GPI

Summary

GPI (glucose-6-phosphate isomerase, HGNC:4458) is a protein-coding gene on chromosome 19q13.11, encoding Glucose-6-phosphate isomerase (P06744). Isomerase that catalyzes the conversion of alpha-D-glucose-6-phosphate to beta-D-fructose-6-phosphate, the second step in glycolysis, and the reverse reaction in gluconeogenesis, within the cytoplasm.

This gene encodes a member of the glucose phosphate isomerase protein family. The encoded protein has been identified as a moonlighting protein based on its ability to perform mechanistically distinct functions. In the cytoplasm, the gene product functions as a glycolytic enzyme (glucose-6-phosphate isomerase) that interconverts glucose-6-phosphate and fructose-6-phosphate. Extracellularly, the encoded protein (also referred to as neuroleukin) functions as a neurotrophic factor that promotes survival of skeletal motor neurons and sensory neurons, and as a lymphokine that induces immunoglobulin secretion. The encoded protein is also referred to as autocrine motility factor based on an additional function as a tumor-secreted cytokine and angiogenic factor. Defects in this gene are the cause of nonspherocytic hemolytic anemia and a severe enzyme deficiency can be associated with hydrops fetalis, immediate neonatal death and neurological impairment. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 2821 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hemolytic anemia due to glucophosphate isomerase deficiency (Strong, GenCC)
• Clinical variants (ClinVar): 279 total — 17 pathogenic, 13 likely-pathogenic
• Druggable target: yes
• MANE Select transcript: NM_000175

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4458
Approved symbol	GPI
Name	glucose-6-phosphate isomerase
Location	19q13.11
Locus type	gene with protein product
Status	Approved
Aliases	AMF, NLK
Ensembl gene	ENSG00000105220
Ensembl biotype	protein_coding
OMIM	172400
Entrez	2821

Gene structure

Transcript identifiers

Ensembl transcripts: 24 — 15 protein_coding, 6 retained_intron, 2 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000356487, ENST00000415930, ENST00000586077, ENST00000586392, ENST00000586425, ENST00000587384, ENST00000587521, ENST00000588991, ENST00000589399, ENST00000589504, ENST00000589640, ENST00000589985, ENST00000590362, ENST00000590375, ENST00000591204, ENST00000592144, ENST00000592277, ENST00000642240, ENST00000643067, ENST00000646312, ENST00000647446, ENST00000899687, ENST00000899688, ENST00000921283

RefSeq mRNA: 7 — MANE Select: NM_000175 NM_000175, NM_001184722, NM_001289789, NM_001289790, NM_001329909, NM_001329910, NM_001329911

CCDS: CCDS12437, CCDS54246, CCDS86742

Canonical transcript exons

ENST00000356487 — 18 exons

Exon	Start	End
ENSE00001423864	34399901	34402413
ENSE00002764830	34365196	34365388
ENSE00003554183	34399719	34399785
ENSE00003572072	34399556	34399631
ENSE00003695277	34393248	34393308
ENSE00003695373	34377503	34377586
ENSE00003695499	34381466	34381519
ENSE00003695798	34377735	34377881
ENSE00003695930	34396581	34396657
ENSE00003697707	34368583	34368702
ENSE00003697972	34396301	34396430
ENSE00003698056	34379518	34379562
ENSE00003698198	34366783	34366851
ENSE00003698373	34393914	34394066
ENSE00003700153	34378934	34379005
ENSE00003700340	34393728	34393771
ENSE00003701173	34399207	34399335
ENSE00003787300	34366345	34366435

Expression profiles

Bgee: expression breadth ubiquitous, 286 present calls, max score 99.39.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 333.4490 / max 1626.9404, expressed in 1827 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
175127	246.5222	1825
175128	60.1149	1821
175129	13.6132	1796
175122	4.9158	1536
175126	4.8530	1631
175124	1.5506	942
175125	0.8974	601
175121	0.6102	274
175123	0.3716	199

Top tissues by expression

288 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
apex of heart	UBERON:0002098	99.39	gold quality
right adrenal gland	UBERON:0001233	99.33	gold quality
right adrenal gland cortex	UBERON:0035827	99.32	gold quality
right frontal lobe	UBERON:0002810	99.25	gold quality
left adrenal gland	UBERON:0001234	99.23	gold quality
right hemisphere of cerebellum	UBERON:0014890	99.23	gold quality
heart left ventricle	UBERON:0002084	99.18	gold quality
cerebellar cortex	UBERON:0002129	99.18	gold quality
cerebellar hemisphere	UBERON:0002245	99.18	gold quality
cardiac ventricle	UBERON:0002082	99.15	gold quality
left adrenal gland cortex	UBERON:0035825	99.14	gold quality
right atrium auricular region	UBERON:0006631	99.11	gold quality
prefrontal cortex	UBERON:0000451	99.08	gold quality
anterior cingulate cortex	UBERON:0009835	99.04	gold quality
cardiac atrium	UBERON:0002081	99.03	gold quality
cingulate cortex	UBERON:0003027	99.03	gold quality
lower esophagus	UBERON:0013473	99.03	gold quality
lower esophagus muscularis layer	UBERON:0035833	99.03	gold quality
heart	UBERON:0000948	98.92	gold quality
cerebellum	UBERON:0002037	98.90	gold quality
muscle layer of sigmoid colon	UBERON:0035805	98.87	gold quality
adrenal cortex	UBERON:0001235	98.86	gold quality
hindlimb stylopod muscle	UBERON:0004252	98.86	gold quality
adrenal gland	UBERON:0002369	98.85	gold quality
heart right ventricle	UBERON:0002080	98.83	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	98.83	gold quality
islet of Langerhans	UBERON:0000006	98.80	gold quality
adenohypophysis	UBERON:0002196	98.80	gold quality
frontal cortex	UBERON:0001870	98.78	gold quality
Brodmann (1909) area 9	UBERON:0013540	98.78	gold quality

