Full text data of FOLH1
FOLH1
(FOLH, NAALAD1, PSM, PSMA)
[Confidence: low (only semi-automatic identification from reviews)]
Glutamate carboxypeptidase 2; 3.4.17.21 (Cell growth-inhibiting gene 27 protein; Folate hydrolase 1; Folylpoly-gamma-glutamate carboxypeptidase; FGCP; Glutamate carboxypeptidase II; GCPII; Membrane glutamate carboxypeptidase; mGCP; N-acetylated-alpha-linked acidic dipeptidase I; NAALADase I; Prostate-specific membrane antigen; PSM; PSMA; Pteroylpoly-gamma-glutamate carboxypeptidase)
Glutamate carboxypeptidase 2; 3.4.17.21 (Cell growth-inhibiting gene 27 protein; Folate hydrolase 1; Folylpoly-gamma-glutamate carboxypeptidase; FGCP; Glutamate carboxypeptidase II; GCPII; Membrane glutamate carboxypeptidase; mGCP; N-acetylated-alpha-linked acidic dipeptidase I; NAALADase I; Prostate-specific membrane antigen; PSM; PSMA; Pteroylpoly-gamma-glutamate carboxypeptidase)
UniProt
Q04609
ID FOLH1_HUMAN Reviewed; 750 AA.
AC Q04609; A4UU12; A9CB79; B7Z312; B7Z343; D3DQS5; E9PDX8; O43748;
read moreAC Q16305; Q541A4; Q8TAY3; Q9NP15; Q9NYE2; Q9P1P8;
DT 01-JUN-1994, integrated into UniProtKB/Swiss-Prot.
DT 01-JUN-1994, sequence version 1.
DT 22-JAN-2014, entry version 155.
DE RecName: Full=Glutamate carboxypeptidase 2;
DE EC=3.4.17.21;
DE AltName: Full=Cell growth-inhibiting gene 27 protein;
DE AltName: Full=Folate hydrolase 1;
DE AltName: Full=Folylpoly-gamma-glutamate carboxypeptidase;
DE Short=FGCP;
DE AltName: Full=Glutamate carboxypeptidase II;
DE Short=GCPII;
DE AltName: Full=Membrane glutamate carboxypeptidase;
DE Short=mGCP;
DE AltName: Full=N-acetylated-alpha-linked acidic dipeptidase I;
DE Short=NAALADase I;
DE AltName: Full=Prostate-specific membrane antigen;
DE Short=PSM;
DE Short=PSMA;
DE AltName: Full=Pteroylpoly-gamma-glutamate carboxypeptidase;
GN Name=FOLH1; Synonyms=FOLH, NAALAD1, PSM, PSMA; ORFNames=GIG27;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM PSMA-1), AND PARTIAL PROTEIN
RP SEQUENCE.
RC TISSUE=Prostatic carcinoma;
RX PubMed=8417812;
RA Israeli R.S., Powell C.T., Fair W.R., Heston W.D.W.;
RT "Molecular cloning of a complementary DNA encoding a prostate-specific
RT membrane antigen.";
RL Cancer Res. 53:227-230(1993).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM PSMA').
RC TISSUE=Prostate;
RX PubMed=7882349;
RA Su S.L., Huang I.-P., Fair W.R., Powell C.T., Heston W.D.W.;
RT "Alternatively spliced variants of prostate-specific membrane antigen
RT RNA: ratio of expression as a potential measurement of progression.";
RL Cancer Res. 55:1441-1443(1995).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM PSMA-1), AND VARIANT
RP HIS-75.
RX PubMed=9838072; DOI=10.1016/S0167-4781(98)00200-0;
RA O'Keefe D.S., Su S.L., Bacich D.J., Horiguchi Y., Luo Y., Powell C.T.,
RA Zandvliet D., Russell P.J., Molloy P.L., Nowak N.J., Shows T.B.,
RA Mullins C., Vonder Haar R.A., Fair W.R., Heston W.D.W.;
RT "Mapping, genomic organization and promoter analysis of the human
RT prostate-specific membrane antigen gene.";
RL Biochim. Biophys. Acta 1443:113-127(1998).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM PSMA-1).
RC TISSUE=Brain;
RX PubMed=9694964;
RA Luthi-Carter R., Barczak A.K., Speno H., Coyle J.T.;
RT "Molecular characterization of human brain N-acetylated alpha-linked
RT acidic dipeptidase (NAALADase).";
RL J. Pharmacol. Exp. Ther. 286:1020-1025(1998).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM PSMA-1), AND CHARACTERIZATION.
RC TISSUE=Prostate;
RX PubMed=10085079; DOI=10.1074/jbc.274.13.8470;
RA Pangalos M.N., Neefs J.-M., Somers M., Verhasselt P., Bekkers M.,
RA van der Helm L., Fraiponts E., Ashton D., Gordon R.D.;
RT "Isolation and expression of novel human glutamate carboxypeptidases
RT with N-acetylated alpha-linked acidic dipeptidase and dipeptidyl
RT peptidase IV activity.";
RL J. Biol. Chem. 274:8470-8483(1999).
RN [6]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM PSMA-1), AND VARIANT TYR-475.
RC TISSUE=Jejunum, and Small intestine;
RX PubMed=11092759; DOI=10.1093/hmg/9.19.2837;
RA Devlin A.M., Ling E.-H., Peerson J.M., Fernando S., Clarke R.,
RA Smith A.D., Halsted C.H.;
RT "Glutamate carboxypeptidase II: a polymorphism associated with lower
RT levels of serum folate and hyperhomocysteinemia.";
RL Hum. Mol. Genet. 9:2837-2844(2000).
RN [7]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM PSMA-1).
RC TISSUE=Prostatic carcinoma;
RA Ye C.Z., Zhang F.L., Zhang Y.K., Chen C.Q.;
RT "Cloning and sequencing of Chinese prostate-specific membrane
RT antigen.";
RL Mian Yi Xue Za Zhi 17:328-330(2001).
RN [8]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM PSMA-9).
RX PubMed=17929272; DOI=10.1002/pros.20664;
RA Cao K.Y., Mao X.P., Wang D.H., Xu L., Yuan G.Q., Dai S.Q., Zheng B.J.,
RA Qiu S.P.;
RT "High expression of PSM-E correlated with tumor grade in prostate
RT cancer: a new alternatively spliced variant of prostate-specific
RT membrane antigen.";
RL Prostate 67:1791-1800(2007).
RN [9]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RA Peace D.J., Zhang Y., Holt G., Ferrer K.T., Heller M., Sosman J.A.,
RA Xue B.H.;
RT "Identification of three novel splice variants of prostate-specific
RT membrane antigen.";
RL Submitted (NOV-1998) to the EMBL/GenBank/DDBJ databases.
RN [10]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM PSMA-8).
RA Kim J.W., Kim H.K., Shin S.M.;
RT "Identification of a cell growth-inhibiting gene.";
RL Submitted (JUN-2005) to the EMBL/GenBank/DDBJ databases.
RN [11]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS PSMA-1; PSMA-7 AND
RP 10).
RC TISSUE=Amygdala, Corpus callosum, and Hippocampus;
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.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA 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.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., 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 [12]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16554811; DOI=10.1038/nature04632;
RA Taylor T.D., Noguchi H., Totoki Y., Toyoda A., Kuroki Y., Dewar K.,
RA Lloyd C., Itoh T., Takeda T., Kim D.-W., She X., Barlow K.F.,
RA Bloom T., Bruford E., Chang J.L., Cuomo C.A., Eichler E.,
RA FitzGerald M.G., Jaffe D.B., LaButti K., Nicol R., Park H.-S.,
RA Seaman C., Sougnez C., Yang X., Zimmer A.R., Zody M.C., Birren B.W.,
RA Nusbaum C., Fujiyama A., Hattori M., Rogers J., Lander E.S.,
RA Sakaki Y.;
RT "Human chromosome 11 DNA sequence and analysis including novel gene
RT identification.";
RL Nature 440:497-500(2006).
RN [13]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [14]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM PSMA-8).
RC TISSUE=Lung;
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
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [15]
RP PARTIAL NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM PSMA-3), AND TISSUE
RP SPECIFICITY.
