G6PC2_HUMAN
ID G6PC2_HUMAN Reviewed; 355 AA.
AC Q9NQR9; E9PAX2; Q6AHZ0;
DT 20-MAY-2008, integrated into UniProtKB/Swiss-Prot.
DT 01-OCT-2000, sequence version 1.
DT 03-AUG-2022, entry version 146.
DE RecName: Full=Glucose-6-phosphatase 2;
DE Short=G-6-Pase 2;
DE Short=G6Pase 2;
DE EC=3.1.3.9;
DE AltName: Full=Islet-specific glucose-6-phosphatase catalytic subunit-related protein;
GN Name=G6PC2; Synonyms=IGRP;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], CHARACTERIZATION, AND TISSUE
RP SPECIFICITY.
RX PubMed=11297555; DOI=10.1074/jbc.m101549200;
RA Martin C.C., Bischof L.J., Bergman B., Hornbuckle L.A., Hilliker C.,
RA Frigeri C., Wahl D., Svitek C.A., Wong R., Goldman J.K., Oeser J.K.,
RA Lepretre F., Froguel P., O'Brien R.M., Hutton J.C.;
RT "Cloning and characterization of the human and rat islet-specific glucose-
RT 6-phosphatase catalytic subunit-related protein (IGRP) genes.";
RL J. Biol. Chem. 276:25197-25207(2001).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3).
RC TISSUE=Pancreas;
RA Melton D., Brown J., Kenty G., Permutt A., Lee C., Kaestner K.,
RA Lemishka I., Scearce M., Brestelli J., Gradwohl G., Clifton S., Hillier L.,
RA Marra M., Pape D., Wylie T., Martin J., Blistain A., Schmitt A.,
RA Theising B., Ritter E., Ronko I., Bennett J., Cardenas M., Gibbons M.,
RA McCann R., Cole R., Tsagareishvili R., Williams T., Jackson Y., Bowers Y.;
RT "Endocrine pancreas consortium.";
RL Submitted (JUL-2002) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Retina;
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D.,
RA Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A.,
RA Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15815621; DOI=10.1038/nature03466;
RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P.,
RA Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C.,
RA Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L.,
RA Du H., Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A.,
RA Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J.,
RA Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M.,
RA Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T.,
RA Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S.,
RA Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S.,
RA Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C.,
RA Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M.,
RA Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C.,
RA Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J.,
RA Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E.,
RA Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X.,
RA Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M.,
RA Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H.,
RA Wilson R.K.;
RT "Generation and annotation of the DNA sequences of human chromosomes 2 and
RT 4.";
RL Nature 434:724-731(2005).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Cerebellum;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [7]
RP SUBCELLULAR LOCATION, TOPOLOGY, MUTAGENESIS OF ASN-50; ASN-92 AND ASN-287,
RP AND GLYCOSYLATION AT ASN-92.
RX PubMed=15044018; DOI=10.1016/s0014-5793(04)00223-6;
RA Shieh J.-J., Pan C.-J., Mansfield B.C., Chou J.Y.;
RT "The islet-specific glucose-6-phosphatase-related protein, implicated in
RT diabetes, is a glycoprotein embedded in the endoplasmic reticulum
RT membrane.";
RL FEBS Lett. 562:160-164(2004).
RN [8]
RP CATALYTIC ACTIVITY.
RX PubMed=14722102; DOI=10.1074/jbc.m307756200;
RA Petrolonis A.J., Yang Q., Tummino P.J., Fish S.M., Prack A.E., Jain S.,
RA Parsons T.F., Li P., Dales N.A., Ge L., Langston S.P., Schuller A.G.P.,
RA An W.F., Tartaglia L.A., Chen H., Hong S.-B.;
RT "Enzymatic characterization of the pancreatic islet-specific glucose-6-
RT phosphatase-related protein (IGRP).";
RL J. Biol. Chem. 279:13976-13983(2004).
RN [9]
RP ALTERNATIVE SPLICING.
RX PubMed=16520917; DOI=10.1007/s00125-006-0185-8;
RA Dogra R.S., Vaidyanathan P., Prabakar K.R., Marshall K.E., Hutton J.C.,
RA Pugliese A.;
RT "Alternative splicing of G6PC2, the gene coding for the islet-specific
RT glucose-6-phosphatase catalytic subunit-related protein (IGRP), results in
RT differential expression in human thymus and spleen compared with
RT pancreas.";
RL Diabetologia 49:953-957(2006).