Single-cell (SCXA)

Detected in 8 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-MTAB-9801	yes	1785.65
E-MTAB-9067	yes	15.97
E-CURD-112	yes	13.76
E-GEOD-137537	yes	4.94
E-MTAB-7606	no	3684.42
E-MTAB-7303	no	2194.77
E-GEOD-125970	no	236.88
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

90 targeting GPI, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-3925-3P	100.00	69.95	1237
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-4713-3P	100.00	65.92	505
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-4487	99.96	64.58	1252
HSA-MIR-6772-5P	99.94	67.01	577
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-6499-3P	99.90	66.38	1212
HSA-MIR-7162-3P	99.89	68.16	1682
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-383-3P	99.85	65.84	1359
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-4495	99.82	72.08	3080
HSA-MIR-1273H-5P	99.77	66.32	2471
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-10393-3P	99.72	66.56	961
HSA-MIR-6801-5P	99.72	66.50	981
HSA-MIR-30B-3P	99.70	65.76	2325
HSA-MIR-3689A-3P	99.70	65.73	2306
HSA-MIR-3689B-3P	99.70	65.71	2311
HSA-MIR-3689C	99.70	65.71	2311

Literature-anchored findings (GeneRIF, showing 40)

• PGI is a moonlighting protein that functions as a cytosolic enzyme involved in glycolysis and gluconeogenesis, and as cytokine through binding to its cell surface receptor. (PMID:11004567)
• hypoxia-induced gene in pancreatic cancer cell lines (PMID:11688991)
• Overexpression induces neoplastic transformation and survival of NIH-3T3 fibroblasts. (PMID:12517804)
• The results demonstrate that the enzymatic activity of PGI is not essential for either receptor binding or cytokine function of human PGI. (PMID:12527360)
• crystal structure and analysis of the initial ring-opening step of catalysis (PMID:12573240)
• This study suggests that the metabolic consequences of a combined deficiency of GPI and G6PD might be responsible for a different clinical outcome, severe congenital hemolytic anemia, than predicted for either defect in isolation. (PMID:12737943)
• role in regulating cell proliferation (PMID:12783864)
• AMF regulates expression of Apaf-1 and caspase-9 genes via a complex signaling pathway and indirectly regulates formation of the apoptosome. (autocrine motility factor) (PMID:14566819)
• The observations are consistent with a downstream mediation role of MMP-3 in Pohophoglucose isomerase/AMF-stimulated tumor cell metastasis. (PMID:14715248)
• T-cell dependent peripheral polyarthritis induced by recombinant human glucose-6-phosphate isomerase in genetically unaltered mice demonstrates for the first time the induction of organ-specific disease by systemic autoimmunity. (PMID:15034067)
• In addition to the findings in rheumatoid arthritis, our results indicate that GPI is not a general target of autoantibodies in juvenile idiopathic arthritis. (PMID:15290745)
• Our results suggest that GPI variants may play a crucial role in the production of autoantibodies against ubiquitous GPI autoantigens. (PMID:15369782)
• AMF expression significantly contributes to the aggressive phenotype of pancreatic cancer (PMID:15570012)
• phosphoglucose isomerase/autocrine motility factor activities are differentially regulated by protein kinase CK2 phosphorylation (PMID:15637053)
• interaction with hypoxia-inducible factor-1 drives mobility of erythroid progenitor cells (PMID:15850830)
• N-glyco side-chain of AMFR is a trigger and that interaction between the 117-C-terminal part of AMF and the extracellular core protein of autocrine motility factor receptor (AMFR) is needed during AMF-AMFR interactions (PMID:16563432)
• elevated G6PI levels present in patients with immune-based inflammatory arthritis may contribute to elevated levels of anti-G6PI Abs and G6PI/anti-G6PI immune complexes (PMID:16949042)
• Missense mutations c.341A>T (p.Asp113Val) in exon 4 and c.663T>G (p.Asn220Lys) in exon 7 are associated with hereditary nonspherocytic hemolytic anemia. (PMID:17041899)
• the receptor molecule for AMF/NLK/MF in leukemic differentiation is not gp78 (PMID:17071500)
• raft-dependent endocytosis of AMF follows a distinct phosphatidylinositol 3-kinase-dependent pathway that is up-regulated in more aggressive tumor cells (PMID:17690101)
• PGI/AMF is involved in oxidative stress-induced cellular senescence and should bring novel insights into the control of cellular growth leading to a new methodology for cancer treatment. (PMID:17925402)
• IL-6 and Th17 play an essential role in GPI-induced arthritis (PMID:18311788)
• Results of this study suggest that AMF stimulation stimulates MMP3 expression via a MAPK signaling pathway. (PMID:18485900)