RC TISSUE=Prostate;
RX PubMed=9375657;
RA Bzdega T., Turi T., Wroblewska B., She D., Chung H.S., Kim H.,
RA Neale J.H.;
RT "Molecular cloning of a peptidase against N-acetylaspartylglutamate
RT from a rat hippocampal cDNA library.";
RL J. Neurochem. 69:2270-2277(1997).
RN [16]
RP PARTIAL NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM PSMA-4).
RA Lupold S.E., Criley S.C., Coffey D.S.;
RT "Alternative splicing of the prostate-specific membrane antigen.";
RL Submitted (APR-2000) to the EMBL/GenBank/DDBJ databases.
RN [17]
RP PROTEIN SEQUENCE OF 60-74, AND SUBCELLULAR LOCATION.
RC TISSUE=Prostatic carcinoma;
RX PubMed=9809977;
RA Grauer L.S., Lawler K.D., Marignac J.L., Kumar A., Goel A.S.,
RA Wolfert R.L.;
RT "Identification, purification, and subcellular localization of
RT prostate-specific membrane antigen PSM' protein in the LNCaP prostatic
RT carcinoma cell line.";
RL Cancer Res. 58:4787-4789(1998).
RN [18]
RP ALTERNATIVE SPLICING.
RA Bzdega T., She D., Turi T., Wroblewska B., Neale J.H.;
RT "Molecular cloning of alternatively spliced variants of the peptidase
RT against N-acetylaspartylglutamate (NAAG) from human and rat nervous
RT systems.";
RL Abstr. - Soc. Neurosci. 24:579-579(1998).
RN [19]
RP CHARACTERIZATION.
RX PubMed=9622670; DOI=10.1016/S0006-8993(98)00244-3;
RA Luthi-Carter R., Barczak A.K., Speno H.D., Coyle J.T.;
RT "Hydrolysis of the neuropeptide N-acetylaspartylglutamate (NAAG) by
RT cloned human glutamate carboxypeptidase II.";
RL Brain Res. 795:341-348(1998).
RN [20]
RP DOMAIN STRUCTURE.
RX PubMed=9187245; DOI=10.1016/S0167-4838(97)00008-3;
RA Rawlings N.D., Barrett A.J.;
RT "Structure of membrane glutamate carboxypeptidase.";
RL Biochim. Biophys. Acta 1339:247-252(1997).
RN [21]
RP MUTAGENESIS.
RX PubMed=9882712;
RA Speno H.S., Luthi-Carter R., Macias W.L., Valentine S.L.,
RA Joshi A.R.T., Coyle J.T.;
RT "Site-directed mutagenesis of predicted active site residues in
RT glutamate carboxypeptidase II.";
RL Mol. Pharmacol. 55:179-185(1999).
RN [22]
RP GLYCOSYLATION AT ASN-76; ASN-336; ASN-459; ASN-476 AND ASN-638.
RX PubMed=12754519; DOI=10.1038/nbt827;
RA Zhang H., Li X.-J., Martin D.B., Aebersold R.;
RT "Identification and quantification of N-linked glycoproteins using
RT hydrazide chemistry, stable isotope labeling and mass spectrometry.";
RL Nat. Biotechnol. 21:660-666(2003).
RN [23]
RP GLYCOSYLATION AT ASN-51; ASN-76; ASN-121; ASN-140; ASN-153; ASN-195;
RP ASN-336; ASN-459; ASN-476 AND ASN-638, AND MUTAGENESIS OF ASN-51;
RP ASN-76; ASN-121; ASN-140; ASN-153; ASN-195; ASN-336; ASN-459; ASN-476;
RP ASN-638 AND THR-640.
RX PubMed=15152093; DOI=10.1110/ps.04622104;
RA Barinka C., Sacha P., Sklenar J., Man P., Bezouska K., Slusher B.S.,
RA Konvalinka J.;
RT "Identification of the N-glycosylation sites on glutamate
RT carboxypeptidase II necessary for proteolytic activity.";
RL Protein Sci. 13:1627-1635(2004).
RN [24]
RP TISSUE SPECIFICITY.
RC TISSUE=Liver;
RX PubMed=14716746; DOI=10.1002/pros.10319;
RA O'Keefe D.S., Bacich D.J., Heston W.D.W.;
RT "Comparative analysis of prostate-specific membrane antigen (PSMA)
RT versus a prostate-specific membrane antigen-like gene.";
RL Prostate 58:200-210(2004).
RN [25]
RP TISSUE SPECIFICITY.
RX PubMed=16555021; DOI=10.1007/s00268-005-0544-5;
RA Kinoshita Y., Kuratsukuri K., Landas S., Imaida K., Rovito P.M. Jr.,
RA Wang C.Y., Haas G.P.;
RT "Expression of prostate-specific membrane antigen in normal and
RT malignant human tissues.";
RL World J. Surg. 30:628-636(2006).
RN [26]
RP TISSUE SPECIFICITY.
RX PubMed=17150306; DOI=10.1016/j.neuroscience.2006.10.022;
RA Sacha P., Zamecnik J., Barinka C., Hlouchova K., Vicha A.,
RA Mlcochova P., Hilgert I., Eckschlager T., Konvalinka J.;
RT "Expression of glutamate carboxypeptidase II in human brain.";
RL Neuroscience 144:1361-1372(2007).
RN [27]
RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 44-750 IN COMPLEXES WITH
RP GLUTAMATE; INHIBITORS; CALCIUM AND ZINC IONS, COFACTOR, SUBUNIT, AND
RP GLYCOSYLATION AT ASN-76; ASN-121; ASN-140; ASN-195; ASN-459; ASN-476
RP AND ASN-638.
RX PubMed=16467855; DOI=10.1038/sj.emboj.7600969;
RA Mesters J.R., Barinka C., Li W., Tsukamoto T., Majer P., Slusher B.S.,
RA Konvalinka J., Hilgenfeld R.;
RT "Structure of glutamate carboxypeptidase II, a drug target in neuronal
RT damage and prostate cancer.";
RL EMBO J. 25:1375-1384(2006).
RN [28]
RP X-RAY CRYSTALLOGRAPHY (2.19 ANGSTROMS) OF 44-750 IN COMPLEXES WITH THE
RP INHIBITORS QUISQUALATE AND 2-PMPA; CALCIUM AND ZINC IONS, AND
RP GLYCOSYLATION AT ASN-76; ASN-121; ASN-140; ASN-195; ASN-459; ASN-476
RP AND ASN-638.
RX PubMed=17372356; DOI=10.1107/S090744490700902X;
RA Mesters J.R., Henning K., Hilgenfeld R.;
RT "Human glutamate carboxypeptidase II inhibition: structures of GCPII
RT in complex with two potent inhibitors, quisqualate and 2-PMPA.";
RL Acta Crystallogr. D 63:508-513(2007).
RN [29]
RP X-RAY CRYSTALLOGRAPHY (1.62 ANGSTROMS) OF 44-750 IN COMPLEXES WITH
RP SUBSTRATE ANALOGS; CALCIUM AND ZINC IONS, ENZYME REGULATION, AND
RP GLYCOSYLATION AT ASN-76; ASN-121; ASN-140 ASN-195; ASN-459; ASN-476
RP AND ASN-638.
RX PubMed=17567119; DOI=10.1021/jm070133w;
RA Barinka C., Rovenska M., Mlcochova P., Hlouchova K., Plechanovova A.,
RA Majer P., Tsukamoto T., Slusher B.S., Konvalinka J., Lubkowski J.;
RT "Structural insight into the pharmacophore pocket of human glutamate
RT carboxypeptidase II.";
RL J. Med. Chem. 50:3267-3273(2007).
RN [30]
RP X-RAY CRYSTALLOGRAPHY (1.54 ANGSTROMS) OF 44-750 IN COMPLEXES WITH
RP UREA-BASED INHIBITORS; CALCIUM AND ZINC IONS, AND GLYCOSYLATION AT
RP ASN-76; ASN-121; ASN-140; ASN-195; ASN-459; ASN-476 AND ASN-638.
RX PubMed=19053759; DOI=10.1021/jm800765e;
RA Barinka C., Byun Y., Dusich C.L., Banerjee S.R., Chen Y.,
RA Castanares M., Kozikowski A.P., Mease R.C., Pomper M.G., Lubkowski J.;
RT "Interactions between human glutamate carboxypeptidase II and urea-
RT based inhibitors: structural characterization.";
RL J. Med. Chem. 51:7737-7743(2008).