RN [10]
RP INVOLVEMENT IN FGQTL1.
RX PubMed=18451265; DOI=10.1126/science.1156849;
RA Bouatia-Naji N., Rocheleau G., Van Lommel L., Lemaire K., Schuit F.,
RA Cavalcanti-Proenca C., Marchand M., Hartikainen A.-L., Sovio U.,
RA De Graeve F., Rung J., Vaxillaire M., Tichet J., Marre M., Balkau B.,
RA Weill J., Elliott P., Jarvelin M.-R., Meyre D., Polychronakos C., Dina C.,
RA Sladek R., Froguel P.;
RT "A polymorphism within the G6PC2 gene is associated with fasting plasma
RT glucose levels.";
RL Science 320:1085-1088(2008).
CC -!- FUNCTION: May hydrolyze glucose-6-phosphate to glucose in the
CC endoplasmic reticulum. May be responsible for glucose production
CC through glycogenolysis and gluconeogenesis (By similarity).
CC {ECO:0000250}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=D-glucose 6-phosphate + H2O = D-glucose + phosphate;
CC Xref=Rhea:RHEA:16689, ChEBI:CHEBI:4167, ChEBI:CHEBI:15377,
CC ChEBI:CHEBI:43474, ChEBI:CHEBI:61548; EC=3.1.3.9;
CC Evidence={ECO:0000269|PubMed:14722102};
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=0.45 mM for glucose-6-phosphate (at pH 6.5);
CC -!- PATHWAY: Carbohydrate biosynthesis; gluconeogenesis.
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
CC {ECO:0000269|PubMed:15044018}; Multi-pass membrane protein
CC {ECO:0000269|PubMed:15044018}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=Q9NQR9-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q9NQR9-2; Sequence=VSP_033648, VSP_033649;
CC Name=3;
CC IsoId=Q9NQR9-3; Sequence=VSP_046180, VSP_046181;
CC -!- TISSUE SPECIFICITY: Specifically expressed in pancreas and also
CC detected to a lower extent in testis. Expressed by most islet cells in
CC the pancreas (at protein level). {ECO:0000269|PubMed:11297555}.
CC -!- PTM: N-glycosylated; the non-glycosylated form is more unstable and is
CC degraded through the proteasome. {ECO:0000269|PubMed:15044018}.
CC -!- POLYMORPHISM: Genetic variations in G6PC2 define the fasting plasma
CC glucose levels quantitative trait locus 1 (FGQTL1) [MIM:612108]. The
CC normal fasting plasma glucose level in the plasma is defined as less
CC than 100 mg per deciliter (5.55 mmol per liter). Higher fasting plasma
CC glucose levels predict type 2 diabetes in young adults and increases
CC the risk of mortality.
CC -!- SIMILARITY: Belongs to the glucose-6-phosphatase family. {ECO:0000305}.
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DR EMBL; AF283835; AAF82810.1; -; Genomic_DNA.
DR EMBL; BQ777188; -; NOT_ANNOTATED_CDS; mRNA.
DR EMBL; CR627438; CAH10524.1; -; mRNA.
DR EMBL; AC069137; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471058; EAX11291.1; -; Genomic_DNA.
DR EMBL; BC104778; AAI04779.1; -; mRNA.
DR EMBL; BC113376; AAI13377.1; -; mRNA.
DR CCDS; CCDS2230.1; -. [Q9NQR9-1]
DR CCDS; CCDS46443.1; -. [Q9NQR9-3]
DR RefSeq; NP_001075155.1; NM_001081686.1. [Q9NQR9-3]
DR RefSeq; NP_066999.1; NM_021176.2. [Q9NQR9-1]
DR AlphaFoldDB; Q9NQR9; -.
DR SMR; Q9NQR9; -.
DR BioGRID; 121777; 1.
DR STRING; 9606.ENSP00000364512; -.
DR DEPOD; G6PC2; -.
DR GlyGen; Q9NQR9; 1 site.
DR iPTMnet; Q9NQR9; -.
DR PhosphoSitePlus; Q9NQR9; -.
DR BioMuta; G6PC2; -.
DR DMDM; 74725272; -.
DR PaxDb; Q9NQR9; -.