• Peptide fragment glucose phosphate isomerase (GPI)325-339 is identified as a major epitope in GPI-induced arthritis, with potential to induce polyarthritis. (PMID:18992137)
• Mutations effect catalytic activity and structural stability of human glucose-6-phosphate isomerase. (PMID:19064002)
• Expression of this protein leads to mesenchymal-topepithelial transition in breast cancer cells. (PMID:19531650)
• overexpression of PGI significantly contributes to the aggressive phenotype of human colon cancer (PMID:19787266)
• melanoma migration induced by AMF is mediated by autocrine production of IL-8 as a novel downstream modulator of the AMF signaling pathway (PMID:19801670)
• autocrine motility factor/phosphoglucose isomerase against TGF-beta-induced apoptosis was correlated with its enzymatic activity (PMID:19819066)
• Data suggest that elevated serum glucose-6-phosphate isomerase may be involved in the synovitis of rheumatoid arthritis and may prove useful as a serum marker for disease activity. (PMID:20810510)
• Data show that effective downregulation of AMF/PGI expression and subsequent abrogation of AMF/PGI secretion, which resulted in morphologic change with reduced growth, motility, and invasion. (PMID:20978190)
• By regulating ER calcium release, AMF/PGI interaction with gp78/AMFR therefore protects against ER stress identifying novel roles for these cancer-associated proteins in promoting tumor cell survival. (PMID:21252914)
• GPI is a target gene of the BACH1 transcription factor according to ChIP-seq analysis in HEK 293 cells. (PMID:21555518)
• For PGI, an extended active site in which residues in the first, second, and third layers around the reacting substrate are predicted. (PMID:21970785)
• A protein encoded by this locus was found to be differentially expressed in postmortem brains from patients with atypical frontotemporal lobar degeneration. (PMID:22360420)
• Findings suggest that autocrine motility factor (AMF)-HER2 interaction might be a novel target for therapeutic management of patients with breast cancer, whose disease is resistant to trastuzumab. (PMID:23248119)
• Serum anti-GPI autoantibodies are useful for the diagnosis of rheumatoid arthritis in Chinese patients. (PMID:23773638)
• High GPI expression is associated with metastatic phenotype of breast cancer. (PMID:24440856)
• The association of ENO1 and GPI with postthaw sperm viability and motility was confirmed using Pearson’s linear correlation. ENO1 and GPI can be used as markers of human sperm freezability before starting the cryopreservation procedure. (PMID:25910678)
• Study supports a role for AMF mediating epithelial-mesenchymal transition in endometrial cancer (EC) through MAPK signaling. Therefore, AMF may provide a potential prognostic and therapeutic target in preventing EC progression. (PMID:26201353)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	gpia	ENSDARG00000012987
danio_rerio	gpib	ENSDARG00000103826
mus_musculus	Gpi1	ENSMUSG00000036427
rattus_norvegicus	Gpi	ENSRNOG00000023150
drosophila_melanogaster	Pgi	FBGN0003074
caenorhabditis_elegans	gpi-1	WBGENE00013597

Protein

Protein identifiers

Glucose-6-phosphate isomerase — P06744 (reviewed: P06744)

Alternative names: Autocrine motility factor, D-hexose-6-phosphate anomerase, Glucose-6-phosphate C2-epimerase, Neuroleukin, Phosphoglucose isomerase, Phosphohexose isomerase, Sperm antigen 36

All UniProt accessions (13): P06744, A0A0G2JLI6, A0A2R8Y6C7, A0A2R8YF08, A0A2U3TZU2, K7EIL4, K7ELR7, K7ENA0, K7EP41, K7EPY4, K7EQ48, K7ERC6, K7ERK8

UniProt curated annotations — full annotation on UniProt →

Function. Isomerase that catalyzes the conversion of alpha-D-glucose-6-phosphate to beta-D-fructose-6-phosphate, the second step in glycolysis, and the reverse reaction in gluconeogenesis, within the cytoplasm. Also shows C2-epimerase activity, interconverting D-glucose-6-phosphate (G6P) and D-mannose-6-phosphate (M6P). Also displays anomerase activity, interconverting alpha and beta-anomeric forms of G6P, D-fructose-6-phosphate and M6P. In addition to its metabolic role, this enzyme functions extracellularly as a cytokine: acts as autocrine motility factor (AMF), a secreted angiogenic factor that enhances endothelial cell motility. Functions as neuroleukin, a neurotrophic factor supporting the survival of spinal and sensory neurons. Released by lectin-stimulated T-cells to induce immunoglobulin secretion.

Subunit / interactions. Homodimer; in the catalytically active form. Monomer in the secreted form.

Subcellular location. Cytoplasm. Secreted.

Post-translational modifications. Phosphorylation at Ser-185 by CK2 has been shown to decrease enzymatic activity and may contribute to secretion by a non-classical secretory pathway. ISGylated.

