PLPL3_HUMAN
ID PLPL3_HUMAN Reviewed; 481 AA.
AC Q9NST1; B0QYI0; B2RCL3; B3KW00; Q6P1A1; Q96CB4;
DT 03-JUL-2003, integrated into UniProtKB/Swiss-Prot.
DT 01-MAR-2002, sequence version 2.
DT 03-AUG-2022, entry version 167.
DE RecName: Full=1-acylglycerol-3-phosphate O-acyltransferase PNPLA3 {ECO:0000305|PubMed:22560221};
DE EC=2.3.1.51 {ECO:0000269|PubMed:21878620, ECO:0000269|PubMed:22560221};
DE AltName: Full=Acylglycerol transacylase {ECO:0000303|PubMed:15364929};
DE AltName: Full=Adiponutrin {ECO:0000303|PubMed:22560221};
DE Short=ADPN {ECO:0000303|PubMed:22560221};
DE AltName: Full=Calcium-independent phospholipase A2-epsilon {ECO:0000303|PubMed:15364929};
DE Short=iPLA2-epsilon {ECO:0000303|PubMed:15364929};
DE EC=3.1.1.4 {ECO:0000269|PubMed:15364929};
DE AltName: Full=Lysophosphatidic acid acyltransferase {ECO:0000303|PubMed:22560221};
DE AltName: Full=Patatin-like phospholipase domain-containing protein 3 {ECO:0000303|PubMed:19224197};
DE EC=3.1.1.3 {ECO:0000269|PubMed:15364929, ECO:0000269|PubMed:20034933, ECO:0000269|PubMed:21878620, ECO:0000269|PubMed:22560221};
GN Name=PNPLA3 {ECO:0000303|PubMed:19224197, ECO:0000303|PubMed:22560221,
GN ECO:0000312|HGNC:HGNC:18590};
GN Synonyms=ADPN {ECO:0000303|PubMed:22560221}, C22orf20;
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 [LARGE SCALE MRNA] (ISOFORM 1).
RX PubMed=12529303; DOI=10.1101/gr.695703;
RA Collins J.E., Goward M.E., Cole C.G., Smink L.J., Huckle E.J., Knowles S.,
RA Bye J.M., Beare D.M., Dunham I.;
RT "Reevaluating human gene annotation: a second-generation analysis of
RT chromosome 22.";
RL Genome Res. 13:27-36(2003).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT GLU-434.
RX PubMed=15461802; DOI=10.1186/gb-2004-5-10-r84;
RA Collins J.E., Wright C.L., Edwards C.A., Davis M.P., Grinham J.A.,
RA Cole C.G., Goward M.E., Aguado B., Mallya M., Mokrab Y., Huckle E.J.,
RA Beare D.M., Dunham I.;
RT "A genome annotation-driven approach to cloning the human ORFeome.";
RL Genome Biol. 5:R84.1-R84.11(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2), AND VARIANTS
RP CYS-115; MET-148 AND GLU-434.
RC TISSUE=Brain, and Teratocarcinoma;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=10591208; DOI=10.1038/990031;
RA Dunham I., Hunt A.R., Collins J.E., Bruskiewich R., Beare D.M., Clamp M.,
RA Smink L.J., Ainscough R., Almeida J.P., Babbage A.K., Bagguley C.,
RA Bailey J., Barlow K.F., Bates K.N., Beasley O.P., Bird C.P., Blakey S.E.,
RA Bridgeman A.M., Buck D., Burgess J., Burrill W.D., Burton J., Carder C.,
RA Carter N.P., Chen Y., Clark G., Clegg S.M., Cobley V.E., Cole C.G.,
RA Collier R.E., Connor R., Conroy D., Corby N.R., Coville G.J., Cox A.V.,
RA Davis J., Dawson E., Dhami P.D., Dockree C., Dodsworth S.J., Durbin R.M.,
RA Ellington A.G., Evans K.L., Fey J.M., Fleming K., French L., Garner A.A.,
RA Gilbert J.G.R., Goward M.E., Grafham D.V., Griffiths M.N.D., Hall C.,
RA Hall R.E., Hall-Tamlyn G., Heathcott R.W., Ho S., Holmes S., Hunt S.E.,
RA Jones M.C., Kershaw J., Kimberley A.M., King A., Laird G.K., Langford C.F.,
RA Leversha M.A., Lloyd C., Lloyd D.M., Martyn I.D., Mashreghi-Mohammadi M.,
RA Matthews L.H., Mccann O.T., Mcclay J., Mclaren S., McMurray A.A.,
RA Milne S.A., Mortimore B.J., Odell C.N., Pavitt R., Pearce A.V., Pearson D.,
RA Phillimore B.J.C.T., Phillips S.H., Plumb R.W., Ramsay H., Ramsey Y.,
RA Rogers L., Ross M.T., Scott C.E., Sehra H.K., Skuce C.D., Smalley S.,
RA Smith M.L., Soderlund C., Spragon L., Steward C.A., Sulston J.E.,