RN [31]
RP X-RAY CRYSTALLOGRAPHY (1.5 ANGSTROMS) OF 44-750 IN COMPLEXES WITH
RP SUBSTRATE ANALOGS; CALCIUM AND ZINC IONS, AND GLYCOSYLATION AT ASN-76;
RP ASN-121; ASN-140; ASN-195; ASN-459; ASN-476 AND ASN-638.
RX PubMed=18234225; DOI=10.1016/j.jmb.2007.12.066;
RA Barinka C., Hlouchova K., Rovenska M., Majer P., Dauter M., Hin N.,
RA Ko Y.-S., Tsukamoto T., Slusher B.S., Konvalinka J., Lubkowski J.;
RT "Structural basis of interactions between human glutamate
RT carboxypeptidase II and its substrate analogs.";
RL J. Mol. Biol. 376:1438-1450(2008).
RN [32]
RP X-RAY CRYSTALLOGRAPHY (1.7 ANGSTROMS) OF 44-750 IN COMPLEX WITH
RP SUBSTRATE; CALCIUM AND ZINC IONS, GLYCOSYLATION AT ASN-76; ASN-121;
RP ASN-140; ASN-195; ASN-459; ASN-476 AND ASN-638, AND MUTAGENESIS OF
RP GLU-424.
RX PubMed=19301871; DOI=10.1021/bi900220s;
RA Klusak V., Barinka C., Plechanovova A., Mlcochova P., Konvalinka J.,
RA Rulisek L., Lubkowski J.;
RT "Reaction mechanism of glutamate carboxypeptidase II revealed by
RT mutagenesis, X-ray crystallography, and computational methods.";
RL Biochemistry 48:4126-4138(2009).
RN [33]
RP VARIANT [LARGE SCALE ANALYSIS] THR-23.
RX PubMed=16959974; DOI=10.1126/science.1133427;
RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S.,
RA Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J.,
RA Dawson D., Willson J.K.V., Gazdar A.F., Hartigan J., Wu L., Liu C.,
RA Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N.,
RA Vogelstein B., Kinzler K.W., Velculescu V.E.;
RT "The consensus coding sequences of human breast and colorectal
RT cancers.";
RL Science 314:268-274(2006).
CC -!- FUNCTION: Has both folate hydrolase and N-acetylated-alpha-linked-
CC acidic dipeptidase (NAALADase) activity. Has a preference for tri-
CC alpha-glutamate peptides. In the intestine, required for the
CC uptake of folate. In the brain, modulates excitatory
CC neurotransmission through the hydrolysis of the neuropeptide, N-
CC aceylaspartylglutamate (NAAG), thereby releasing glutamate.
CC Isoform PSM-4 and isoform PSM-5 would appear to be physiologically
CC irrelevant. Involved in prostate tumor progression.
CC -!- FUNCTION: Also exhibits a dipeptidyl-peptidase IV type activity.
CC In vitro, cleaves Gly-Pro-AMC.
CC -!- CATALYTIC ACTIVITY: Release of an unsubstituted, C-terminal
CC glutamyl residue, typically from Ac-Asp-Glu or folylpoly-gamma-
CC glutamates.
CC -!- COFACTOR: Binds 2 zinc ions per subunit. Required for NAALADase
CC activity.
CC -!- ENZYME REGULATION: The NAALADase activity is inhibited by beta-
CC NAAG, quisqualic acid, 2-(phosphonomethyl) pentanedioic acid
CC (PMPA) and EDTA. Activated by cobalt.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC pH dependence:
CC Stable at pH greater than 6.5;
CC -!- SUBUNIT: Homodimer.
CC -!- SUBCELLULAR LOCATION: Cell membrane; Single-pass type II membrane
CC protein.
CC -!- SUBCELLULAR LOCATION: Isoform PSMA': Cytoplasm.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=8;
CC Name=PSMA-1;
CC IsoId=Q04609-1; Sequence=Displayed;
CC Note=No experimental confirmation available;
CC Name=PSMA-3;
CC IsoId=Q04609-3; Sequence=VSP_040242, VSP_040245;
CC Note=No experimental confirmation available. Incomplete
CC sequence;
CC Name=PSMA-4;
CC IsoId=Q04609-4; Sequence=VSP_040241, VSP_040243, VSP_040244;
CC Note=No experimental confirmation available. Incomplete
CC sequence;
CC Name=PSMA';
CC IsoId=Q04609-6; Sequence=VSP_005336;
CC Name=PSMA-7;
CC IsoId=Q04609-7; Sequence=VSP_038058;
CC Name=PSMA-8;
CC IsoId=Q04609-8; Sequence=VSP_038059;
CC Name=PSMA-9; Synonyms=PSM-E;
CC IsoId=Q04609-9; Sequence=VSP_038058, VSP_038059;
CC Name=10;
CC IsoId=Q04609-10; Sequence=VSP_044287;
CC -!- TISSUE SPECIFICITY: Highly expressed in prostate epithelium.
CC Detected in urinary bladder, kidney, testis, ovary, fallopian
CC tube, breast, adrenal gland, liver, esophagus, stomach, small
CC intestine, colon and brain (at protein level). Detected in the
CC small intestine, brain, kidney, liver, spleen, colon, trachea,
CC spinal cord and the capillary endothelium of a variety of tumors.
CC Expressed specifically in jejunum brush border membranes. In the
CC brain, highly expressed in the ventral striatum and brain stem.
CC Also expressed in fetal liver and kidney. Isoform PSMA' is the
CC most abundant form in normal prostate. Isoform PSMA-1 is the most
CC abundant form in primary prostate tumors. Isoform PSMA-2 is also
CC found in normal prostate as well as in brain and liver. Isoform
CC PSMA-9 is specifically expressed in prostate cancer.
CC -!- INDUCTION: In the prostate, up-regulated in response to androgen
CC deprivation.
CC -!- DOMAIN: The NAALADase activity is found in the central region, the
CC dipeptidyl peptidase IV type activity in the C-terminal.
CC -!- PTM: The first two amino acids at the N-terminus of isoform PSMA'
CC appear to be cleaved by limited proteolysis.
CC -!- PTM: The N-terminus is blocked.
CC -!- POLYMORPHISM: Genetic variation in FOLH1 may be associated with
CC low folate levels and consequent hyperhomocysteinemia. This
CC condition can result in increased risk of cardiovascular disease,
CC neural tube defects, and cognitive deficits.
CC -!- MISCELLANEOUS: PSMA is used as a diagnostic and prognostic
CC indicator of prostate cancer, and as a possible marker for various
CC neurological disorders such as schizophrenia, Alzheimer disease
CC and Huntington disease.
CC -!- SIMILARITY: Belongs to the peptidase M28 family. M28B subfamily.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAF31167.1; Type=Erroneous gene model prediction;
CC -----------------------------------------------------------------------
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DR EMBL; M99487; AAA60209.1; -; mRNA.
DR EMBL; S76978; AAB33750.2; -; mRNA.
DR EMBL; AF007544; AAC83972.1; -; Genomic_DNA.
DR EMBL; AF176574; AAD51121.1; -; mRNA.
DR EMBL; EF488811; ABO93402.2; -; mRNA.
DR EMBL; AY101595; AAM34479.1; -; mRNA.
DR EMBL; AF107214; AAF31167.1; ALT_SEQ; Genomic_DNA.
DR EMBL; DQ088979; AAZ66619.1; -; mRNA.
DR EMBL; AK312366; BAG35284.1; -; mRNA.
DR EMBL; AK295368; BAH12048.1; -; mRNA.
DR EMBL; AK295470; BAH12079.1; -; mRNA.
DR EMBL; AC110742; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC118273; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471064; EAW67858.1; -; Genomic_DNA.
DR EMBL; CH471064; EAW67861.1; -; Genomic_DNA.
DR EMBL; CH471064; EAW67857.1; -; Genomic_DNA.
DR EMBL; CH471064; EAW67859.1; -; Genomic_DNA.
DR EMBL; BC025672; AAH25672.1; -; mRNA.
DR EMBL; AF254358; AAF71358.1; -; mRNA.
