Reviewed, UniProtKB/Swiss-Prot P06744 (G6PI_HUMAN)

Names and origin

Protein names

Recommended name:
    Glucose-6-phosphate isomerase
      Short name=GPI
    EC=5.3.1.9
Alternative name(s):
    Phosphoglucose isomerase
      Short name=PGI
    Phosphohexose isomerase
      Short name=PHI
    Autocrine motility factor
      Short name=AMF
    Neuroleukin
      Short name=NLK
    Sperm antigen 36
      Short name=SA-36

Gene names

Name:

GPI

Organism

Homo sapiens (Human) [Complete proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	558 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	Besides it's role as a glycolytic enzyme, mammalian GPI can function as a tumor-secreted cytokine and an angiogenic factor (AMF) that stimulates endothelial cell motility. GPI is also a neurotrophic factor (Neuroleukin) for spinal and sensory neurons. Ref.8 Ref.9 Ref.10
Catalytic activity	D-glucose 6-phosphate = D-fructose 6-phosphate.
Pathway	Carbohydrate degradation; glycolysis; D-glyceraldehyde 3-phosphate and glycerone phosphate from D-glucose: step 2/4.
Subunit structure	Homodimer in the catalytically active form, monomer in the secreted form. Ref.17
Subcellular location	Cytoplasm. Secreted.
Post-translational modification	Phosphorylation at Ser-185 by CK2 has been shown to decrease enzymatic activity and may contribute to secretion by a non-classical secretory pathway.
Involvement in disease	Defects in GPI are a cause of hereditary nonspherocytic hemolytic anemia (HA) [MIM:172400]. Severe GPI deficiency can be associated with hydrops fetalis, immediate neonatal death and neurological impairment. Ref.21 Ref.22 Ref.23 Ref.24 Ref.25 Ref.26
Sequence similarities	Belongs to the GPI family.

Ontologies

Keywords
Biological process	Angiogenesis Gluconeogenesis Glycolysis
Cellular component	Cytoplasm Secreted
Coding sequence diversity	Polymorphism
Disease	Disease mutation
Molecular function	Cytokine Growth factor Isomerase
PTM	Acetylation Phosphoprotein
Technical term	3D-structure Complete proteome Direct protein sequencing
Gene Ontology (GO)
Biological process	angiogenesis Inferred from electronic annotation. Source: UniProtKB-KW gluconeogenesis Inferred from electronic annotation. Source: UniProtKB-KW glycolysis Inferred from electronic annotation. Source: UniProtKB-KW hemostasis Traceable author statement. Source: ProtInc humoral immune response Traceable author statement. Source: ProtInc
Cellular component	cytoplasm Inferred from electronic annotation. Source: UniProtKB-SubCell extracellular space Inferred from electronic annotation. Source: UniProtKB-KW
Molecular function	cytokine activity Inferred from electronic annotation. Source: UniProtKB-KW glucose-6-phosphate isomerase activity Inferred from electronic annotation. Source: EC growth factor activity Inferred from electronic annotation. Source: UniProtKB-KW
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Initiator methionine

1

1

Removed Ref.6

Chain

2 – 558

557

Glucose-6-phosphate isomerase

PRO_0000180537

Sites

Active site

358

1

Proton donor Ref.17 Ref.19 Ref.20

Active site

389

1

Ref.17 Ref.19 Ref.20

Active site

519

1

Ref.17 Ref.19 Ref.20

Amino acid modifications

Modified residue

2

1

N-acetylalanine Ref.6

Modified residue

12

1

N6-acetyllysine Ref.16

Modified residue

109

1

Phosphothreonine Ref.12

Modified residue

142

1

N6-acetyllysine Ref.16

Modified residue

185

1

Phosphoserine; by CK2 Ref.8 Ref.11

Natural variations

Natural variant

5

1

T → I in HA; GPI Matsumoto. Ref.24

VAR_002516

Natural variant

20

1

H → P in HA; severe form with neurological deficits; GPI Homburg. Ref.26

VAR_002517

Natural variant

75

1

R → G in HA; GPI Elyria. Ref.25

VAR_002518

Natural variant

83

1

R → W in HA. Ref.22

VAR_002519

Natural variant

101

1

V → M in HA; GPI Sarcina. Ref.23

VAR_002521

Natural variant

159

1

G → S in HA. Ref.21

VAR_002520

Natural variant

195

1

T → I in HA; GPI Bari and Mola. Ref.23

VAR_002522

Natural variant

208

1

I → T: dbSNP rs8191371. Ref.3

VAR_018816

Natural variant

224

1

T → M in HA; GPI Iwate. Ref.22 Ref.24

VAR_002523

Natural variant

273

1

R → H in HA. Ref.22

VAR_002524

Natural variant

278

1

S → L in HA. dbSNP rs34306618. Ref.22

VAR_002525

Natural variant

300

1

A → P in HA. Ref.25

VAR_002526

Natural variant

308

1

R → H: dbSNP rs2230294.