RA Swann R.M., Vaudin M., Wall M., Wallis J.M., Whiteley M.N., Willey D.L.,
RA Williams L., Williams S.A., Williamson H., Wilmer T.E., Wilming L.,
RA Wright C.L., Hubbard T., Bentley D.R., Beck S., Rogers J., Shimizu N.,
RA Minoshima S., Kawasaki K., Sasaki T., Asakawa S., Kudoh J., Shintani A.,
RA Shibuya K., Yoshizaki Y., Aoki N., Mitsuyama S., Roe B.A., Chen F., Chu L.,
RA Crabtree J., Deschamps S., Do A., Do T., Dorman A., Fang F., Fu Y., Hu P.,
RA Hua A., Kenton S., Lai H., Lao H.I., Lewis J., Lewis S., Lin S.-P., Loh P.,
RA Malaj E., Nguyen T., Pan H., Phan S., Qi S., Qian Y., Ray L., Ren Q.,
RA Shaull S., Sloan D., Song L., Wang Q., Wang Y., Wang Z., White J.,
RA Willingham D., Wu H., Yao Z., Zhan M., Zhang G., Chissoe S., Murray J.,
RA Miller N., Minx P., Fulton R., Johnson D., Bemis G., Bentley D.,
RA Bradshaw H., Bourne S., Cordes M., Du Z., Fulton L., Goela D., Graves T.,
RA Hawkins J., Hinds K., Kemp K., Latreille P., Layman D., Ozersky P.,
RA Rohlfing T., Scheet P., Walker C., Wamsley A., Wohldmann P., Pepin K.,
RA Nelson J., Korf I., Bedell J.A., Hillier L.W., Mardis E., Waterston R.,
RA Wilson R., Emanuel B.S., Shaikh T., Kurahashi H., Saitta S., Budarf M.L.,
RA McDermid H.E., Johnson A., Wong A.C.C., Morrow B.E., Edelmann L., Kim U.J.,
RA Shizuya H., Simon M.I., Dumanski J.P., Peyrard M., Kedra D., Seroussi E.,
RA Fransson I., Tapia I., Bruder C.E., O'Brien K.P., Wilkinson P.,
RA Bodenteich A., Hartman K., Hu X., Khan A.S., Lane L., Tilahun Y.,
RA Wright H.;
RT "The DNA sequence of human chromosome 22.";
RL Nature 402:489-495(1999).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], AND VARIANT GLU-434.
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 (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANTS GLY-99;
RP MET-148 AND GLU-434.
RC TISSUE=Brain, and Skin;
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 FUNCTION, PATHWAY, SUBCELLULAR LOCATION, CATALYTIC ACTIVITY, AND ACTIVITY
RP REGULATION.
RX PubMed=15364929; DOI=10.1074/jbc.m407841200;
RA Jenkins C.M., Mancuso D.J., Yan W., Sims H.F., Gibson B., Gross R.W.;
RT "Identification, cloning, expression, and purification of three novel human
RT calcium-independent phospholipase A2 family members possessing
RT triacylglycerol lipase and acylglycerol transacylase activities.";
RL J. Biol. Chem. 279:48968-48975(2004).
RN [8]
RP INDUCTION.
RX PubMed=15181042; DOI=10.1210/jc.2003-031978;
RA Liu Y.-M., Moldes M., Bastard J.-P., Bruckert E., Viguerie N., Hainque B.,
RA Basdevant A., Langin D., Pairault J., Clement K.;
RT "Adiponutrin: A new gene regulated by energy balance in human adipose
RT tissue.";
RL J. Clin. Endocrinol. Metab. 89:2684-2689(2004).
RN [9]
RP VARIANT MET-148, AND POLYMORPHISM.
RX PubMed=18728122; DOI=10.1530/eje-08-0426;
RA Johansson L.E., Lindblad U., Larsson C.A., Raastam L., Ridderstraale M.;
RT "Polymorphisms in the adiponutrin gene are associated with increased
RT insulin secretion and obesity.";
RL Eur. J. Endocrinol. 159:577-583(2008).
RN [10]
RP VARIANTS MET-148 AND ILE-453, AND INVOLVEMENT IN SUSCEPTIBILITY TO NAFLD1.
RX PubMed=18820647; DOI=10.1038/ng.257;
RA Romeo S., Kozlitina J., Xing C., Pertsemlidis A., Cox D., Pennacchio L.A.,
RA Boerwinkle E., Cohen J.C., Hobbs H.H.;
RT "Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty
RT liver disease.";
RL Nat. Genet. 40:1461-1465(2008).
RN [11]
RP VARIANT MET-148, AND INVOLVEMENT IN SUSCEPTIBILITY TO NAFLD1.