DR EMBL; AF254357; AAF71357.1; -; mRNA.
DR PIR; A56881; A56881.
DR RefSeq; NP_001014986.1; NM_001014986.1.
DR RefSeq; NP_001180400.1; NM_001193471.1.
DR RefSeq; NP_001180401.1; NM_001193472.1.
DR RefSeq; NP_001180402.1; NM_001193473.1.
DR RefSeq; NP_004467.1; NM_004476.1.
DR UniGene; Hs.654487; -.
DR PDB; 1Z8L; X-ray; 3.50 A; A/B/C/D=56-750.
DR PDB; 2C6C; X-ray; 2.00 A; A=44-750.
DR PDB; 2C6G; X-ray; 2.20 A; A=44-750.
DR PDB; 2C6P; X-ray; 2.39 A; A=44-750.
DR PDB; 2CIJ; X-ray; 2.40 A; A=44-750.
DR PDB; 2JBJ; X-ray; 2.19 A; A=44-750.
DR PDB; 2JBK; X-ray; 2.99 A; A=44-750.
DR PDB; 2OOT; X-ray; 1.64 A; A=44-750.
DR PDB; 2OR4; X-ray; 1.62 A; A=44-750.
DR PDB; 2PVV; X-ray; 2.11 A; A=44-750.
DR PDB; 2PVW; X-ray; 1.71 A; A=44-750.
DR PDB; 2XEF; X-ray; 1.59 A; A=44-750.
DR PDB; 2XEG; X-ray; 1.59 A; A=44-750.
DR PDB; 2XEI; X-ray; 1.69 A; A=44-750.
DR PDB; 2XEJ; X-ray; 1.78 A; A=44-750.
DR PDB; 3BHX; X-ray; 1.60 A; A=44-750.
DR PDB; 3BI0; X-ray; 1.67 A; A=44-750.
DR PDB; 3BI1; X-ray; 1.50 A; A=44-750.
DR PDB; 3BXM; X-ray; 1.71 A; A=44-750.
DR PDB; 3D7D; X-ray; 1.69 A; A=44-750.
DR PDB; 3D7F; X-ray; 1.54 A; A=44-750.
DR PDB; 3D7G; X-ray; 1.75 A; A=44-750.
DR PDB; 3D7H; X-ray; 1.55 A; A=44-750.
DR PDB; 3IWW; X-ray; 2.30 A; A=44-750.
DR PDB; 3RBU; X-ray; 1.60 A; A=44-750.
DR PDB; 3SJE; X-ray; 1.70 A; A=44-750.
DR PDB; 3SJF; X-ray; 1.65 A; A=44-750.
DR PDB; 3SJG; X-ray; 1.65 A; A=44-750.
DR PDB; 3SJX; X-ray; 1.66 A; A=44-750.
DR PDBsum; 1Z8L; -.
DR PDBsum; 2C6C; -.
DR PDBsum; 2C6G; -.
DR PDBsum; 2C6P; -.
DR PDBsum; 2CIJ; -.
DR PDBsum; 2JBJ; -.
DR PDBsum; 2JBK; -.
DR PDBsum; 2OOT; -.
DR PDBsum; 2OR4; -.
DR PDBsum; 2PVV; -.
DR PDBsum; 2PVW; -.
DR PDBsum; 2XEF; -.
DR PDBsum; 2XEG; -.
DR PDBsum; 2XEI; -.
DR PDBsum; 2XEJ; -.
DR PDBsum; 3BHX; -.
DR PDBsum; 3BI0; -.
DR PDBsum; 3BI1; -.
DR PDBsum; 3BXM; -.
DR PDBsum; 3D7D; -.
DR PDBsum; 3D7F; -.
DR PDBsum; 3D7G; -.
DR PDBsum; 3D7H; -.
DR PDBsum; 3IWW; -.
DR PDBsum; 3RBU; -.
DR PDBsum; 3SJE; -.
DR PDBsum; 3SJF; -.
DR PDBsum; 3SJG; -.
DR PDBsum; 3SJX; -.
DR ProteinModelPortal; Q04609; -.
DR SMR; Q04609; 55-750.
DR IntAct; Q04609; 4.
DR MINT; MINT-3025010; -.
DR BindingDB; Q04609; -.
DR ChEMBL; CHEMBL1892; -.
DR DrugBank; DB00089; Capromab.
DR DrugBank; DB00142; L-Glutamic Acid.
DR MEROPS; M28.010; -.
DR PhosphoSite; Q04609; -.
DR DMDM; 548615; -.
DR PaxDb; Q04609; -.
DR PRIDE; Q04609; -.
DR DNASU; 2346; -.
DR Ensembl; ENST00000256999; ENSP00000256999; ENSG00000086205.
DR Ensembl; ENST00000340334; ENSP00000344131; ENSG00000086205.
DR Ensembl; ENST00000343844; ENSP00000344086; ENSG00000086205.
DR Ensembl; ENST00000356696; ENSP00000349129; ENSG00000086205.
DR Ensembl; ENST00000533034; ENSP00000431463; ENSG00000086205.
DR GeneID; 2346; -.
DR KEGG; hsa:2346; -.
DR UCSC; uc001ngy.3; human.
DR CTD; 2346; -.
DR GeneCards; GC11M049168; -.
DR H-InvDB; HIX0129475; -.
DR HGNC; HGNC:3788; FOLH1.
DR HPA; CAB001451; -.
DR HPA; HPA010593; -.
DR MIM; 600934; gene.
DR neXtProt; NX_Q04609; -.
DR PharmGKB; PA28205; -.
DR eggNOG; NOG74799; -.
DR HOVERGEN; HBG051639; -.
DR KO; K14592; -.
DR OMA; QDFDKSN; -.
DR OrthoDB; EOG7QK0BC; -.
DR PhylomeDB; Q04609; -.
DR EvolutionaryTrace; Q04609; -.
DR GeneWiki; Glutamate_carboxypeptidase_II; -.
DR GenomeRNAi; 2346; -.
DR NextBio; 9513; -.
DR PRO; PR:Q04609; -.
DR ArrayExpress; Q04609; -.
DR Bgee; Q04609; -.
DR CleanEx; HS_FOLH1; -.
DR Genevestigator; Q04609; -.
DR GO; GO:0005737; C:cytoplasm; IDA:HPA.
DR GO; GO:0005887; C:integral to plasma membrane; TAS:ProtInc.
DR GO; GO:0005634; C:nucleus; IDA:HPA.
DR GO; GO:0004180; F:carboxypeptidase activity; IEA:UniProtKB-KW.
DR GO; GO:0016805; F:dipeptidase activity; IEA:UniProtKB-KW.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0008237; F:metallopeptidase activity; IEA:UniProtKB-KW.
DR GO; GO:0008233; F:peptidase activity; NAS:UniProtKB.
DR GO; GO:0006760; P:folic acid-containing compound metabolic process; IEA:Ensembl.
DR GO; GO:0006508; P:proteolysis; NAS:UniProtKB.
DR Gene3D; 1.20.930.40; -; 1.
DR InterPro; IPR007484; Peptidase_M28.
DR InterPro; IPR003137; Protease-assoc_domain.
DR InterPro; IPR007365; TFR-like_dimer_dom.
DR Pfam; PF02225; PA; 1.
DR Pfam; PF04389; Peptidase_M28; 1.
DR Pfam; PF04253; TFR_dimer; 1.
DR SUPFAM; SSF47672; SSF47672; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Calcium; Carboxypeptidase;
KW Cell membrane; Complete proteome; Cytoplasm; Dipeptidase;
KW Direct protein sequencing; Glycoprotein; Hydrolase; Membrane;
KW Metal-binding; Metalloprotease; Multifunctional enzyme; Polymorphism;
KW Protease; Reference proteome; Signal-anchor; Transmembrane;
KW Transmembrane helix; Zinc.
FT CHAIN 1 750 Glutamate carboxypeptidase 2.
FT /FTId=PRO_0000174117.
FT TOPO_DOM 1 19 Cytoplasmic (Probable).
FT TRANSMEM 20 43 Helical; Signal-anchor for type II
FT membrane protein; (Probable).
FT TOPO_DOM 44 750 Extracellular (Probable).
FT REGION 274 587 NAALADase.
FT REGION 534 536 Substrate binding.