Disease relevance. Anemia, congenital, non-spherocytic hemolytic, 4 (CNSHA4) [MIM:613470] An autosomal recessive form of anemia in which there is no abnormal hemoglobin or spherocytosis. It is caused by glucose phosphate isomerase deficiency. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Strongly inhibited by erythrose 4-phosphate.

Pathway. Carbohydrate degradation; glycolysis; D-glyceraldehyde 3-phosphate and glycerone phosphate from D-glucose: step 2/4.

Similarity. Belongs to the GPI family.

Isoforms (2)

UniProt ID	Names	Canonical?
P06744-1	1	yes
P06744-2	2

RefSeq proteins (7): NP_000166, NP_001171651, NP_001276718, NP_001276719, NP_001316838, NP_001316839, NP_001316840 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001672	G6P_Isomerase	Family
IPR018189	Phosphoglucose_isomerase_CS	Conserved_site
IPR023096	G6P_Isomerase_C	Homologous_superfamily
IPR035476	SIS_PGI_1	Domain
IPR035482	SIS_PGI_2	Domain
IPR046348	SIS_dom_sf	Homologous_superfamily

Pfam: PF00342

Enzyme classification (BRENDA):

• EC 5.3.1.9 — glucose-6-phosphate isomerase (BRENDA: 71 organisms, 64 substrates, 125 inhibitors, 179 Km, 80 kcat entries)

Substrate kinetics (BRENDA)

9 substrates with measured Km, best-characterized 9. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
D-FRUCTOSE 6-PHOSPHATE	0.031–170	60
D-GLUCOSE 6-PHOSPHATE	0.084–267.4	43
FRUCTOSE 6-PHOSPHATE	0.0186–0.74	33
GLUCOSE 6-PHOSPHATE	0.25–8	20
BETA-D-FRUCTOSE 6-PHOSPHATE	0.31–478	4
ALPHA-D-GLUCOSE 6-PHOSPHATE	0.1258–0.1778	2
D-MANNOSE 6-PHOSPHATE	0.25–1.1	2
D-GALACTOSE	1.029	1
L-TALOSE	133	1

Catalyzed reactions (Rhea), 5 shown:

• alpha-D-glucose 6-phosphate = beta-D-fructose 6-phosphate (RHEA:11816)
• alpha-D-glucose 6-phosphate = beta-D-glucose 6-phosphate (RHEA:16249)
• D-glucose 6-phosphate = D-mannose 6-phosphate (RHEA:85575)
• alpha-D-fructose 6-phosphate = beta-D-fructose 6-phosphate (RHEA:85579)
• alpha-D-mannose 6-phosphate = beta-D-mannose 6-phosphate (RHEA:85583)

UniProt features (114 total): helix 38, sequence variant 27, strand 17, modified residue 12, binding site 6, active site 3, sequence conflict 3, splice variant 2, mutagenesis site 2, turn 2, initiator methionine 1, chain 1

Structure

Experimental structures (PDB)

13 structures.

PDB	Method	Resolution (Å)
9FCW	X-RAY DIFFRACTION	1.4
9FKC	X-RAY DIFFRACTION	1.6
9FKF	X-RAY DIFFRACTION	1.6
8BBH	X-RAY DIFFRACTION	1.62
1IAT	X-RAY DIFFRACTION	1.62
9FHF	X-RAY DIFFRACTION	1.8
1JIQ	X-RAY DIFFRACTION	1.9
6XUI	X-RAY DIFFRACTION	1.95
1JLH	X-RAY DIFFRACTION	2.1
6XUH	X-RAY DIFFRACTION	2.38
1IRI	X-RAY DIFFRACTION	2.4
1NUH	X-RAY DIFFRACTION	2.51
8P2K	ELECTRON MICROSCOPY	2.9

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P06744-F1	97.94	0.98

Antibody-complex structures (SAbDab): 1 — 8BBH

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (3): 358 (proton donor); 389; 519

Ligand- & substrate-binding residues (6): 519; 159–160; 210–215; 354; 358; 389

Post-translational modifications (12): 2, 12, 34, 107, 109, 142, 185, 250, 454, 454, 454, 455

Mutagenesis-validated functional residues (2):

Position	Phenotype
185	retained full enzymatic activity.
185	decreased enzymatic activity.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-5628897	TP53 Regulates Metabolic Genes
R-HSA-6798695	Neutrophil degranulation
R-HSA-70171	Glycolysis
R-HSA-70263	Gluconeogenesis

MSigDB gene sets: 821 (showing top): RNGTGGGC_UNKNOWN, CREL_01, AP1_01, GOBP_NUCLEOSIDE_DIPHOSPHATE_METABOLIC_PROCESS, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_COGNITION, ZHAN_MULTIPLE_MYELOMA_PR_DN, GOBP_BEHAVIOR, DORSAM_HOXA9_TARGETS_UP, GCM_PTPRD, GOBP_RESPONSE_TO_ESTRADIOL, GOBP_RESPONSE_TO_MUSCLE_STRETCH, GOBP_RESPONSE_TO_IMMOBILIZATION_STRESS, GOCC_SECRETORY_GRANULE