RX PubMed=19224197; DOI=10.1007/s00125-009-1285-z;
RA Kotronen A., Johansson L.E., Johansson L.M., Roos C., Westerbacka J.,
RA Hamsten A., Bergholm R., Arkkila P., Arola J., Kiviluoto T., Fisher R.M.,
RA Ehrenborg E., Orho-Melander M., Ridderstrale M., Groop L., Yki-Jarvinen H.;
RT "A common variant in PNPLA3, which encodes adiponutrin, is associated with
RT liver fat content in humans.";
RL Diabetologia 52:1056-1060(2009).
RN [12]
RP VARIANT MET-148, AND INVOLVEMENT IN SUSCEPTIBILITY TO NAFLD1.
RX PubMed=19738004; DOI=10.1194/jlr.p900013-jlr200;
RA Sookoian S., Castano G.O., Burgueno A.L., Gianotti T.F., Rosselli M.S.,
RA Pirola C.J.;
RT "A nonsynonymous gene variant in the adiponutrin gene is associated with
RT nonalcoholic fatty liver disease severity.";
RL J. Lipid Res. 50:2111-2116(2009).
RN [13]
RP CATALYTIC ACTIVITY, FUNCTION, SUBCELLULAR LOCATION, PATHWAY, CAUTION, AND
RP CHARACTERIZATION OF VARIANT MET-148.
RX PubMed=20034933; DOI=10.1074/jbc.m109.064501;
RA He S., McPhaul C., Li J.Z., Garuti R., Kinch L., Grishin N.V., Cohen J.C.,
RA Hobbs H.H.;
RT "A sequence variation (I148M) in PNPLA3 associated with nonalcoholic fatty
RT liver disease disrupts triglyceride hydrolysis.";
RL J. Biol. Chem. 285:6706-6715(2010).
RN [14]
RP CHARACTERIZATION OF VARIANT MET-148, INVOLVEMENT IN SUSCEPTIBILITY TO
RP NAFLD1, CATALYTIC ACTIVITY, FUNCTION, BIOPHYSICOCHEMICAL PROPERTIES, AND
RP MUTAGENESIS OF SER-47.
RX PubMed=21878620; DOI=10.1074/jbc.m111.290114;
RA Huang Y., Cohen J.C., Hobbs H.H.;
RT "Expression and characterization of a PNPLA3 protein isoform (I148M)
RT associated with nonalcoholic fatty liver disease.";
RL J. Biol. Chem. 286:37085-37093(2011).
RN [15]
RP FUNCTION, CATALYTIC ACTIVITY, CHARACTERIZATION OF VARIANT MET-148,
RP MUTAGENESIS OF CYS-15; SER-47; ASP-206 AND PRO-311, PATHWAY, SUBCELLULAR
RP LOCATION, AND CAUTION.
RX PubMed=22560221; DOI=10.1016/j.cmet.2012.04.008;
RA Kumari M., Schoiswohl G., Chitraju C., Paar M., Cornaciu I., Rangrez A.Y.,
RA Wongsiriroj N., Nagy H.M., Ivanova P.T., Scott S.A., Knittelfelder O.,
RA Rechberger G.N., Birner-Gruenberger R., Eder S., Brown H.A., Haemmerle G.,
RA Oberer M., Lass A., Kershaw E.E., Zimmermann R., Zechner R.;
RT "Adiponutrin functions as a nutritionally regulated lysophosphatidic acid
RT acyltransferase.";
RL Cell Metab. 15:691-702(2012).
RN [16]
RP VARIANTS NAFLD1 THR-76; VAL-104 AND MET-200.
RX PubMed=27288299; DOI=10.1016/j.clinre.2016.05.004;
RA Zegers D., Verrijken A., Francque S., de Freitas F., Beckers S., Aerts E.,
RA Ruppert M., Hubens G., Michielsen P., Van Hul W., Van Gaal L.F.;
RT "Screening for rare variants in the PNPLA3 gene in obese liver biopsy
RT patients.";
RL Clin. Res. Hepatol. Gastroenterol. 40:715-721(2016).
CC -!- FUNCTION: Specifically catalyzes coenzyme A (CoA)-dependent acylation
CC of 1-acyl-sn-glycerol 3-phosphate (2-lysophosphatidic acid/LPA) to
CC generate phosphatidic acid (PA), an important metabolic intermediate
CC and precursor for both triglycerides and glycerophospholipids. Does not
CC esterify other lysophospholipids. Acyl donors are long chain (at least
CC C16) fatty acyl-CoAs: arachidonoyl-CoA, linoleoyl-CoA, oleoyl-CoA and
CC at a lesser extent palmitoyl-CoA (PubMed:22560221). Additionally
CC possesses low triacylglycerol lipase and CoA-independent acylglycerol
CC transacylase activities and thus may play a role in acyl-chain
CC remodeling of triglycerides (PubMed:15364929, PubMed:20034933,
CC PubMed:22560221). Has hydrolytic activity against glycerolipids
CC triacylglycerol, diacylglycerol and monoacylglycerol, with a strong
CC preference for oleic acid as the acyl moiety (PubMed:21878620).