FT REGION 699 700 Substrate binding.
FT COMPBIAS 146 149 Poly-Pro.
FT ACT_SITE 424 424 For NAALADase activity.
FT ACT_SITE 628 628 Charge relay system (Potential).
FT ACT_SITE 666 666 Charge relay system (Potential).
FT ACT_SITE 689 689 Charge relay system (Potential).
FT METAL 269 269 Calcium.
FT METAL 272 272 Calcium; via carbonyl oxygen.
FT METAL 377 377 Zinc 1.
FT METAL 387 387 Zinc 1.
FT METAL 387 387 Zinc 2.
FT METAL 425 425 Zinc 2.
FT METAL 433 433 Calcium.
FT METAL 436 436 Calcium.
FT METAL 453 453 Zinc 1.
FT METAL 553 553 Zinc 2.
FT BINDING 210 210 Substrate.
FT BINDING 257 257 Substrate.
FT BINDING 519 519 Substrate.
FT BINDING 552 552 Substrate.
FT CARBOHYD 51 51 N-linked (GlcNAc...).
FT CARBOHYD 76 76 N-linked (GlcNAc...).
FT CARBOHYD 121 121 N-linked (GlcNAc...).
FT CARBOHYD 140 140 N-linked (GlcNAc...).
FT CARBOHYD 153 153 N-linked (GlcNAc...).
FT CARBOHYD 195 195 N-linked (GlcNAc...).
FT CARBOHYD 336 336 N-linked (GlcNAc...).
FT CARBOHYD 459 459 N-linked (GlcNAc...).
FT CARBOHYD 476 476 N-linked (GlcNAc...).
FT CARBOHYD 638 638 N-linked (GlcNAc...).
FT VAR_SEQ 1 585 Missing (in isoform PSMA-3).
FT /FTId=VSP_040242.
FT VAR_SEQ 1 308 Missing (in isoform 10).
FT /FTId=VSP_044287.
FT VAR_SEQ 1 159 Missing (in isoform PSMA-4).
FT /FTId=VSP_040241.
FT VAR_SEQ 1 57 Missing (in isoform PSMA').
FT /FTId=VSP_005336.
FT VAR_SEQ 1 39 MWNLLHETDSAVATARRPRWLCAGALVLAGGFFLLGFLF
FT -> MTAGSSYPLFLAAYACTGCLAERL (in isoform
FT PSMA-7 and isoform PSMA-9).
FT /FTId=VSP_038058.
FT VAR_SEQ 214 243 VKNAQLAGAKGVILYSDPADYFAPGVKSYP -> NMLIGVE
FT LQRLLVFQVFLFIQLDTMMHRSS (in isoform PSMA-
FT 4).
FT /FTId=VSP_040243.
FT VAR_SEQ 244 750 Missing (in isoform PSMA-4).
FT /FTId=VSP_040244.
FT VAR_SEQ 657 750 NPIVLRMMNDQLMFLERAFIDPLGLPDRPFYRHVIYAPSSH
FT NKYAGESFPGIYDALFDIESKVDPSKAWGEVKRQIYVAAFT
FT VQAAAETLSEVA -> MSSMLQAATTSMQGSHSQEFMMLCL
FT ILKAKWTLPRPGEK (in isoform PSMA-3).
FT /FTId=VSP_040245.
FT VAR_SEQ 657 688 NPIVLRMMNDQLMFLERAFIDPLGLPDRPFYR -> K (in
FT isoform PSMA-8 and isoform PSMA-9).
FT /FTId=VSP_038059.
FT VARIANT 23 23 A -> T (in a colorectal cancer sample;
FT somatic mutation).
FT /FTId=VAR_036398.
FT VARIANT 75 75 Y -> H (in dbSNP:rs202676).
FT /FTId=VAR_024592.
FT VARIANT 475 475 H -> Y (can be associated with lower
FT folate and higher homocysteine levels;
FT dbSNP:rs61886492).
FT /FTId=VAR_012736.
FT VARIANT 627 627 V -> L (in dbSNP:rs2988342).
FT /FTId=VAR_028882.
FT MUTAGEN 51 51 N->A: Loss of glycosylation. Reduces
FT enzyme activity.
FT MUTAGEN 76 76 N->A: Loss of glycosylation. Reduces
FT enzyme activity.
FT MUTAGEN 121 121 N->A: Loss of glycosylation. Severely
FT reduced enzyme activity.
FT MUTAGEN 140 140 N->A: Loss of glycosylation. Severely
FT reduced enzyme activity.
FT MUTAGEN 153 153 N->A: Loss of glycosylation. Severely
FT reduced enzyme activity.
FT MUTAGEN 195 195 N->A: Loss of glycosylation. Severely
FT reduced enzyme activity.
FT MUTAGEN 336 336 N->A: Loss of glycosylation. Reduces
FT enzyme activity.
FT MUTAGEN 377 377 H->A,G,Q: Complete loss of activity.
FT MUTAGEN 379 379 D->E,N: Complete loss of activity.
FT MUTAGEN 387 387 D->E,L: Complete loss of activity.
FT MUTAGEN 387 387 D->N: No effect on enzyme activity.
FT MUTAGEN 388 388 P->A: No effect on enzyme activity.
FT MUTAGEN 424 424 E->A: Complete loss of activity.
FT MUTAGEN 424 424 E->D: Reduces enzyme activity.
FT MUTAGEN 424 424 E->Q: Reduces enzyme activity.
FT MUTAGEN 425 425 E->Q,D: Complete loss of activity.
FT MUTAGEN 453 453 D->N,L: Complete loss of activity.
FT MUTAGEN 453 453 D->Q: Reduces enzyme activity.
FT MUTAGEN 454 454 S->A: Reduces enzyme activity.
FT MUTAGEN 459 459 N->A: Loss of glycosylation. Reduces
FT enzyme activity.
FT MUTAGEN 476 476 N->A: Loss of glycosylation. Reduces
FT enzyme activity.
FT MUTAGEN 638 638 N->A: Loss of glycosylation. Abolishes
FT enzyme activity.
FT MUTAGEN 640 640 T->A: Abolishes enzyme activity.
FT CONFLICT 194 194 I -> V (in Ref. 9; AAZ66619).
FT CONFLICT 354 354 R -> K (in Ref. 1; AA sequence).
FT CONFLICT 398 398 I -> N (in Ref. 8; ABO93402).
FT HELIX 58 64
FT HELIX 67 77
FT STRAND 78 80
FT HELIX 87 103
FT STRAND 106 119
FT STRAND 122 124
FT STRAND 127 131
FT STRAND 137 140
FT TURN 149 151
FT HELIX 154 156
FT STRAND 174 176
FT HELIX 182 190
FT STRAND 200 204
FT HELIX 210 219
FT STRAND 223 228
FT HELIX 231 234
FT STRAND 244 247
FT STRAND 269 272
FT HELIX 283 285
FT STRAND 294 297
FT HELIX 299 306
FT HELIX 317 319
FT STRAND 322 325
FT STRAND 330 333
FT HELIX 335 337
FT STRAND 341 346
FT STRAND 349 362
FT STRAND 365 377
FT STRAND 381 383
FT TURN 385 388
FT HELIX 389 407
FT STRAND 413 423
FT HELIX 424 426
FT HELIX 429 445
FT STRAND 446 451
FT STRAND 455 457
FT STRAND 459 466
FT HELIX 468 470
FT HELIX 471 479
FT STRAND 480 482
FT TURN 486 490
FT HELIX 493 500
FT STRAND 504 506
FT STRAND 517 519
FT HELIX 521 526
FT STRAND 531 538
FT STRAND 541 543
FT TURN 545 547
FT TURN 550 553
FT HELIX 559 565
FT HELIX 571 589
FT HELIX 597 615
FT HELIX 619 624
FT HELIX 630 652
FT HELIX 658 673
FT STRAND 684 686
FT STRAND 689 695
FT STRAND 698 705
FT HELIX 706 712
FT HELIX 715 717
FT HELIX 721 744
SQ SEQUENCE 750 AA; 84331 MW; AD8C0A7DBF47901A CRC64;
MWNLLHETDS AVATARRPRW LCAGALVLAG GFFLLGFLFG WFIKSSNEAT NITPKHNMKA
FLDELKAENI KKFLYNFTQI PHLAGTEQNF QLAKQIQSQW KEFGLDSVEL AHYDVLLSYP
NKTHPNYISI INEDGNEIFN TSLFEPPPPG YENVSDIVPP FSAFSPQGMP EGDLVYVNYA
RTEDFFKLER DMKINCSGKI VIARYGKVFR GNKVKNAQLA GAKGVILYSD PADYFAPGVK
SYPDGWNLPG GGVQRGNILN LNGAGDPLTP GYPANEYAYR RGIAEAVGLP SIPVHPIGYY
DAQKLLEKMG GSAPPDSSWR GSLKVPYNVG PGFTGNFSTQ KVKMHIHSTN EVTRIYNVIG
TLRGAVEPDR YVILGGHRDS WVFGGIDPQS GAAVVHEIVR SFGTLKKEGW RPRRTILFAS
WDAEEFGLLG STEWAEENSR LLQERGVAYI NADSSIEGNY TLRVDCTPLM YSLVHNLTKE
LKSPDEGFEG KSLYESWTKK SPSPEFSGMP RISKLGSGND FEVFFQRLGI ASGRARYTKN
WETNKFSGYP LYHSVYETYE LVEKFYDPMF KYHLTVAQVR GGMVFELANS IVLPFDCRDY
AVVLRKYADK IYSISMKHPQ EMKTYSVSFD SLFSAVKNFT EIASKFSERL QDFDKSNPIV
LRMMNDQLMF LERAFIDPLG LPDRPFYRHV IYAPSSHNKY AGESFPGIYD ALFDIESKVD
PSKAWGEVKR QIYVAAFTVQ AAAETLSEVA
//
ID FOLH1_HUMAN Reviewed; 750 AA.