VAR_033943

Natural variant

339

1

L → P in HA; severe form with neurological deficits; GPI Homburg. Ref.26

VAR_002527

Natural variant

343

1

Q → R in HA; GPI Narita and Morcone. Ref.23 Ref.24

VAR_002528

Natural variant

347

1

R → C in HA; GPI Mount Scopus. Ref.22 Ref.25

VAR_002529

Natural variant

347

1

R → H in HA. Ref.21

VAR_002530

Natural variant

375

1

T → R in HA; GPI Kinki. Ref.24

VAR_002531

Natural variant

389

1

H → R in HA; severe form; GPI Calden. Ref.26

VAR_002532

Natural variant

472

1

R → H in HA. Ref.25

VAR_002533

Natural variant

487

1

L → F in HA. Ref.22

VAR_002534

Natural variant

495

1

E → K in HA. Ref.22

VAR_002535

Natural variant

517

1

L → V in HA; severe form; GPI Calden. Ref.26

VAR_002536

Natural variant

525

1

I → T in HA. Ref.21 Ref.23

VAR_002537

Natural variant

539

1

D → N in HA; GPI Fukuoka and Kinki. Ref.24

VAR_002538

Experimental info

Mutagenesis

185

1

S → A: Retained full enzymatic activity. Ref.11

Mutagenesis

185

1

S → E: Decreased enzymatic activity. Ref.11

Sequence conflict

158

1

G → V in AAA36368. Ref.1

Sequence conflict

426

1

L → V in AAF22645. Ref.2

Sequence conflict

436

1

L → V in AAF22645. Ref.2

Secondary structure

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558

Helix Strand Turn

Details...