DR PRIDE; Q9NQR9; -.
DR Antibodypedia; 53147; 75 antibodies from 12 providers.
DR DNASU; 57818; -.
DR Ensembl; ENST00000282075.5; ENSP00000282075.4; ENSG00000152254.11. [Q9NQR9-2]
DR Ensembl; ENST00000375363.8; ENSP00000364512.3; ENSG00000152254.11. [Q9NQR9-1]
DR Ensembl; ENST00000429379.2; ENSP00000396939.2; ENSG00000152254.11. [Q9NQR9-3]
DR Ensembl; ENST00000612807.1; ENSP00000481098.1; ENSG00000278373.4. [Q9NQR9-3]
DR Ensembl; ENST00000617403.1; ENSP00000483899.1; ENSG00000278373.4. [Q9NQR9-2]
DR Ensembl; ENST00000622133.4; ENSP00000482583.1; ENSG00000278373.4. [Q9NQR9-1]
DR GeneID; 57818; -.
DR KEGG; hsa:57818; -.
DR MANE-Select; ENST00000375363.8; ENSP00000364512.3; NM_021176.3; NP_066999.1.
DR UCSC; uc002uem.4; human. [Q9NQR9-1]
DR CTD; 57818; -.
DR DisGeNET; 57818; -.
DR GeneCards; G6PC2; -.
DR HGNC; HGNC:28906; G6PC2.
DR HPA; ENSG00000152254; Group enriched (pancreas, retina).
DR MIM; 608058; gene.
DR MIM; 612108; phenotype.
DR neXtProt; NX_Q9NQR9; -.
DR OpenTargets; ENSG00000152254; -.
DR PharmGKB; PA134944773; -.
DR VEuPathDB; HostDB:ENSG00000152254; -.
DR eggNOG; ENOG502QS9B; Eukaryota.
DR GeneTree; ENSGT00950000183150; -.
DR HOGENOM; CLU_052517_0_0_1; -.
DR InParanoid; Q9NQR9; -.
DR OMA; PKAKKWC; -.
DR OrthoDB; 743717at2759; -.
DR PhylomeDB; Q9NQR9; -.
DR TreeFam; TF324388; -.
DR BioCyc; MetaCyc:HS14422-MON; -.
DR BRENDA; 3.1.3.9; 2681.
DR PathwayCommons; Q9NQR9; -.
DR Reactome; R-HSA-70263; Gluconeogenesis.
DR SABIO-RK; Q9NQR9; -.
DR SIGNOR; Q9NQR9; -.
DR UniPathway; UPA00138; -.
DR BioGRID-ORCS; 57818; 12 hits in 1073 CRISPR screens.
DR GeneWiki; G6PC2; -.
DR GenomeRNAi; 57818; -.
DR Pharos; Q9NQR9; Tbio.
DR PRO; PR:Q9NQR9; -.
DR Proteomes; UP000005640; Chromosome 2.
DR RNAct; Q9NQR9; protein.
DR Bgee; ENSG00000152254; Expressed in islet of Langerhans and 47 other tissues.
DR ExpressionAtlas; Q9NQR9; baseline and differential.
DR Genevisible; Q9NQR9; HS.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; TAS:Reactome.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0016020; C:membrane; IBA:GO_Central.
DR GO; GO:0004346; F:glucose-6-phosphatase activity; EXP:Reactome.
DR GO; GO:0006094; P:gluconeogenesis; IBA:GO_Central.
DR GO; GO:0051156; P:glucose 6-phosphate metabolic process; IBA:GO_Central.
DR GO; GO:0042593; P:glucose homeostasis; IMP:BHF-UCL.
DR GO; GO:0050796; P:regulation of insulin secretion; IMP:BHF-UCL.
DR InterPro; IPR016275; Glucose-6-phosphatase.
DR InterPro; IPR036938; P_Acid_Pase_2/haloperoxi_sf.
DR InterPro; IPR000326; P_Acid_Pase_2/haloperoxidase.
DR Pfam; PF01569; PAP2; 1.
DR PIRSF; PIRSF000905; Glucose-6-phosphatase; 1.
DR SMART; SM00014; acidPPc; 1.
DR SUPFAM; SSF48317; SSF48317; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Endoplasmic reticulum; Gluconeogenesis; Glycoprotein;
KW Hydrolase; Membrane; Reference proteome; Transmembrane;
KW Transmembrane helix.