AC Q04609; A4UU12; A9CB79; B7Z312; B7Z343; D3DQS5; E9PDX8; O43748;
read moreAC Q16305; Q541A4; Q8TAY3; Q9NP15; Q9NYE2; Q9P1P8;
DT 01-JUN-1994, integrated into UniProtKB/Swiss-Prot.
DT 01-JUN-1994, sequence version 1.
DT 22-JAN-2014, entry version 155.
DE RecName: Full=Glutamate carboxypeptidase 2;
DE EC=3.4.17.21;
DE AltName: Full=Cell growth-inhibiting gene 27 protein;
DE AltName: Full=Folate hydrolase 1;
DE AltName: Full=Folylpoly-gamma-glutamate carboxypeptidase;
DE Short=FGCP;
DE AltName: Full=Glutamate carboxypeptidase II;
DE Short=GCPII;
DE AltName: Full=Membrane glutamate carboxypeptidase;
DE Short=mGCP;
DE AltName: Full=N-acetylated-alpha-linked acidic dipeptidase I;
DE Short=NAALADase I;
DE AltName: Full=Prostate-specific membrane antigen;
DE Short=PSM;
DE Short=PSMA;
DE AltName: Full=Pteroylpoly-gamma-glutamate carboxypeptidase;
GN Name=FOLH1; Synonyms=FOLH, NAALAD1, PSM, PSMA; ORFNames=GIG27;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM PSMA-1), AND PARTIAL PROTEIN
RP SEQUENCE.
RC TISSUE=Prostatic carcinoma;
RX PubMed=8417812;
RA Israeli R.S., Powell C.T., Fair W.R., Heston W.D.W.;
RT "Molecular cloning of a complementary DNA encoding a prostate-specific
RT membrane antigen.";
RL Cancer Res. 53:227-230(1993).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM PSMA').
RC TISSUE=Prostate;
RX PubMed=7882349;
RA Su S.L., Huang I.-P., Fair W.R., Powell C.T., Heston W.D.W.;
RT "Alternatively spliced variants of prostate-specific membrane antigen
RT RNA: ratio of expression as a potential measurement of progression.";
RL Cancer Res. 55:1441-1443(1995).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM PSMA-1), AND VARIANT
RP HIS-75.
RX PubMed=9838072; DOI=10.1016/S0167-4781(98)00200-0;
RA O'Keefe D.S., Su S.L., Bacich D.J., Horiguchi Y., Luo Y., Powell C.T.,
RA Zandvliet D., Russell P.J., Molloy P.L., Nowak N.J., Shows T.B.,
RA Mullins C., Vonder Haar R.A., Fair W.R., Heston W.D.W.;
RT "Mapping, genomic organization and promoter analysis of the human
RT prostate-specific membrane antigen gene.";
RL Biochim. Biophys. Acta 1443:113-127(1998).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM PSMA-1).
RC TISSUE=Brain;
RX PubMed=9694964;
RA Luthi-Carter R., Barczak A.K., Speno H., Coyle J.T.;
RT "Molecular characterization of human brain N-acetylated alpha-linked
RT acidic dipeptidase (NAALADase).";
RL J. Pharmacol. Exp. Ther. 286:1020-1025(1998).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM PSMA-1), AND CHARACTERIZATION.
RC TISSUE=Prostate;
RX PubMed=10085079; DOI=10.1074/jbc.274.13.8470;
RA Pangalos M.N., Neefs J.-M., Somers M., Verhasselt P., Bekkers M.,
RA van der Helm L., Fraiponts E., Ashton D., Gordon R.D.;
RT "Isolation and expression of novel human glutamate carboxypeptidases
RT with N-acetylated alpha-linked acidic dipeptidase and dipeptidyl
RT peptidase IV activity.";
RL J. Biol. Chem. 274:8470-8483(1999).
RN [6]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM PSMA-1), AND VARIANT TYR-475.
RC TISSUE=Jejunum, and Small intestine;
RX PubMed=11092759; DOI=10.1093/hmg/9.19.2837;
RA Devlin A.M., Ling E.-H., Peerson J.M., Fernando S., Clarke R.,
RA Smith A.D., Halsted C.H.;
RT "Glutamate carboxypeptidase II: a polymorphism associated with lower
RT levels of serum folate and hyperhomocysteinemia.";
RL Hum. Mol. Genet. 9:2837-2844(2000).
RN [7]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM PSMA-1).
RC TISSUE=Prostatic carcinoma;
RA Ye C.Z., Zhang F.L., Zhang Y.K., Chen C.Q.;
RT "Cloning and sequencing of Chinese prostate-specific membrane
RT antigen.";
RL Mian Yi Xue Za Zhi 17:328-330(2001).
RN [8]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM PSMA-9).
RX PubMed=17929272; DOI=10.1002/pros.20664;
RA Cao K.Y., Mao X.P., Wang D.H., Xu L., Yuan G.Q., Dai S.Q., Zheng B.J.,
RA Qiu S.P.;
RT "High expression of PSM-E correlated with tumor grade in prostate
RT cancer: a new alternatively spliced variant of prostate-specific
RT membrane antigen.";
RL Prostate 67:1791-1800(2007).
RN [9]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RA Peace D.J., Zhang Y., Holt G., Ferrer K.T., Heller M., Sosman J.A.,
RA Xue B.H.;
RT "Identification of three novel splice variants of prostate-specific
RT membrane antigen.";
RL Submitted (NOV-1998) to the EMBL/GenBank/DDBJ databases.
RN [10]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM PSMA-8).
RA Kim J.W., Kim H.K., Shin S.M.;
RT "Identification of a cell growth-inhibiting gene.";
RL Submitted (JUN-2005) to the EMBL/GenBank/DDBJ databases.
RN [11]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS PSMA-1; PSMA-7 AND
RP 10).
RC TISSUE=Amygdala, Corpus callosum, and Hippocampus;
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.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA 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.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., 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 [12]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16554811; DOI=10.1038/nature04632;
RA Taylor T.D., Noguchi H., Totoki Y., Toyoda A., Kuroki Y., Dewar K.,
RA Lloyd C., Itoh T., Takeda T., Kim D.-W., She X., Barlow K.F.,
RA Bloom T., Bruford E., Chang J.L., Cuomo C.A., Eichler E.,
RA FitzGerald M.G., Jaffe D.B., LaButti K., Nicol R., Park H.-S.,
RA Seaman C., Sougnez C., Yang X., Zimmer A.R., Zody M.C., Birren B.W.,
RA Nusbaum C., Fujiyama A., Hattori M., Rogers J., Lander E.S.,
RA Sakaki Y.;
RT "Human chromosome 11 DNA sequence and analysis including novel gene
RT identification.";
RL Nature 440:497-500(2006).