CC Possesses phospholipase A2 activity (PubMed:15364929).
CC {ECO:0000269|PubMed:15364929, ECO:0000269|PubMed:20034933,
CC ECO:0000269|PubMed:21878620, ECO:0000269|PubMed:22560221}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=a 1-acyl-sn-glycero-3-phosphate + an acyl-CoA = a 1,2-diacyl-
CC sn-glycero-3-phosphate + CoA; Xref=Rhea:RHEA:19709,
CC ChEBI:CHEBI:57287, ChEBI:CHEBI:57970, ChEBI:CHEBI:58342,
CC ChEBI:CHEBI:58608; EC=2.3.1.51;
CC Evidence={ECO:0000269|PubMed:21878620, ECO:0000269|PubMed:22560221};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=a triacylglycerol + H2O = a diacylglycerol + a fatty acid +
CC H(+); Xref=Rhea:RHEA:12044, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:17855, ChEBI:CHEBI:18035, ChEBI:CHEBI:28868; EC=3.1.1.3;
CC Evidence={ECO:0000269|PubMed:15364929, ECO:0000269|PubMed:20034933,
CC ECO:0000269|PubMed:21878620, ECO:0000269|PubMed:22560221};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=a 1,3-diacylglycerol + a 1-acylglycerol = a triacylglycerol +
CC glycerol; Xref=Rhea:RHEA:44440, ChEBI:CHEBI:17754, ChEBI:CHEBI:17855,
CC ChEBI:CHEBI:35759, ChEBI:CHEBI:47777;
CC Evidence={ECO:0000269|PubMed:15364929};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=a 1,2-diacylglycerol + a 1-acylglycerol = a triacylglycerol +
CC glycerol; Xref=Rhea:RHEA:44436, ChEBI:CHEBI:17754, ChEBI:CHEBI:17855,
CC ChEBI:CHEBI:35759, ChEBI:CHEBI:49172;
CC Evidence={ECO:0000269|PubMed:15364929};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=2 a 1-acylglycerol = a 1,2-diacylglycerol + glycerol;
CC Xref=Rhea:RHEA:44432, ChEBI:CHEBI:17754, ChEBI:CHEBI:35759,
CC ChEBI:CHEBI:49172; Evidence={ECO:0000269|PubMed:15364929};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(9Z)-octadecenoyl-CoA + 1-(9Z-octadecenoyl)-sn-glycero-3-
CC phosphate = 1,2-di-(9Z-octadecenoyl)-sn-glycero-3-phosphate + CoA;
CC Xref=Rhea:RHEA:37131, ChEBI:CHEBI:57287, ChEBI:CHEBI:57387,
CC ChEBI:CHEBI:74544, ChEBI:CHEBI:74546;
CC Evidence={ECO:0000269|PubMed:22560221};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:37132;
CC Evidence={ECO:0000305|PubMed:22560221};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=1-(9Z-octadecenoyl)-sn-glycero-3-phosphate + hexadecanoyl-CoA
CC = 1-(9Z)-octadecenoyl-2-hexadecanoyl-sn-glycero-3-phosphate + CoA;
CC Xref=Rhea:RHEA:37143, ChEBI:CHEBI:57287, ChEBI:CHEBI:57379,
CC ChEBI:CHEBI:74544, ChEBI:CHEBI:74551;
CC Evidence={ECO:0000269|PubMed:22560221};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:37144;
CC Evidence={ECO:0000305|PubMed:22560221};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(9Z,12Z)-octadecadienoyl-CoA + 1-(9Z-octadecenoyl)-sn-glycero-
CC 3-phosphate = 1-(9Z)-octadecenoyl-2-(9Z,12Z)-octadecadienoyl-sn-
CC glycero-3-phosphate + CoA; Xref=Rhea:RHEA:37159, ChEBI:CHEBI:57287,
CC ChEBI:CHEBI:57383, ChEBI:CHEBI:74544, ChEBI:CHEBI:74563;
CC Evidence={ECO:0000269|PubMed:22560221};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:37160;
CC Evidence={ECO:0000305|PubMed:22560221};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(5Z,8Z,11Z,14Z)-eicosatetraenoyl-CoA + 1-(9Z-octadecenoyl)-sn-
CC glycero-3-phosphate = 1-(9Z)-octadecenoyl-2-(5Z,8Z,11Z,14Z)-
CC eicosatetraenoyl-sn-glycero-3-phosphate + CoA; Xref=Rhea:RHEA:37443,
CC ChEBI:CHEBI:57287, ChEBI:CHEBI:57368, ChEBI:CHEBI:74544,
CC ChEBI:CHEBI:74928; Evidence={ECO:0000269|PubMed:22560221};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:37444;
CC Evidence={ECO:0000305|PubMed:22560221};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=2 1-(9Z-octadecenoyl)-glycerol = 1,2-di-(9Z-octadecenoyl)-
CC glycerol + glycerol; Xref=Rhea:RHEA:38323, ChEBI:CHEBI:17754,
CC ChEBI:CHEBI:52323, ChEBI:CHEBI:75342;
CC Evidence={ECO:0000269|PubMed:15364929};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:38324;
