Post-translational modification: synthesis of GPI-anchored proteins (Homo sapiens)

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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.</div>

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1. 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
2. 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
3. Schofield JN, Rademacher TW.; ''Structure and expression of the human glycosylphosphatidylinositol phospholipase D1 (GPLD1) gene.''; PubMed Europe PMC Scholia
4. 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
5. 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
6. 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
7. 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
8. 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
9. 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
10. 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
11. 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
12. 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
13. 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
14. Low MG, Prasad AR.; ''A phospholipase D specific for the phosphatidylinositol anchor of cell-surface proteins is abundant in plasma.''; PubMed Europe PMC Scholia
15. 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
16. 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
17. 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
18. 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
19. Kinoshita T, Inoue N.; ''Dissecting and manipulating the pathway for glycosylphos-phatidylinositol-anchor biosynthesis.''; PubMed Europe PMC Scholia
20. 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
21. 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
22. 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
23. 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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Compare	Revision	Action	Time	User	Comment
	114905	view	16:42, 25 January 2021	ReactomeTeam	Reactome version 75
	113350	view	11:42, 2 November 2020	ReactomeTeam	Reactome version 74
	112559	view	15:52, 9 October 2020	ReactomeTeam	Reactome version 73
	101472	view	11:33, 1 November 2018	ReactomeTeam	reactome version 66
	101010	view	21:13, 31 October 2018	ReactomeTeam	reactome version 65
	100546	view	19:47, 31 October 2018	ReactomeTeam	reactome version 64
	100094	view	16:32, 31 October 2018	ReactomeTeam	reactome version 63
	99644	view	15:03, 31 October 2018	ReactomeTeam	reactome version 62 (2nd attempt)
	99246	view	12:44, 31 October 2018	ReactomeTeam	reactome version 62
	93983	view	13:49, 16 August 2017	ReactomeTeam	reactome version 61
	93587	view	11:28, 9 August 2017	ReactomeTeam	reactome version 61
	88102	view	09:33, 26 July 2016	Ryanmiller	Ontology Term : 'peptide and protein metabolic process' added !
	88101	view	09:31, 26 July 2016	Ryanmiller	Ontology Term : 'classic metabolic pathway' added !
	86827	view	08:17, 12 July 2016	MaintBot	CHEBI:53058 is a Metabolite in ChEBI (which partially defined structure)
	86695	view	09:24, 11 July 2016	ReactomeTeam	reactome version 56
	83233	view	10:26, 18 November 2015	ReactomeTeam	Version54
	81631	view	13:10, 21 August 2015	ReactomeTeam	Version53
	80028	view	09:40, 1 May 2015	Egonw	Renamed 1,2-Diacylglyceroll to 1,2-Diacylglycerol.
	77093	view	08:39, 17 July 2014	ReactomeTeam	Fixed remaining interactions
	76799	view	12:18, 16 July 2014	ReactomeTeam	Fixed remaining interactions
	76122	view	10:18, 11 June 2014	ReactomeTeam	Re-fixing comment source
	75834	view	11:40, 10 June 2014	ReactomeTeam	Reactome 48 Update
	75194	view	09:41, 9 May 2014	Anwesha
	74840	view	10:06, 30 April 2014	ReactomeTeam	Reactome46
	68929	view	17:33, 8 July 2013	MaintBot	Updated to 2013 gpml schema
	42103	view	21:57, 4 March 2011	MaintBot	Automatic update
	39913	view	05:56, 21 January 2011	MaintBot	New pathway

External references

DataNodes

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Name	Type	Database reference	Comment
(ethanolamineP) mannose (a1-2) (ethanolamineP) mannose (a1-6) (ethanolamineP) mannose (a1-4) glucosaminyl-acyl-PI	Unknown	G00151 (GLYCAN)
(ethanolamineP) mannose (a1-2) mannose (a1-6) (ethanolamineP) mannose (a1-4) glucosaminyl-acyl-PI	Unknown	G00150 (GLYCAN)
(ethanolamineP) mannose (a1-4) glucosaminyl-acyl-PI	Unknown	REACT_2468 (Reactome)
Acetate	Metabolite	15366 (ChEBI)
CoA-SH	Metabolite	15346 (ChEBI)
Diacylglycerol	Unknown	18035 (ChEBI)
Fatty acyl CoA	Unknown	C06709 (COMPOUND)
GDP-alpha-D- mannose	Metabolite	15820 (ChEBI)
GPI mannosyltransferase I	Complex	REACT_2364 (Reactome)
GPI transamidase	Complex	REACT_4592 (Reactome)
GPI-N- acetylglucosaminyltran sferase	Complex	REACT_5237 (Reactome)
H2O	Metabolite	15377 (ChEBI)
N- acetylglucosaminyl- PI	Unknown	G00143 (GLYCAN)
PIG-B	Protein	Q92521 (UniProt)
PIG-F:GPI7 complex	Complex	REACT_5313 (Reactome)
PIG-F:PIG-O complex	Complex	REACT_5770 (Reactome)
PIG-L	Protein	Q9Y2B2 (UniProt)
PIG-N	Protein	O95427 (UniProt)
PIG-V	Protein	Q9NUD9 (UniProt)
PIG-W	Protein	Q7Z7B1 (UniProt)
Post GPI Attachment to Proteins 1	Protein	Q75T13 (UniProt)
SMP3	Protein	Q9H9G5 (UniProt)
UDP-N-acetyl-D- glucosamine	Metabolite	16264 (ChEBI)
dolichyl phosphate	Unknown	C00110 (COMPOUND)
dolichyl phosphate D-mannose	Unknown	C03862 (COMPOUND)
dolichyl-phosphate mannosyltransferase	Complex	REACT_3881 (Reactome)
glucosaminyl-PI	Unknown	G00144 (GLYCAN)
glucosaminyl-acyl-PI	Unknown	G00145 (GLYCAN)
long-chain fatty acid	Unknown	15904 (ChEBI)
mannose (a1) mannose (a1-2) mannose (a1-6) (ethanolamineP) mannose (a1-4) glucosaminyl-acyl-PI	Unknown	REACT_2710 (Reactome)
mannose (a1-2) mannose (a1-6) (ethanolamineP) mannose (a1-4) glucosaminyl-acyl-PI	Unknown	G00149 (GLYCAN)
mannose (a1-4) glucosaminyl-acyl-PI	Unknown	G00146 (GLYCAN)
mannose (a1-6) (ethanolamineP) mannose (a1-4) glucosaminyl-acyl-PI	Unknown	G00148 (GLYCAN)
phosphatidylethanola mine	Unknown	C00350 (COMPOUND)
phosphatidylinositol	Unknown	C01194 (COMPOUND)
uridine 5'- diphosphate	Metabolite	17659 (ChEBI)
urokinase plasminogen activator receptor	Protein	Q03405 (UniProt)
urokinase plasminogen activator receptor precursor	Protein	Q03405 (UniProt)
urokinase plasminogen activator receptor precursor propeptide	Protein	Q03405 (UniProt)
urokinase plasminogen activator receptor- acyl-GPI	Protein	Q03405 (UniProt)

Annotated Interactions

No annotated interactions