RN [13]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [14]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM PSMA-8).
RC TISSUE=Lung;
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
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [15]
RP PARTIAL NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM PSMA-3), AND TISSUE
RP SPECIFICITY.
RC TISSUE=Prostate;
RX PubMed=9375657;
RA Bzdega T., Turi T., Wroblewska B., She D., Chung H.S., Kim H.,
RA Neale J.H.;
RT "Molecular cloning of a peptidase against N-acetylaspartylglutamate
RT from a rat hippocampal cDNA library.";
RL J. Neurochem. 69:2270-2277(1997).
RN [16]
RP PARTIAL NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM PSMA-4).
RA Lupold S.E., Criley S.C., Coffey D.S.;
RT "Alternative splicing of the prostate-specific membrane antigen.";
RL Submitted (APR-2000) to the EMBL/GenBank/DDBJ databases.
RN [17]
RP PROTEIN SEQUENCE OF 60-74, AND SUBCELLULAR LOCATION.
RC TISSUE=Prostatic carcinoma;
RX PubMed=9809977;
RA Grauer L.S., Lawler K.D., Marignac J.L., Kumar A., Goel A.S.,
RA Wolfert R.L.;
RT "Identification, purification, and subcellular localization of
RT prostate-specific membrane antigen PSM' protein in the LNCaP prostatic
RT carcinoma cell line.";
RL Cancer Res. 58:4787-4789(1998).
RN [18]
RP ALTERNATIVE SPLICING.
RA Bzdega T., She D., Turi T., Wroblewska B., Neale J.H.;
RT "Molecular cloning of alternatively spliced variants of the peptidase
RT against N-acetylaspartylglutamate (NAAG) from human and rat nervous
RT systems.";
RL Abstr. - Soc. Neurosci. 24:579-579(1998).
RN [19]
RP CHARACTERIZATION.
RX PubMed=9622670; DOI=10.1016/S0006-8993(98)00244-3;
RA Luthi-Carter R., Barczak A.K., Speno H.D., Coyle J.T.;
RT "Hydrolysis of the neuropeptide N-acetylaspartylglutamate (NAAG) by
RT cloned human glutamate carboxypeptidase II.";
RL Brain Res. 795:341-348(1998).
RN [20]
RP DOMAIN STRUCTURE.
RX PubMed=9187245; DOI=10.1016/S0167-4838(97)00008-3;
RA Rawlings N.D., Barrett A.J.;
RT "Structure of membrane glutamate carboxypeptidase.";
RL Biochim. Biophys. Acta 1339:247-252(1997).
RN [21]
RP MUTAGENESIS.
RX PubMed=9882712;
RA Speno H.S., Luthi-Carter R., Macias W.L., Valentine S.L.,
RA Joshi A.R.T., Coyle J.T.;
RT "Site-directed mutagenesis of predicted active site residues in
RT glutamate carboxypeptidase II.";
RL Mol. Pharmacol. 55:179-185(1999).
RN [22]
RP GLYCOSYLATION AT ASN-76; ASN-336; ASN-459; ASN-476 AND ASN-638.
RX PubMed=12754519; DOI=10.1038/nbt827;
RA Zhang H., Li X.-J., Martin D.B., Aebersold R.;
RT "Identification and quantification of N-linked glycoproteins using
RT hydrazide chemistry, stable isotope labeling and mass spectrometry.";
RL Nat. Biotechnol. 21:660-666(2003).
RN [23]
RP GLYCOSYLATION AT ASN-51; ASN-76; ASN-121; ASN-140; ASN-153; ASN-195;
RP ASN-336; ASN-459; ASN-476 AND ASN-638, AND MUTAGENESIS OF ASN-51;
RP ASN-76; ASN-121; ASN-140; ASN-153; ASN-195; ASN-336; ASN-459; ASN-476;
RP ASN-638 AND THR-640.
RX PubMed=15152093; DOI=10.1110/ps.04622104;
RA Barinka C., Sacha P., Sklenar J., Man P., Bezouska K., Slusher B.S.,
RA Konvalinka J.;
RT "Identification of the N-glycosylation sites on glutamate
RT carboxypeptidase II necessary for proteolytic activity.";
RL Protein Sci. 13:1627-1635(2004).
RN [24]
RP TISSUE SPECIFICITY.
RC TISSUE=Liver;
RX PubMed=14716746; DOI=10.1002/pros.10319;
RA O'Keefe D.S., Bacich D.J., Heston W.D.W.;
RT "Comparative analysis of prostate-specific membrane antigen (PSMA)
RT versus a prostate-specific membrane antigen-like gene.";
RL Prostate 58:200-210(2004).
RN [25]
RP TISSUE SPECIFICITY.
RX PubMed=16555021; DOI=10.1007/s00268-005-0544-5;
RA Kinoshita Y., Kuratsukuri K., Landas S., Imaida K., Rovito P.M. Jr.,
RA Wang C.Y., Haas G.P.;
RT "Expression of prostate-specific membrane antigen in normal and
RT malignant human tissues.";
RL World J. Surg. 30:628-636(2006).
RN [26]
RP TISSUE SPECIFICITY.
RX PubMed=17150306; DOI=10.1016/j.neuroscience.2006.10.022;
RA Sacha P., Zamecnik J., Barinka C., Hlouchova K., Vicha A.,
RA Mlcochova P., Hilgert I., Eckschlager T., Konvalinka J.;
RT "Expression of glutamate carboxypeptidase II in human brain.";
RL Neuroscience 144:1361-1372(2007).
RN [27]
RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 44-750 IN COMPLEXES WITH
RP GLUTAMATE; INHIBITORS; CALCIUM AND ZINC IONS, COFACTOR, SUBUNIT, AND
RP GLYCOSYLATION AT ASN-76; ASN-121; ASN-140; ASN-195; ASN-459; ASN-476
RP AND ASN-638.
RX PubMed=16467855; DOI=10.1038/sj.emboj.7600969;
RA Mesters J.R., Barinka C., Li W., Tsukamoto T., Majer P., Slusher B.S.,
RA Konvalinka J., Hilgenfeld R.;
RT "Structure of glutamate carboxypeptidase II, a drug target in neuronal
RT damage and prostate cancer.";
RL EMBO J. 25:1375-1384(2006).
RN [28]
RP X-RAY CRYSTALLOGRAPHY (2.19 ANGSTROMS) OF 44-750 IN COMPLEXES WITH THE
RP INHIBITORS QUISQUALATE AND 2-PMPA; CALCIUM AND ZINC IONS, AND
RP GLYCOSYLATION AT ASN-76; ASN-121; ASN-140; ASN-195; ASN-459; ASN-476
RP AND ASN-638.
RX PubMed=17372356; DOI=10.1107/S090744490700902X;
RA Mesters J.R., Henning K., Hilgenfeld R.;
RT "Human glutamate carboxypeptidase II inhibition: structures of GCPII
RT in complex with two potent inhibitors, quisqualate and 2-PMPA.";
RL Acta Crystallogr. D 63:508-513(2007).
RN [29]
RP X-RAY CRYSTALLOGRAPHY (1.62 ANGSTROMS) OF 44-750 IN COMPLEXES WITH
RP SUBSTRATE ANALOGS; CALCIUM AND ZINC IONS, ENZYME REGULATION, AND
RP GLYCOSYLATION AT ASN-76; ASN-121; ASN-140 ASN-195; ASN-459; ASN-476
RP AND ASN-638.
RX PubMed=17567119; DOI=10.1021/jm070133w;
RA Barinka C., Rovenska M., Mlcochova P., Hlouchova K., Plechanovova A.,
RA Majer P., Tsukamoto T., Slusher B.S., Konvalinka J., Lubkowski J.;
RT "Structural insight into the pharmacophore pocket of human glutamate
RT carboxypeptidase II.";
RL J. Med. Chem. 50:3267-3273(2007).
RN [30]
RP X-RAY CRYSTALLOGRAPHY (1.54 ANGSTROMS) OF 44-750 IN COMPLEXES WITH
RP UREA-BASED INHIBITORS; CALCIUM AND ZINC IONS, AND GLYCOSYLATION AT
RP ASN-76; ASN-121; ASN-140; ASN-195; ASN-459; ASN-476 AND ASN-638.