GO Biological Process (25): in utero embryonic development (GO:0001701), mesoderm formation (GO:0001707), positive regulation of immunoglobulin production (GO:0002639), carbohydrate metabolic process (GO:0005975), fructose 6-phosphate metabolic process (GO:0006002), gluconeogenesis (GO:0006094), glycolytic process (GO:0006096), humoral immune response (GO:0006959), hemostasis (GO:0007599), learning or memory (GO:0007611), positive regulation of endothelial cell migration (GO:0010595), response to estradiol (GO:0032355), response to progesterone (GO:0032570), response to testosterone (GO:0033574), erythrocyte homeostasis (GO:0034101), response to immobilization stress (GO:0035902), response to muscle stretch (GO:0035994), glucose homeostasis (GO:0042593), negative regulation of apoptotic process (GO:0043066), response to cadmium ion (GO:0046686), glucose 6-phosphate metabolic process (GO:0051156), canonical glycolysis (GO:0061621), negative regulation of glycolytic process through fructose-6-phosphate (GO:1904539), signal transduction (GO:0007165), carbohydrate derivative metabolic process (GO:1901135)

GO Molecular Function (9): glucose-6-phosphate isomerase activity (GO:0004347), cytokine activity (GO:0005125), growth factor activity (GO:0008083), racemase and epimerase activity, acting on carbohydrates and derivatives (GO:0016857), ubiquitin protein ligase binding (GO:0031625), monosaccharide binding (GO:0048029), carbohydrate derivative binding (GO:0097367), protein binding (GO:0005515), isomerase activity (GO:0016853)

GO Cellular Component (10): extracellular region (GO:0005576), cytosol (GO:0005829), membrane (GO:0016020), secretory granule lumen (GO:0034774), ciliary membrane (GO:0060170), extracellular exosome (GO:0070062), ficolin-1-rich granule lumen (GO:1904813), obsolete extracellular space (GO:0005615), cytoplasm (GO:0005737), plasma membrane (GO:0005886)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Glucose metabolism	2
Transcriptional Regulation by TP53	1
Innate Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
response to lipid	2
response to ketone	2
receptor ligand activity	2
binding	2
chordate embryonic development	1
formation of primary germ layer	1
mesoderm morphogenesis	1
immunoglobulin production	1
regulation of immunoglobulin production	1
positive regulation of production of molecular mediator of immune response	1
primary metabolic process	1
organophosphate metabolic process	1
carbohydrate derivative metabolic process	1
glucose metabolic process	1
hexose biosynthetic process	1
phosphoglycerate kinase activity	1
phosphoglycerate mutase activity	1
phosphopyruvate hydratase activity	1
pyruvate kinase activity	1
pyruvate metabolic process	1
generation of precursor metabolites and energy	1
aerobic respiration	1
carbohydrate catabolic process	1
pyridine nucleotide catabolic process	1
glyceraldehyde-3-phosphate dehydrogenase [NAD(P)+] (phosphorylating) activity	1
ADP catabolic process	1
ATP metabolic process	1
nicotinamide nucleotide metabolic process	1
immune response	1
regulation of body fluid levels	1
behavior	1
cognition	1
regulation of endothelial cell migration	1
positive regulation of cell migration	1
endothelial cell migration	1
response to oxygen-containing compound	1
response to steroid hormone	1
myeloid cell homeostasis	1
response to stress	1

Protein interactions and networks

STRING

4332 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GPI	AMFR	P26442	991
GPI	G6PD	P11413	971
GPI	H6PD	O95479	955
GPI	MPI	P34949	933
GPI	GAPDH	P00354	921
GPI	TPI1	P00938	846
GPI	PGD	P52209	846
GPI	ALDOA	P04075	823
GPI	ENO1	P06733	812
GPI	LDHA	P00338	809
GPI	PFKM	P08237	781
GPI	PGK2	P07205	773
GPI	PIGQ	Q9BRB3	771
GPI	PGK1	P00558	767
GPI	ALDOC	P09972	767

IntAct

89 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
LMTK3	GPI	psi-mi:“MI:0914”(association)	0.420
MET	NDUFA4	psi-mi:“MI:2364”(proximity)	0.420
Csnk1e		psi-mi:“MI:0915”(physical association)	0.400
Bles03		psi-mi:“MI:0915”(physical association)	0.400
SPG11	GPI	psi-mi:“MI:0915”(physical association)	0.370
JUN	TPM3	psi-mi:“MI:0914”(association)	0.350
EYA2	GPI	psi-mi:“MI:0914”(association)	0.350
PPM1D	ACTN4	psi-mi:“MI:0914”(association)	0.350
DUSP7	MYO1C	psi-mi:“MI:0914”(association)	0.350
PPTC7	MYO1C	psi-mi:“MI:0914”(association)	0.350
PHOSPHO1	DDX39A	psi-mi:“MI:0914”(association)	0.350
TAMM41	GPI	psi-mi:“MI:0914”(association)	0.350
ADCK2	SLC25A5	psi-mi:“MI:0914”(association)	0.350
SPRYD4	ALDH1L1	psi-mi:“MI:0914”(association)	0.350
TAMM41	ALDH1L1	psi-mi:“MI:0914”(association)	0.350
ADCK2	ALDH1L1	psi-mi:“MI:0914”(association)	0.350
	AP3B1	psi-mi:“MI:0914”(association)	0.350
M		psi-mi:“MI:0914”(association)	0.350
	SHTN1	psi-mi:“MI:0914”(association)	0.350
	CLIC1	psi-mi:“MI:0914”(association)	0.350
BMI1	MEIS3P1	psi-mi:“MI:0914”(association)	0.350
MAP2K2	IPO5	psi-mi:“MI:0914”(association)	0.350
RIPK4	TBCA	psi-mi:“MI:0914”(association)	0.350
PRKCZ	PGRMC1	psi-mi:“MI:0914”(association)	0.350