Helix

3 – 6

4

Helix

8 – 20

13

Helix

21 – 23

3

Helix

26 – 32

7

Helix

36 – 39

4

Beta strand

41 – 45

5

Beta strand

50 – 54

5

Beta strand

57 – 59

3

Helix

62 – 74

13

Helix

77 – 85

9

Turn

92 – 95

4

Helix

100 – 103

4

Beta strand

116 – 118

3

Helix

119 – 137

19

Beta strand

151 – 155

5

Helix

158 – 160

3

Helix

162 – 170

9

Helix

172 – 174

3

Beta strand

180 – 184

5

Helix

189 – 196

8

Helix

201 – 203

3

Beta strand

204 – 209

6

Beta strand

211 – 213

3

Helix

216 – 233

18

Helix

236 – 238

3

Helix

239 – 242

4

Beta strand

243 – 248

6

Helix

250 – 256

7

Helix

260 – 262

3

Beta strand

263 – 265

3

Helix

272 – 274

3

Turn

276 – 278

3

Helix

279 – 281

3

Helix

282 – 288

7

Helix

290 – 309

20

Helix

312 – 314

3

Helix

316 – 329

14

Beta strand

335 – 341

7

Helix

343 – 345

3

Helix

348 – 360

13

Beta strand

378 – 380

3

Helix

386 – 389

4

Helix

392 – 397

6

Beta strand

404 – 411

8

Helix

416 – 419

4

Helix

420 – 438

19

Helix

442 – 451

10

Helix

456 – 462

7

Helix

463 – 466

4

Beta strand

474 – 481

8

Helix

484 – 505

22

Helix

513 – 515

3

Helix

516 – 528

13

Beta strand

530 – 532

3

Helix

540 – 552

13

Sequences

	Sequence		Length	Mass (Da)
	P06744-1 [UniParc]. Last modified January 23, 2007. Version 4. Checksum: 7C8E95277BDC79A6	FASTA	558	63,147
	10 20 30 40 50 60 MAALTRDPQF QKLQQWYREH RSELNLRRLF DANKDRFNHF SLTLNTNHGH ILVDYSKNLV 70 80 90 100 110 120 TEDVMRMLVD LAKSRGVEAA RERMFNGEKI NYTEGRAVLH VALRNRSNTP ILVDGKDVMP 130 140 150 160 170 180 EVNKVLDKMK SFCQRVRSGD WKGYTGKTIT DVINIGIGGS DLGPLMVTEA LKPYSSGGPR 190 200 210 220 230 240 VWYVSNIDGT HIAKTLAQLN PESSLFIIAS KTFTTQETIT NAETAKEWFL QAAKDPSAVA 250 260 270 280 290 300 KHFVALSTNT TKVKEFGIDP QNMFEFWDWV GGRYSLWSAI GLSIALHVGF DNFEQLLSGA 310 320 330 340 350 360 HWMDQHFRTT PLEKNAPVLL ALLGIWYINC FGCETHAMLP YDQYLHRFAA YFQQGDMESN 370 380 390 400 410 420 GKYITKSGTR VDHQTGPIVW GEPGTNGQHA FYQLIHQGTK MIPCDFLIPV QTQHPIRKGL 430 440 450 460 470 480 HHKILLANFL AQTEALMRGK STEEARKELQ AAGKSPEDLE RLLPHKVFEG NRPTNSIVFT 490 500 510 520 530 540 KLTPFMLGAL VAMYEHKIFV QGIIWDINSF DQWGVELGKQ LAKKIEPELD GSAQVTSHDA 550 STNGLINFIK QQREARVQ