CC Evidence={ECO:0000305|PubMed:15364929};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=1,2-di-(9Z-octadecenoyl)-glycerol + 1-(9Z-octadecenoyl)-
CC glycerol = 1,2,3-tri-(9Z-octadecenoyl)-glycerol + glycerol;
CC Xref=Rhea:RHEA:38327, ChEBI:CHEBI:17754, ChEBI:CHEBI:52323,
CC ChEBI:CHEBI:53753, ChEBI:CHEBI:75342;
CC Evidence={ECO:0000269|PubMed:15364929};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:38328;
CC Evidence={ECO:0000305|PubMed:15364929};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=1,3-di-(9Z-octadecenoyl)-glycerol + 1-(9Z-octadecenoyl)-
CC glycerol = 1,2,3-tri-(9Z-octadecenoyl)-glycerol + glycerol;
CC Xref=Rhea:RHEA:38331, ChEBI:CHEBI:17754, ChEBI:CHEBI:53753,
CC ChEBI:CHEBI:75342, ChEBI:CHEBI:75735;
CC Evidence={ECO:0000269|PubMed:15364929};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:38332;
CC Evidence={ECO:0000305|PubMed:15364929};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=1,2,3-tri-(9Z-octadecenoyl)-glycerol + H2O = (9Z)-
CC octadecenoate + 1,3-di-(9Z-octadecenoyl)-glycerol + H(+);
CC Xref=Rhea:RHEA:38387, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:30823, ChEBI:CHEBI:53753, ChEBI:CHEBI:75735;
CC Evidence={ECO:0000269|PubMed:21878620};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:38388;
CC Evidence={ECO:0000269|PubMed:21878620};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=a 1,2-diacyl-sn-glycero-3-phosphocholine + H2O = a 1-acyl-sn-
CC glycero-3-phosphocholine + a fatty acid + H(+); Xref=Rhea:RHEA:15801,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:28868,
CC ChEBI:CHEBI:57643, ChEBI:CHEBI:58168; EC=3.1.1.4;
CC Evidence={ECO:0000269|PubMed:15364929};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:15802;
CC Evidence={ECO:0000305|PubMed:15364929};
CC -!- ACTIVITY REGULATION: The triglyceride lipase activity is inhibited by
CC BEL ((E)-6-(bromomethylene)-3-(1-naphthalenyl)-2H-tetrahydropyran-2-
CC one), a suicide substrate inhibitor. {ECO:0000269|PubMed:15364929}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=32.2 uM for triacylglycerol {ECO:0000269|PubMed:21878620};
CC KM=29.1 uM for diacylglycerol {ECO:0000269|PubMed:21878620};
CC KM=32.9 uM for monoacylglycerol {ECO:0000269|PubMed:21878620};
CC KM=6.2 uM for oleoyl-CoA {ECO:0000269|PubMed:21878620};
CC Vmax=10.5 nmol/min/mg enzyme toward triacylglycerol
CC {ECO:0000269|PubMed:21878620};
CC Vmax=21.8 nmol/min/mg enzyme toward diacylglycerol
CC {ECO:0000269|PubMed:21878620};
CC Vmax=27.4 nmol/min/mg enzyme toward monoacylglycerol
CC {ECO:0000269|PubMed:21878620};
CC Vmax=2.8 nmol/min/mg enzyme toward oleoyl-CoA
CC {ECO:0000269|PubMed:21878620};
CC -!- PATHWAY: Phospholipid metabolism. {ECO:0000269|PubMed:22560221}.
CC -!- PATHWAY: Glycerolipid metabolism. {ECO:0000269|PubMed:15364929,
CC ECO:0000269|PubMed:20034933, ECO:0000269|PubMed:22560221}.
CC -!- SUBCELLULAR LOCATION: Membrane {ECO:0000269|PubMed:15364929,
CC ECO:0000269|PubMed:22560221}; Single-pass type II membrane protein
CC {ECO:0000269|PubMed:15364929}. Lipid droplet
CC {ECO:0000269|PubMed:20034933, ECO:0000269|PubMed:22560221}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q9NST1-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q9NST1-2; Sequence=VSP_036222;
CC -!- INDUCTION: By changes in energy balance: down-regulated following very
CC low-calorie diet, whereas refeeding elevates the mRNA level.
CC {ECO:0000269|PubMed:15181042}.
CC -!- POLYMORPHISM: Polymorphic variation at position 148 influences insulin
CC secretion levels and obesity. In obese subjects the body mass index and
CC waist are higher in carriers of the Ile-148 allele. The Ile-148
CC carriers also display decreased insulin secretion in response to oral
CC glucose tolerance test. Met-148 allele carriers are seemingly more
CC insulin resistant at a lower body mass index.