BioGRID (288): GPI (Affinity Capture-MS), GPI (Affinity Capture-MS), GPI (Affinity Capture-MS), GPI (Affinity Capture-MS), ALDH4A1 (Co-fractionation), ANXA7 (Co-fractionation), DCXR (Co-fractionation), FH (Co-fractionation), GPI (Co-fractionation), GPI (Co-fractionation), GPI (Co-fractionation), GPI (Co-fractionation), GPI (Co-fractionation), GPI (Co-fractionation), GPI (Co-fractionation)

ESM2 similar proteins: A0LPA9, A1BFF9, A3PJI8, A4WTF5, A5V1D8, A6U5N9, A7NH85, B8FK51, B8JGW9, B9KRX7, C0QL01, C0RH03, C1CWW2, C4K8I7, C4XST3, P06744, P06745, P08059, P50309, P52029, P52030, P52031, Q1H1P4, Q1IYT4, Q2IE39, Q2LRD0, Q2NR04, Q2VYV7, Q2YBU4, Q3A201, Q3ASZ0, Q3B3Q8, Q3J2U4, Q3JCN1, Q3SH73, Q3SK65, Q3ZBD7, Q4R591, Q5F8P8, Q5R4E3

Diamond homologs: A0KEM2, A0L900, A0LPA9, A1AIK3, A1JRV9, A3N1E1, A4STE1, A4TH39, A4W5E0, A5F3J3, A5UCG6, A6TGT4, A7FDG8, A7MPC2, A7MSY9, A7ZUP3, A8A7C4, A8ANA6, A8GKD1, A9MHA7, A9N1J6, A9R536, B0BQ77, B1IUM7, B1JJM7, B1LPI9, B1XC24, B2K4Y6, B2TX50, B2VKB1, B3GY24, B4EYR8, B4T1R5, B4TDK4, B4TQN8, B5BJU4, B5F1P0, B5FGI2, B5FQP5, B5QYI4

SIGNOR signaling

7 interactions.

A	Effect	B	Mechanism
CSNK2A1	“down-regulates activity”	GPI	phosphorylation
GPI	“down-regulates quantity”	“alpha-D-glucose 6-phosphate(2-)”	“chemical modification”
GPI	“up-regulates quantity”	“β-D-fructose 6-phosphate”	“chemical modification”
AMFR	“down-regulates quantity by destabilization”	GPI	polyubiquitination
TRIM25	“down-regulates quantity by destabilization”	GPI	ubiquitination
PPM1D	“down-regulates activity”	GPI	dephosphorylation
GPI	up-regulates	AMFR	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 103 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Defective CFTR causes cystic fibrosis	5	14.8×	6e-03
CLEC7A (Dectin-1) signaling	6	11.6×	6e-03
Infectious disease	12	4.0×	7e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

279 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	17
Likely pathogenic	13
Uncertain significance	116
Likely benign	56
Benign	15

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1068750	NM_000175.5(GPI):c.286C>T (p.Arg96Ter)	Pathogenic
1176072	NM_000175.5(GPI):c.1414C>T (p.Arg472Cys)	Pathogenic
1323032	NM_000175.5(GPI):c.244del (p.Glu82fs)	Pathogenic
13642	NM_000175.5(GPI):c.1615G>A (p.Asp539Asn)	Pathogenic
13644	NM_000175.5(GPI):c.59A>C (p.His20Pro)	Pathogenic
13645	NM_000175.5(GPI):c.1016T>C (p.Leu339Pro)	Pathogenic
13646	NM_000175.5(GPI):c.1028A>G (p.Gln343Arg)	Pathogenic
13647	NM_000175.5(GPI):c.14C>T (p.Thr5Ile)	Pathogenic
13648	NM_000175.5(GPI):c.1124C>G (p.Thr375Arg)	Pathogenic
1679475	NM_000175.5(GPI):c.1144G>T (p.Glu382Ter)	Pathogenic
1697237	NM_000175.5(GPI):c.301G>A (p.Val101Met)	Pathogenic
2436673	NM_000175.5(GPI):c.1415G>A (p.Arg472His)	Pathogenic
2683541	NM_000175.5(GPI):c.818G>A (p.Arg273His)	Pathogenic
2705368	NM_000175.5(GPI):c.1140G>A (p.Trp380Ter)	Pathogenic
3339453	NC_000019.9:g.(34884972_34887205)(34893319?)del	Pathogenic
3602726	NM_000175.5(GPI):c.1010C>T (p.Ala337Val)	Pathogenic
4702959	NM_000175.5(GPI):c.259G>T (p.Gly87Cys)	Pathogenic
1697238	NM_000175.5(GPI):c.812del (p.Gly271fs)	Likely pathogenic
2432248	NM_000175.5(GPI):c.833C>T (p.Ser278Leu)	Likely pathogenic
2505370	NM_000175.5(GPI):c.283-2A>G	Likely pathogenic
2506149	NM_000175.5(GPI):c.1269+1G>A	Likely pathogenic
2585258	NM_000175.5(GPI):c.804+1_804+2del	Likely pathogenic
2690617	NM_000175.5(GPI):c.1498_1501del (p.Val500fs)	Likely pathogenic
2690618	NM_000175.5(GPI):c.937_952dup (p.Val318fs)	Likely pathogenic
3033365	NM_001289789.1(GPI):c.82C>T (p.Gln28Ter)	Likely pathogenic
3779707	NM_000175.5(GPI):c.48dup (p.Tyr17fs)	Likely pathogenic
4081434	NM_000175.5(GPI):c.866-1G>A	Likely pathogenic
4081435	NM_000175.5(GPI):c.1475-2A>G	Likely pathogenic
4081436	NM_000175.5(GPI):c.1162del (p.Gln388fs)	Likely pathogenic
4542338	NM_000175.5(GPI):c.838A>G (p.Ile280Val)	Likely pathogenic

