While the mannose donor and the nature of the bond linking the third and fourth mannose residues have not been established directly in studies with the human enzyme, these features are known for yeast and the normal human gene restores GPI synthesis in mutant yeast. This observation, tegether with the sequence similarities among PIG-B and SMP3, it is reasonable to infer that the human enzyme uses dolichol-P-mannose as a donor. The functional distinction between GPI anchors with three and four mannose residues is unknown, although the latter appear to be abundant in many human tissues (Tauron et al. 2004). | |||
| REACT_464 (Reactome) | In the sixth step of GPI synthesis, a phosphoethanolamine group is transferred from phosphatidylethanolamine onto the first mannose of the GPI precursor. The human protein that catalyzes this reaction was first identified because it could complement a yeast mutant strain defective for GPI synthesis (Gaynor et al. 1999); its specific function in phosphoethanolamine transfer is inferred from functional studies of the homologous mouse protein (Hong et al. 1999). The reaction is annotated here with phosphatidylethanolamine as the donor of the phosphoethanolamine group on the basis of studies in yeast (Imhof et al. 2000). | |||
| REACT_652 (Reactome) | Dolichyl phosphate D-mannose is flipped in the endoplasmic reticulum membrane so that its mannose moiety is oriented inwards, towards the endoplasmic reticulum lumen, where it is accessible to transferases catalyzing the synthesis of glycolipids and glycoproteins (Kinoshita and Inoue 2000). | |||
| REACT_779 (Reactome) | In the second step of GPI synthesis, N-acetylglucosaminyl-PI is hydrolyzed to yield glucosaminyl-PI and acetate. The phosphatidylinositol (PI) derivatives involved in this reaction are located in the endoplasmic reticulum membrane, as is the PIG-L enzyme that catalyzes it (Sharma et al. 1999; Pottekat and Menon 2004). | |||
| SMP3 | mim-catalysis | REACT_2179 (Reactome) | ||
| UDP-AcGlcN | REACT_1240 (Reactome) | |||
| UDP | Arrow | REACT_1240 (Reactome) | ||
| dolichyl phosphate | Arrow | REACT_1018 (Reactome) | ||
| dolichyl phosphate | Arrow | REACT_1308 (Reactome) | ||
| dolichyl phosphate | Arrow | REACT_1848 (Reactome) | ||
| glucosaminyl-PI | Arrow | REACT_779 (Reactome) | ||
| glucosaminyl-PI | REACT_1049 (Reactome) | |||
| glucosaminyl-acyl-PI | Arrow | REACT_1049 (Reactome) | ||
| glucosaminyl-acyl-PI | REACT_1018 (Reactome) | |||
| mannose | Arrow | REACT_1018 (Reactome) | ||
| mannose | Arrow | REACT_1308 (Reactome) | ||
| mannose | Arrow | REACT_1848 (Reactome) | ||
| mannose | REACT_1308 (Reactome) | |||
| mannose | REACT_2043 (Reactome) | |||
| mannose | REACT_2179 (Reactome) | |||
| mannose | REACT_464 (Reactome) | |||
| phosphatidylinositol | REACT_1240 (Reactome) |