FT CHAIN 1..355
FT /note="Glucose-6-phosphatase 2"
FT /id="PRO_0000334509"
FT TOPO_DOM 1..24
FT /note="Lumenal"
FT /evidence="ECO:0000255"
FT TRANSMEM 25..45
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 46..56
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 57..77
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 78..115
FT /note="Lumenal"
FT /evidence="ECO:0000255"
FT TRANSMEM 116..136
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 137..146
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 147..167
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 168
FT /note="Lumenal"
FT /evidence="ECO:0000255"
FT TRANSMEM 169..189
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 190..211
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 212..232
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 233..261
FT /note="Lumenal"
FT /evidence="ECO:0000255"
FT TRANSMEM 262..282
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 283..293
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 294..314
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 315..318
FT /note="Lumenal"
FT /evidence="ECO:0000255"
FT TRANSMEM 319..339
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 340..355
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT MOTIF 352..355
FT /note="Prevents secretion from ER"
FT /evidence="ECO:0000255"
FT ACT_SITE 115
FT /note="Proton donor"
FT /evidence="ECO:0000255"
FT ACT_SITE 174
FT /note="Nucleophile"
FT /evidence="ECO:0000250"
FT BINDING 79
FT /ligand="substrate"
FT /evidence="ECO:0000255"
FT BINDING 168
FT /ligand="substrate"
FT /evidence="ECO:0000255"
FT CARBOHYD 92
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:15044018"
FT VAR_SEQ 74..102
FT /note="ILFGHRPYWWVQETQIYPNHSSPCLEQFP -> KSIWPCNGRILCLVCHGNR
FT CPEPHCLWDG (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:17974005"
FT /id="VSP_033648"
FT VAR_SEQ 103..355
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:17974005"
FT /id="VSP_033649"
FT VAR_SEQ 148..154
FT /note="LTWSFLW -> HAGGRGL (in isoform 3)"
FT /evidence="ECO:0000303|Ref.2"
FT /id="VSP_046180"
FT VAR_SEQ 155..355
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000303|Ref.2"
FT /id="VSP_046181"
FT VARIANT 171
FT /note="I -> V (in dbSNP:rs2232322)"
FT /id="VAR_043372"
FT VARIANT 207
FT /note="Y -> S (in dbSNP:rs2232323)"
FT /id="VAR_043373"
FT VARIANT 219
FT /note="V -> L (in dbSNP:rs492594)"
FT /id="VAR_043374"
FT VARIANT 324
FT /note="S -> P (in dbSNP:rs2232326)"
FT /id="VAR_043375"
FT VARIANT 340
FT /note="P -> L (in dbSNP:rs2232327)"
FT /id="VAR_043376"
FT VARIANT 342
FT /note="S -> C (in dbSNP:rs2232328)"
FT /id="VAR_043377"
FT MUTAGEN 50
FT /note="N->A: No effect on N-glycosylation."
FT /evidence="ECO:0000269|PubMed:15044018"
FT MUTAGEN 92
FT /note="N->A: Loss of N-glycosylation."
FT /evidence="ECO:0000269|PubMed:15044018"
FT MUTAGEN 287
FT /note="N->A: No effect on N-glycosylation."
FT /evidence="ECO:0000269|PubMed:15044018"
SQ SEQUENCE 355 AA; 40580 MW; D642C37496B6C4EB CRC64;
MDFLHRNGVL IIQHLQKDYR AYYTFLNFMS NVGDPRNIFF IYFPLCFQFN QTVGTKMIWV
AVIGDWLNLI FKWILFGHRP YWWVQETQIY PNHSSPCLEQ FPTTCETGPG SPSGHAMGAS
CVWYVMVTAA LSHTVCGMDK FSITLHRLTW SFLWSVFWLI QISVCISRVF IATHFPHQVI
LGVIGGMLVA EAFEHTPGIQ TASLGTYLKT NLFLFLFAVG FYLLLRVLNI DLLWSVPIAK
KWCANPDWIH IDTTPFAGLV RNLGVLFGLG FAINSEMFLL SCRGGNNYTL SFRLLCALTS
LTILQLYHFL QIPTHEEHLF YVLSFCKSAS IPLTVVAFIP YSVHMLMKQS GKKSQ