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

3685 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:34366842:C:A	N91K	0.999
19:34366842:C:G	N91K	0.999
19:34377806:C:A	N186K	0.999
19:34377806:C:G	N186K	0.999
19:34377877:C:T	S210F	0.999
19:34377881:G:C	K211N	0.999
19:34377881:G:T	K211N	0.999
19:34378964:G:C	A222P	0.999
19:34396310:G:A	E358K	0.999
19:34396311:A:T	E358V	0.999
19:34396312:G:C	E358D	0.999
19:34396312:G:T	E358D	0.999
19:34396313:T:C	S359P	0.999
19:34396424:C:G	H396D	0.999
19:34399780:G:C	Q512H	0.999
19:34399780:G:T	Q512H	0.999
19:34399784:G:A	G514R	0.999
19:34399784:G:C	G514R	0.999
19:34399916:G:C	K519N	0.999
19:34399916:G:T	K519N	0.999
19:34377567:G:A	G156D	0.998
19:34377573:G:A	G158D	0.998
19:34377578:T:C	S160P	0.998
19:34377877:C:A	S210Y	0.998
19:34378937:T:C	F213L	0.998
19:34378939:T:A	F213L	0.998
19:34378939:T:G	F213L	0.998
19:34378950:A:T	E217V	0.998
19:34378963:T:A	N221K	0.998
19:34378963:T:G	N221K	0.998

dbSNP variants (sampled 300 via entrez): RS1000086624 (19:34397827 A>T), RS1000140868 (19:34364695 A>C,G), RS1000188786 (19:34361410 CCT>C), RS1000241391 (19:34358734 G>A), RS1000291020 (19:34389105 A>G), RS1000311793 (19:34373266 A>C,G), RS1000409678 (19:34399455 C>G,T), RS1000412798 (19:34395505 G>A), RS1000598824 (19:34389981 G>T), RS1000600158 (19:34377338 T>A,G), RS1000630161 (19:34357741 C>G), RS1000640337 (19:34372842 C>T), RS1000655427 (19:34367075 G>A), RS1000660600 (19:34401427 TAGTC>T), RS1000691101 (19:34398429 A>G)

Disease associations

OMIM: gene MIM:172400 | disease phenotypes: MIM:613470, MIM:615802

GenCC curated gene-disease

Disease	Classification	Inheritance
hemolytic anemia due to glucophosphate isomerase deficiency	Strong	Autosomal recessive

Mondo (4): hemolytic anemia due to glucophosphate isomerase deficiency (MONDO:0013275), hereditary spherocytosis (MONDO:0019350), intellectual disability, autosomal recessive 42 (MONDO:0014348), hemolytic anemia (MONDO:0003664)

Orphanet (3): Hemolytic anemia due to glucophosphate isomerase deficiency (Orphanet:712), Hereditary spherocytosis (Orphanet:822), Autosomal recessive non-syndromic intellectual disability (Orphanet:88616)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

0 associations (top):

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D000743	Anemia, Hemolytic	C15.378.050.141
D013103	Spherocytosis, Hereditary	C15.378.050.141.150.785; C16.320.070.785

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4295702 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

ChEMBL bioactivities

2 potent at pChembl≥5 of 3 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.34	Kd	4549	nM	CHEMBL3752910
5.34	ED50	4549	nM	CHEMBL3752910

PubChem BioAssay actives

1 with measured affinity, of 5 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148454: Binding affinity to human GPI incubated for 45 mins by Kinobead based pull down assay	kd	4.5491	uM