CC {ECO:0000269|PubMed:18728122}.
CC -!- DISEASE: Non-alcoholic fatty liver disease 1 (NAFLD1) [MIM:613282]: A
CC condition characterized by accumulation of triglycerides in the liver.
CC It is associated with adverse metabolic consequences, including insulin
CC resistance and dyslipidemia. In a subset of individuals, hepatic
CC steatosis promotes an inflammatory response in the liver, referred to
CC as steatohepatitis, which can progress to cirrhosis and liver cancer.
CC NAFLD is the most common form of liver disease in Western countries.
CC {ECO:0000269|PubMed:18820647, ECO:0000269|PubMed:19224197,
CC ECO:0000269|PubMed:19738004, ECO:0000269|PubMed:27288299}. Note=Disease
CC susceptibility is associated with variants affecting the gene
CC represented in this entry.
CC -!- CAUTION: Variant Met-148 was initially reported to reduce triglyceride
CC hydrolysis activity in vitro (PubMed:20034933, PubMed:21878620).
CC However further in vitro and in vivo data demonstrated that it actually
CC does not affect triglyceride hydrolysis activity, but rather increases
CC 1-acylglycerol-3-phosphate O-acyltransferase activity
CC (PubMed:22560221). {ECO:0000269|PubMed:20034933,
CC ECO:0000269|PubMed:21878620, ECO:0000269|PubMed:22560221}.
CC ---------------------------------------------------------------------------
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DR EMBL; AL138578; CAB71238.2; -; mRNA.
DR EMBL; CR456476; CAG30362.1; -; mRNA.
DR EMBL; AK123806; BAG53962.1; -; mRNA.
DR EMBL; AK315166; BAG37610.1; -; mRNA.
DR EMBL; AL023654; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AL035398; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471138; EAW73324.1; -; Genomic_DNA.
DR EMBL; BC014449; AAH14449.2; -; mRNA.
DR EMBL; BC065195; AAH65195.1; -; mRNA.
DR CCDS; CCDS14054.1; -. [Q9NST1-1]
DR RefSeq; NP_079501.2; NM_025225.2. [Q9NST1-1]
DR AlphaFoldDB; Q9NST1; -.
DR SMR; Q9NST1; -.
DR BioGRID; 123247; 7.
DR IntAct; Q9NST1; 5.
DR STRING; 9606.ENSP00000216180; -.
DR SwissLipids; SLP:000000282; -.
DR GlyGen; Q9NST1; 2 sites.
DR iPTMnet; Q9NST1; -.
DR PhosphoSitePlus; Q9NST1; -.
DR BioMuta; PNPLA3; -.
DR DMDM; 32469599; -.
DR EPD; Q9NST1; -.
DR MassIVE; Q9NST1; -.
DR MaxQB; Q9NST1; -.
DR PaxDb; Q9NST1; -.
DR PeptideAtlas; Q9NST1; -.
DR PRIDE; Q9NST1; -.
DR ProteomicsDB; 82577; -. [Q9NST1-1]
DR ProteomicsDB; 82578; -. [Q9NST1-2]
DR Antibodypedia; 27572; 246 antibodies from 32 providers.
DR DNASU; 80339; -.
DR Ensembl; ENST00000216180.8; ENSP00000216180.3; ENSG00000100344.11. [Q9NST1-1]
DR Ensembl; ENST00000423180.2; ENSP00000397987.2; ENSG00000100344.11. [Q9NST1-2]
DR GeneID; 80339; -.
DR KEGG; hsa:80339; -.
DR MANE-Select; ENST00000216180.8; ENSP00000216180.3; NM_025225.3; NP_079501.2.
DR UCSC; uc003bei.1; human. [Q9NST1-1]
DR CTD; 80339; -.
DR DisGeNET; 80339; -.
DR GeneCards; PNPLA3; -.
DR HGNC; HGNC:18590; PNPLA3.
DR HPA; ENSG00000100344; Tissue enriched (liver).
DR MIM; 609567; gene.
DR MIM; 613282; phenotype.
DR neXtProt; NX_Q9NST1; -.
DR OpenTargets; ENSG00000100344; -.
DR Orphanet; 33271; NON RARE IN EUROPE: Non-alcoholic fatty liver disease.
DR PharmGKB; PA38592; -.
DR VEuPathDB; HostDB:ENSG00000100344; -.
DR eggNOG; KOG3773; Eukaryota.
DR GeneTree; ENSGT00940000155662; -.
DR HOGENOM; CLU_018371_0_1_1; -.
DR InParanoid; Q9NST1; -.
DR OMA; LCSENVY; -.
DR OrthoDB; 1204225at2759; -.
DR PhylomeDB; Q9NST1; -.
DR TreeFam; TF314272; -.
DR PathwayCommons; Q9NST1; -.
DR Reactome; R-HSA-1482883; Acyl chain remodeling of DAG and TAG.
DR SignaLink; Q9NST1; -.