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	Gurney M.E. Submitted (MAR-1987) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[2]	"Cloning of a glucose phosphate isomerase/neuroleukin-like sperm antigen involved in sperm agglutination." Yakirevich E., Naot Y. Biol. Reprod. 62:1016-1023(2000) [PubMed: 10727272] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Testis.
[3]	NIEHS SNPs program Submitted (JUN-2003) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANT THR-208.
[4]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Brain and Skin.
[5]	"Characterization of the 5' end of the gene for human glucose phosphate isomerase (GPI)." Walker J.I.H., Faik P., Morgan M.J. Genomics 7:638-643(1990) [PubMed: 2387591] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-71.
[6]	Bienvenut W.V. Submitted (OCT-2004) to UniProtKB Cited for: PROTEIN SEQUENCE OF 2-12; 58-73; 97-104; 181-226; 424-438 AND 455-461, CLEAVAGE OF INITIATOR METHIONINE, ACETYLATION AT ALA-2, MASS SPECTROMETRY. Tissue: B-cell lymphoma.
[7]	"Mouse glucose-6-phosphate isomerase and neuroleukin have identical 3' sequences." Faik P., Walker J.I.H., Redmill A.A.M., Morgan M.J. Nature 332:455-456(1988) [PubMed: 3352745] [Abstract] Cited for: IDENTITY OF NEUROLEUKIN AS PGI.
[8]	"Phosphohexose isomerase/autocrine motility factor/neuroleukin/maturation factor is a multifunctional phosphoprotein." Haga A., Niinaka Y., Raz A. Biochim. Biophys. Acta 1480:235-244(2000) [PubMed: 11004567] [Abstract] Cited for: FUNCTION, PHOSPHORYLATION AT SER-185.
[9]	"Tumor autocrine motility factor is an angiogenic factor that stimulates endothelial cell motility." Funasaka T., Haga A., Raz A., Nagase H. Biochem. Biophys. Res. Commun. 285:118-128(2001) [PubMed: 11437381] [Abstract] Cited for: SUBCELLULAR LOCATION, CYTOKINE AND ANGIOGENIC FUNCTIONS.
[10]	"Species specificity of the cytokine function of phosphoglucose isomerase." Amraei M., Nabi I.R. FEBS Lett. 525:151-155(2002) [PubMed: 12163179] [Abstract] Cited for: SPECIES SPECIFICITY OF THE CYTOKINE FUNCTION.
[11]	"Differential regulation of phosphoglucose isomerase/autocrine motility factor activities by protein kinase CK2 phosphorylation." Yanagawa T., Funasaka T., Tsutsumi S., Raz T., Tanaka N., Raz A. J. Biol. Chem. 280:10419-10426(2005) [PubMed: 15637053] [Abstract] Cited for: PHOSPHORYLATION AT SER-185, MUTAGENESIS OF SER-185.
[12]	"A quantitative atlas of mitotic phosphorylation." Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., Elledge S.J., Gygi S.P. Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008) [PubMed: 18669648] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-109, MASS SPECTROMETRY.
[13]	Colinge J., Superti-Furga G., Bennett K.L. Submitted (OCT-2008) to UniProtKB Cited for: IDENTIFICATION [LARGE SCALE ANALYSIS], MASS SPECTROMETRY.
[14]	"Lys-N and trypsin cover complementary parts of the phosphoproteome in a refined SCX-based approach." Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S. Anal. Chem. 81:4493-4501(2009) [PubMed: 19413330] [Abstract] Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, MASS SPECTROMETRY.
[15]	"Quantitative phosphoproteomic analysis of T cell receptor signaling reveals system-wide modulation of protein-protein interactions." Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., Rodionov V., Han D.K. Sci. Signal. 2:RA46-RA46(2009) [PubMed: 19690332] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-109, MASS SPECTROMETRY. Tissue: T-cell.
[16]	"Lysine acetylation targets protein complexes and co-regulates major cellular functions." Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T., Olsen J.V., Mann M. Science 325:834-840(2009) [PubMed: 19608861] [Abstract] Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-12 AND LYS-142, MASS SPECTROMETRY.
[17]	"The crystal structure of human phosphoglucose isomerase at 1.6 A resolution: implications for catalytic mechanism, cytokine activity and haemolytic anaemia." Read J., Pearce J., Li X., Muirhead H., Chirgwin J., Davies C. J. Mol. Biol. 309:447-463(2001) [PubMed: 11371164] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.62 ANGSTROMS), SUBUNIT, ACTIVE SITE.
[18]	"Inhibition mechanism of cytokine activity of human autocrine motility factor examined by crystal structure analyses and site-directed mutagenesis studies." Tanaka N., Haga A., Uemura H., Akiyama H., Funasaka T., Nagase H., Raz A., Nakamura K.T. J. Mol. Biol. 318:985-997(2002) [PubMed: 12054796] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS) ALONE AND IN COMPLEX WITH INHIBITOR.
[19]	"The structure of human phosphoglucose isomerase complexed with a transition-state analogue." Davies C., Muirhead H., Chirgwin J. Acta Crystallogr. D 59:1111-1113(2003) [PubMed: 12777791] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.51 ANGSTROMS) IN COMPLEX WITH INHIBITOR, ACTIVE SITE.
[20]	"Crystal structure of human phosphoglucose isomerase and analysis of the initial catalytic steps." Cordeiro A.T., Godoi P.H., Silva C.H., Garratt R.C., Oliva G., Thiemann O.H. Biochim. Biophys. Acta 1645:117-122(2003) [PubMed: 12573240] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS), ACTIVE SITE.
[21]	"DNA sequence abnormalities in human glucose 6-phosphate isomerase deficiency." Walker J.I.H., Layton D.M., Bellingham A.J., Morgan M.J., Faik P. Hum. Mol. Genet. 2:327-329(1993) [PubMed: 8499925] [Abstract] Cited for: VARIANTS HA SER-159; HIS-347 AND THR-525.
[22]	"The characterization of gene mutations for human glucose phosphate isomerase deficiency associated with chronic hemolytic anemia." Xu W., Beutler E. J. Clin. Invest. 94:2326-2329(1994) [PubMed: 7989588] [Abstract] Cited for: VARIANTS HA TRP-83; MET-224; HIS-273; LEU-278; CYS-347; PHE-487 AND LYS-495.
[23]	"Study of the molecular defects in glucose phosphate isomerase-deficient patients affected by chronic hemolytic anemia." Baronciani L., Zanella A., Bianchi P., Zappa M., Alfinito F., Iolascon A., Tannoia N., Beutler E., Sirchia G. Blood 88:2306-2310(1996) [PubMed: 8822952] [Abstract] Cited for: VARIANTS HA MET-101; ILE-195; ARG-343 AND THR-525.
[24]	"Molecular analysis of glucose phosphate isomerase deficiency associated with hereditary hemolytic anemia." Kanno H., Fujii H., Hirono A., Ishida Y., Ohga S., Fukumoto Y., Matsuzawa K., Ogawa S., Miwa S. Blood 88:2321-2325(1996) [PubMed: 8822954] [Abstract] Cited for: VARIANTS HA ILE-5; MET-224; ARG-343; ARG-375 AND ASN-539.
[25]	"Glucosephosphate isomerase (GPI) deficiency mutations associated with hereditary nonspherocytic hemolytic anemia (HNSHA)." Beutler E., West C., Britton H.A., Harris J., Forman L. Blood Cells Mol. Dis. 23:402-409(1997) [PubMed: 9446754] [Abstract] Cited for: VARIANTS HA GLY-75; PRO-300; CYS-347 AND HIS-472.
[26]	"Molecular basis of neurological dysfunction coupled with haemolytic anaemia in human glucose-6-phosphate isomerase (GPI) deficiency." Kugler W., Breme K., Laspe P., Muirhead H., Davies C., Winkler H., Schroter W., Lakomek M. Hum. Genet. 103:450-454(1998) [PubMed: 9856489] [Abstract] Cited for: VARIANTS HA PRO-20; PRO-339; ARG-389 AND VAL-517.
+	Additional computationally mapped references.