CTD chemical–gene interactions

80 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases abundance, increases expression	5
bisphenol A	affects expression, increases expression	2
Acetaminophen	decreases expression	2
Caffeine	decreases expression, increases phosphorylation	2
Oxygen	increases expression	2
Quercetin	increases expression	2
Smoke	increases abundance, increases expression, decreases expression	2
Tetrachlorodibenzodioxin	decreases expression, decreases reaction, increases expression	2
Tobacco Smoke Pollution	affects expression, increases expression	2
Cyclosporine	decreases expression	2
aristolochic acid I	decreases expression, increases expression	1
GSK-J4	increases expression	1
FR900359	increases phosphorylation	1
TAK-243	decreases sumoylation	1
dicrotophos	increases expression	1
tungsten carbide	affects binding, increases expression	1
deoxynivalenol	decreases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, increases expression, decreases expression	1
alpha-naphthoflavone	decreases expression, decreases reaction, increases expression	1
trichostatin A	increases expression	1
beta-lapachone	decreases expression, increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
cobaltous chloride	increases expression	1
2-bromopalmitate	decreases reaction, increases abundance, increases palmitoylation	1
ochratoxin A	decreases expression	1
artenimol	affects binding	1
dinophysistoxin 1	affects expression	1
cobalt oxide	increases expression	1
di-n-butylphosphoric acid	affects expression	1
yessotoxin	increases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4118947	Binding	Binding affinity to GPI in human NCI-H358 cells at 1 uM by mass spectrometry based pull down assay	Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors. — Bioorg Med Chem

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B2Y5	Abcam HEK293T GPI KO	Transformed cell line	Female

Clinical trials (associated diseases)

23 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT05777993	PHASE4	ENROLLING_BY_INVITATION	A Study to Provide Continued Access to Mitapivat for Participants Who Previously Completed an Agios-Sponsored Mitapivat Study
NCT00001729	PHASE3	COMPLETED	Combination Drug Therapy for Patients With Hepatitis C
NCT03548220	PHASE3	COMPLETED	A Study to Evaluate Efficacy and Safety of AG-348 in Not Regularly Transfused Adult Participants With Pyruvate Kinase Deficiency (PKD)
NCT03559699	PHASE3	COMPLETED	A Study Evaluating the Efficacy and Safety of AG-348 in Regularly Transfused Adult Participants With Pyruvate Kinase Deficiency (PKD)
NCT00110617	PHASE2	COMPLETED	Study of Deferasirox Relative to Subcutaneous Deferoxamine in Sickle Cell Disease Patients
NCT01579110	PHASE2	UNKNOWN	Efficacy and Safety of Levamisole Combined With Standard Prednisolone in Warm Antibody Autoimmune Hemolytic Anemia.
NCT01642979	PHASE2	UNKNOWN	Safety and Efficacy of Levamisole Combined With Cyclosporine A in Patients With Classic Paroxysmal Nocturnal Hemoglobinuria
NCT01760096	PHASE2	UNKNOWN	Safety and Efficacy of Levamisole Combined With Cyclosporine A in Patients With Subclinical Paroxysmal Nocturnal Hemoglobinuria and PNH in the Setting of Another Bone Marrow Failure Syndromes(PNH-2013)
NCT05004259	PHASE1	COMPLETED	The Safety of Repurposing Daratumumab for Relapsed or Refractory Autoimmune Antibody Mediated Hemolytic Anemia
NCT06684041	PHASE1	COMPLETED	A Safety, Tolerability, Pharmacokinetic/Pharmacodynamic Study, and QT Interval Study of HRS-5965 Capsules in Healthy Subjects
NCT07040787	PHASE1	COMPLETED	Investigation of Drug-drug Interaction of HRS-5965 With Clopidogrel and Clarithromycin in Healthy Subjects
NCT01141621	Not specified	TERMINATED	The Dallas Hereditary Spherocytosis Cohort Study
NCT01276561	Not specified	WITHDRAWN	Single Incision Versus Standard Laparoscopic Splenectomy
NCT04451785	Not specified	COMPLETED	Hereditary Spherocytosis and Vascular Function
NCT03513328	PHASE1/PHASE2	COMPLETED	Conditioning Regimen for Allogeneic Hematopoietic Stem-Cell Transplantation
NCT04610866	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Long-term Mitapivat Dosing in Subjects With Stable Sickle Cell Disease: An Extension of a Phase I Pilot Study of Mitapivat
NCT00842621	Not specified	COMPLETED	Long Term Effects of Erythrocyte Lysis
NCT00971984	Not specified	COMPLETED	Demographic, Clinical and Laboratory Characteristics of Children With Alpha Thalassemia in Northern Israel
NCT02111590	Not specified	COMPLETED	Immunoglobulin Dosage and Administration Form in CIDP and MMN
NCT03006718	Not specified	COMPLETED	SCD-PROMIS: A Software Platform to Enhance Self-efficacy and Patient-provider Engagement for Patients With Sickle Cell Pain
NCT04721262	Not specified	COMPLETED	Ferumoxytol Enhanced Hyperfine Low Field Strength MRI
NCT04964323	Not specified	TERMINATED	Pyruvate Kinase (PK) Deficiency Global Longitudinal Registry: Patient-Reported Outcomes (PRO)
NCT06708728	Not specified	NOT_YET_RECRUITING	Study of Acquired Hemolytic Anemia in Adult Hospitalized Patients