DR BioGRID-ORCS; 80339; 5 hits in 1065 CRISPR screens.
DR ChiTaRS; PNPLA3; human.
DR GeneWiki; PNPLA3; -.
DR GenomeRNAi; 80339; -.
DR Pharos; Q9NST1; Tbio.
DR PRO; PR:Q9NST1; -.
DR Proteomes; UP000005640; Chromosome 22.
DR RNAct; Q9NST1; protein.
DR Bgee; ENSG00000100344; Expressed in pigmented layer of retina and 131 other tissues.
DR ExpressionAtlas; Q9NST1; baseline and differential.
DR Genevisible; Q9NST1; HS.
DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
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:0005811; C:lipid droplet; IDA:UniProtKB.
DR GO; GO:0016020; C:membrane; IDA:BHF-UCL.
DR GO; GO:0003841; F:1-acylglycerol-3-phosphate O-acyltransferase activity; IDA:UniProtKB.
DR GO; GO:0016411; F:acylglycerol O-acyltransferase activity; TAS:Reactome.
DR GO; GO:0051265; F:diolein transacylation activity; IDA:UniProtKB.
DR GO; GO:0004465; F:lipoprotein lipase activity; TAS:Reactome.
DR GO; GO:0036042; F:long-chain fatty acyl-CoA binding; IDA:BHF-UCL.
DR GO; GO:0042171; F:lysophosphatidic acid acyltransferase activity; IDA:BHF-UCL.
DR GO; GO:0035727; F:lysophosphatidic acid binding; IDA:BHF-UCL.
DR GO; GO:0051264; F:mono-olein transacylation activity; IDA:UniProtKB.
DR GO; GO:0004623; F:phospholipase A2 activity; IDA:UniProtKB.
DR GO; GO:0004806; F:triglyceride lipase activity; IDA:UniProtKB.
DR GO; GO:0036155; P:acylglycerol acyl-chain remodeling; TAS:Reactome.
DR GO; GO:1905243; P:cellular response to 3,3',5-triiodo-L-thyronine; IEA:Ensembl.
DR GO; GO:0032869; P:cellular response to insulin stimulus; IEA:Ensembl.
DR GO; GO:0006650; P:glycerophospholipid metabolic process; IDA:BHF-UCL.
DR GO; GO:0034389; P:lipid droplet organization; IMP:BHF-UCL.
DR GO; GO:0055088; P:lipid homeostasis; IBA:GO_Central.
DR GO; GO:0001676; P:long-chain fatty acid metabolic process; IDA:BHF-UCL.
DR GO; GO:0006654; P:phosphatidic acid biosynthetic process; IDA:BHF-UCL.
DR GO; GO:0009744; P:response to sucrose; IEA:Ensembl.
DR GO; GO:0036153; P:triglyceride acyl-chain remodeling; IDA:CACAO.
DR GO; GO:0019432; P:triglyceride biosynthetic process; IDA:UniProtKB.
DR GO; GO:0019433; P:triglyceride catabolic process; IDA:UniProtKB.
DR GO; GO:0050872; P:white fat cell differentiation; IEA:Ensembl.
DR CDD; cd07221; Pat_PNPLA3; 1.
DR InterPro; IPR016035; Acyl_Trfase/lysoPLipase.
DR InterPro; IPR039185; Pat_PNPLA3.
DR InterPro; IPR033562; PLPL.
DR InterPro; IPR002641; PNPLA_dom.
DR PANTHER; PTHR12406; PTHR12406; 1.
DR Pfam; PF01734; Patatin; 1.
DR SUPFAM; SSF52151; SSF52151; 1.
DR PROSITE; PS51635; PNPLA; 1.
PE 1: Evidence at protein level;
KW Acyltransferase; Alternative splicing; Disease variant; Glycoprotein;
KW Hydrolase; Lipid biosynthesis; Lipid droplet; Lipid metabolism; Membrane;
KW Obesity; Phospholipid biosynthesis; Phospholipid metabolism;
KW Reference proteome; Signal-anchor; Transferase; Transmembrane;
KW Transmembrane helix.