Web resources

SHMPD

The Singapore human mutation and polymorphism database

Wikipedia

Phosphoglucose isomerase entry

NIEHS-SNPs

Cross-references

Sequence databases

EMBLGenBankDDBJ

K03515 mRNA. Translation: AAA36368.1.
AF187554 mRNA. Translation: AAF22645.1.
AY324386 Genomic DNA. Translation: AAP72966.1.
BC004982 mRNA. Translation: AAH04982.1.
BC006342 mRNA. Translation: AAH06342.4.
M61214, M55538 Genomic DNA. Translation: AAA52593.1.

IPI

IPI00027497.

PIR

A35333.

RefSeq

NP_000166.2.

UniGene

Hs.466471

3D structure databases

PDBPDBe

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1IAT	X-ray	1.62	A	2-558	[»]
1IRI	X-ray	2.40	A/B/C/D	1-558	[»]
1JIQ	X-ray	1.90	A/B/C/D	1-558	[»]
1JLH	X-ray	2.10	A/B/C/D	1-558	[»]
1NUH	X-ray	2.51	A	1-558	[»]

ModBase

Search...

Protein-protein interaction databases

STRING

P06744.

PTM databases

PhosphoSite

P06744.

Proteomic databases

PeptideAtlas

P06744.

PRIDE

P06744.

Genome annotation databases

Ensembl

ENST00000356487; ENSP00000348877; ENSG00000105220; Homo sapiens. [Genome view]

GeneID

2821.

KEGG

hsa:2821.

UCSC

uc002nvf.1. human.

Organism-specific databases

CTD

2821.

GeneCards

GC19P039547.

H-InvDB

HIX0015008.

HGNC

HGNC:4458. GPI.

HPA

CAB018655.
HPA024305.

MIM

172400. gene.

Orphanet

712. Glucosephosphate isomerase deficiency.

PharmGKB

PA28841.

GenAtlas

Search...

Phylogenomic databases

HOGENOM

P06744.

HOVERGEN

P06744.

Enzyme and pathway databases

BRENDA

5.3.1.9. 247.

Reactome

REACT_1505. Integration of energy metabolism.
REACT_15380. Diabetes pathways.
REACT_474. Metabolism of carbohydrates.

Gene expression databases

ArrayExpress

P06744.

Bgee

P06744.

CleanEx

HS_GPI.

Genevestigator

P06744.

GermOnline

ENSG00000105220. Homo sapiens.

Family and domain databases

InterPro

IPR001672. G6P_Isomerase.
IPR018189. Phosphoglucose_isomerase_CS.
[Graphical view]

PANTHER

PTHR11469. G6P_Isomerase. 1 hit.

Pfam

PF00342. PGI. 1 hit.
[Graphical view]

PRINTS

PR00662. G6PISOMERASE.

PROSITE

PS00765. P_GLUCOSE_ISOMERASE_1. 1 hit.
PS00174. P_GLUCOSE_ISOMERASE_2. 1 hit.
PS51463. P_GLUCOSE_ISOMERASE_3. 1 hit.
[Graphical view]

ProtoNet

Search...

Other Resources

NextBio

11117.

SOURCE

Search...

Entry information

Entry name

G6PI_HUMAN

Accession

Primary (citable) accession number: P06744
Secondary accession number(s): Q9BRD3, Q9BSK5, Q9UHE6

Entry history

Integrated into UniProtKB/Swiss-Prot:	January 1, 1988
Last sequence update:	January 23, 2007
Last modified:	November 24, 2009
This is version 122 of the entry and version 4 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.