FT CHAIN 1..481
FT /note="1-acylglycerol-3-phosphate O-acyltransferase PNPLA3"
FT /id="PRO_0000064458"
FT TOPO_DOM 1..41
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 42..62
FT /note="Helical; Signal-anchor for type II membrane protein"
FT /evidence="ECO:0000255"
FT TOPO_DOM 63..481
FT /note="Lumenal"
FT /evidence="ECO:0000255"
FT DOMAIN 10..179
FT /note="PNPLA"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01161"
FT MOTIF 14..19
FT /note="GXGXXG"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01161"
FT MOTIF 45..49
FT /note="GXSXG"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01161"
FT MOTIF 166..168
FT /note="DGA/G"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01161"
FT ACT_SITE 47
FT /note="Nucleophile"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01161"
FT ACT_SITE 166
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01161"
FT CARBOHYD 89
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 280
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT VAR_SEQ 59..62
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_036222"
FT VARIANT 76
FT /note="A -> T (in NAFLD1; unknown pathological
FT significance; dbSNP:rs746140741)"
FT /evidence="ECO:0000269|PubMed:27288299"
FT /id="VAR_077543"
FT VARIANT 99
FT /note="C -> G (in dbSNP:rs2076213)"
FT /evidence="ECO:0000269|PubMed:15489334"
FT /id="VAR_015845"
FT VARIANT 104
FT /note="A -> V (in NAFLD1; unknown pathological
FT significance)"
FT /evidence="ECO:0000269|PubMed:27288299"
FT /id="VAR_077544"
FT VARIANT 115
FT /note="G -> C (in dbSNP:rs2076212)"
FT /evidence="ECO:0000269|PubMed:14702039"
FT /id="VAR_015846"
FT VARIANT 148
FT /note="I -> M (associated with increased hepatic fat
FT content and serum aspartate aminotransferase
FT concentrations; increases 1-acylglycerol-3-phosphate O-
FT acyltransferase activity 2-fold; may reduce
FT triacylglycerol, diacylglycerol and monoacylglycerol
FT hydrolase activity; dbSNP:rs738409)"
FT /evidence="ECO:0000269|PubMed:14702039,
FT ECO:0000269|PubMed:15489334, ECO:0000269|PubMed:18728122,
FT ECO:0000269|PubMed:18820647, ECO:0000269|PubMed:19224197,
FT ECO:0000269|PubMed:19738004, ECO:0000269|PubMed:20034933,
FT ECO:0000269|PubMed:21878620, ECO:0000269|PubMed:22560221"
FT /id="VAR_019961"
FT VARIANT 200
FT /note="T -> M (in NAFLD1; unknown pathological
FT significance; dbSNP:rs190477302)"
FT /evidence="ECO:0000269|PubMed:27288299"
FT /id="VAR_077545"
FT VARIANT 216
FT /note="T -> P (in dbSNP:rs35726887)"
FT /id="VAR_053814"
FT VARIANT 434
FT /note="K -> E (in dbSNP:rs2294918)"
FT /evidence="ECO:0000269|PubMed:14702039,
FT ECO:0000269|PubMed:15461802, ECO:0000269|PubMed:15489334,
FT ECO:0000269|Ref.5"
FT /id="VAR_015847"
FT VARIANT 453
FT /note="S -> I (associated with lower hepatic fat content in
FT African Americans; dbSNP:rs6006460)"
FT /evidence="ECO:0000269|PubMed:18820647"
FT /id="VAR_053815"
FT MUTAGEN 15
FT /note="C->S: 65% loss of 1-acylglycerol-3-phosphate O-
FT acyltransferase catalytic activity."
FT /evidence="ECO:0000269|PubMed:22560221"
FT MUTAGEN 47
FT /note="S->A: No effect on 1-acylglycerol-3-phosphate O-
FT acyltransferase catalytic activity. Almost completely
FT abolishes triacylglycerol, diacylglycerol and
FT monoacylglycerol hydrolase activity."
FT /evidence="ECO:0000269|PubMed:21878620,
FT ECO:0000269|PubMed:22560221"
FT MUTAGEN 206
FT /note="D->A: No effect on 1-acylglycerol-3-phosphate O-
FT acyltransferase catalytic activity."
FT /evidence="ECO:0000269|PubMed:22560221"
FT MUTAGEN 311
FT /note="P->G: 67% loss of 1-acylglycerol-3-phosphate O-
FT acyltransferase catalytic activity."
FT /evidence="ECO:0000269|PubMed:22560221"
SQ SEQUENCE 481 AA; 52865 MW; 1ED0341B5AF5B6CB CRC64;
MYDAERGWSL SFAGCGFLGF YHVGATRCLS EHAPHLLRDA RMLFGASAGA LHCVGVLSGI
PLEQTLQVLS DLVRKARSRN IGIFHPSFNL SKFLRQGLCK CLPANVHQLI SGKIGISLTR
VSDGENVLVS DFRSKDEVVD ALVCSCFIPF YSGLIPPSFR GVRYVDGGVS DNVPFIDAKT
TITVSPFYGE YDICPKVKST NFLHVDITKL SLRLCTGNLY LLSRAFVPPD LKVLGEICLR
GYLDAFRFLE EKGICNRPQP GLKSSSEGMD PEVAMPSWAN MSLDSSPESA ALAVRLEGDE
LLDHLRLSIL PWDESILDTL SPRLATALSE EMKDKGGYMS KICNLLPIRI MSYVMLPCTL
PVESAIAIVQ RLVTWLPDMP DDVLWLQWVT SQVFTRVLMC LLPASRSQMP VSSQQASPCT
PEQDWPCWTP CSPKGCPAET KAEATPRSIL RSSLNFFLGN KVPAGAEGLS TFPSFSLEKS
L