RX PubMed=19053759; DOI=10.1021/jm800765e;
RA Barinka C., Byun Y., Dusich C.L., Banerjee S.R., Chen Y.,
RA Castanares M., Kozikowski A.P., Mease R.C., Pomper M.G., Lubkowski J.;
RT "Interactions between human glutamate carboxypeptidase II and urea-
RT based inhibitors: structural characterization.";
RL J. Med. Chem. 51:7737-7743(2008).
RN [31]
RP X-RAY CRYSTALLOGRAPHY (1.5 ANGSTROMS) OF 44-750 IN COMPLEXES WITH
RP SUBSTRATE ANALOGS; CALCIUM AND ZINC IONS, AND GLYCOSYLATION AT ASN-76;
RP ASN-121; ASN-140; ASN-195; ASN-459; ASN-476 AND ASN-638.
RX PubMed=18234225; DOI=10.1016/j.jmb.2007.12.066;
RA Barinka C., Hlouchova K., Rovenska M., Majer P., Dauter M., Hin N.,
RA Ko Y.-S., Tsukamoto T., Slusher B.S., Konvalinka J., Lubkowski J.;
RT "Structural basis of interactions between human glutamate
RT carboxypeptidase II and its substrate analogs.";
RL J. Mol. Biol. 376:1438-1450(2008).
RN [32]
RP X-RAY CRYSTALLOGRAPHY (1.7 ANGSTROMS) OF 44-750 IN COMPLEX WITH
RP SUBSTRATE; CALCIUM AND ZINC IONS, GLYCOSYLATION AT ASN-76; ASN-121;
RP ASN-140; ASN-195; ASN-459; ASN-476 AND ASN-638, AND MUTAGENESIS OF
RP GLU-424.
RX PubMed=19301871; DOI=10.1021/bi900220s;
RA Klusak V., Barinka C., Plechanovova A., Mlcochova P., Konvalinka J.,
RA Rulisek L., Lubkowski J.;
RT "Reaction mechanism of glutamate carboxypeptidase II revealed by
RT mutagenesis, X-ray crystallography, and computational methods.";
RL Biochemistry 48:4126-4138(2009).
RN [33]
RP VARIANT [LARGE SCALE ANALYSIS] THR-23.
RX PubMed=16959974; DOI=10.1126/science.1133427;
RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S.,
RA Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J.,
RA Dawson D., Willson J.K.V., Gazdar A.F., Hartigan J., Wu L., Liu C.,
RA Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N.,
RA Vogelstein B., Kinzler K.W., Velculescu V.E.;
RT "The consensus coding sequences of human breast and colorectal
RT cancers.";
RL Science 314:268-274(2006).
CC -!- FUNCTION: Has both folate hydrolase and N-acetylated-alpha-linked-
CC acidic dipeptidase (NAALADase) activity. Has a preference for tri-
CC alpha-glutamate peptides. In the intestine, required for the
CC uptake of folate. In the brain, modulates excitatory
CC neurotransmission through the hydrolysis of the neuropeptide, N-
CC aceylaspartylglutamate (NAAG), thereby releasing glutamate.
CC Isoform PSM-4 and isoform PSM-5 would appear to be physiologically
CC irrelevant. Involved in prostate tumor progression.
CC -!- FUNCTION: Also exhibits a dipeptidyl-peptidase IV type activity.
CC In vitro, cleaves Gly-Pro-AMC.
CC -!- CATALYTIC ACTIVITY: Release of an unsubstituted, C-terminal
CC glutamyl residue, typically from Ac-Asp-Glu or folylpoly-gamma-
CC glutamates.
CC -!- COFACTOR: Binds 2 zinc ions per subunit. Required for NAALADase
CC activity.
CC -!- ENZYME REGULATION: The NAALADase activity is inhibited by beta-
CC NAAG, quisqualic acid, 2-(phosphonomethyl) pentanedioic acid
CC (PMPA) and EDTA. Activated by cobalt.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC pH dependence:
CC Stable at pH greater than 6.5;
CC -!- SUBUNIT: Homodimer.
CC -!- SUBCELLULAR LOCATION: Cell membrane; Single-pass type II membrane
CC protein.
CC -!- SUBCELLULAR LOCATION: Isoform PSMA': Cytoplasm.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=8;
CC Name=PSMA-1;
CC IsoId=Q04609-1; Sequence=Displayed;
CC Note=No experimental confirmation available;
CC Name=PSMA-3;
CC IsoId=Q04609-3; Sequence=VSP_040242, VSP_040245;
CC Note=No experimental confirmation available. Incomplete
CC sequence;
CC Name=PSMA-4;
CC IsoId=Q04609-4; Sequence=VSP_040241, VSP_040243, VSP_040244;
CC Note=No experimental confirmation available. Incomplete
CC sequence;
CC Name=PSMA';
CC IsoId=Q04609-6; Sequence=VSP_005336;
CC Name=PSMA-7;
CC IsoId=Q04609-7; Sequence=VSP_038058;
CC Name=PSMA-8;
CC IsoId=Q04609-8; Sequence=VSP_038059;
CC Name=PSMA-9; Synonyms=PSM-E;
CC IsoId=Q04609-9; Sequence=VSP_038058, VSP_038059;
CC Name=10;
CC IsoId=Q04609-10; Sequence=VSP_044287;
CC -!- TISSUE SPECIFICITY: Highly expressed in prostate epithelium.
CC Detected in urinary bladder, kidney, testis, ovary, fallopian
CC tube, breast, adrenal gland, liver, esophagus, stomach, small
CC intestine, colon and brain (at protein level). Detected in the
CC small intestine, brain, kidney, liver, spleen, colon, trachea,
CC spinal cord and the capillary endothelium of a variety of tumors.
CC Expressed specifically in jejunum brush border membranes. In the
CC brain, highly expressed in the ventral striatum and brain stem.
CC Also expressed in fetal liver and kidney. Isoform PSMA' is the
CC most abundant form in normal prostate. Isoform PSMA-1 is the most
CC abundant form in primary prostate tumors. Isoform PSMA-2 is also
CC found in normal prostate as well as in brain and liver. Isoform
CC PSMA-9 is specifically expressed in prostate cancer.
CC -!- INDUCTION: In the prostate, up-regulated in response to androgen
CC deprivation.
CC -!- DOMAIN: The NAALADase activity is found in the central region, the
CC dipeptidyl peptidase IV type activity in the C-terminal.
CC -!- PTM: The first two amino acids at the N-terminus of isoform PSMA'
CC appear to be cleaved by limited proteolysis.
CC -!- PTM: The N-terminus is blocked.
CC -!- POLYMORPHISM: Genetic variation in FOLH1 may be associated with
CC low folate levels and consequent hyperhomocysteinemia. This
CC condition can result in increased risk of cardiovascular disease,
CC neural tube defects, and cognitive deficits.
CC -!- MISCELLANEOUS: PSMA is used as a diagnostic and prognostic
CC indicator of prostate cancer, and as a possible marker for various
CC neurological disorders such as schizophrenia, Alzheimer disease
CC and Huntington disease.
CC -!- SIMILARITY: Belongs to the peptidase M28 family. M28B subfamily.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAF31167.1; Type=Erroneous gene model prediction;
CC -----------------------------------------------------------------------
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DR EMBL; M99487; AAA60209.1; -; mRNA.
DR EMBL; S76978; AAB33750.2; -; mRNA.
DR EMBL; AF007544; AAC83972.1; -; Genomic_DNA.
DR EMBL; AF176574; AAD51121.1; -; mRNA.
DR EMBL; EF488811; ABO93402.2; -; mRNA.
DR EMBL; AY101595; AAM34479.1; -; mRNA.
DR EMBL; AF107214; AAF31167.1; ALT_SEQ; Genomic_DNA.
DR EMBL; DQ088979; AAZ66619.1; -; mRNA.
DR EMBL; AK312366; BAG35284.1; -; mRNA.
DR EMBL; AK295368; BAH12048.1; -; mRNA.
DR EMBL; AK295470; BAH12079.1; -; mRNA.
DR EMBL; AC110742; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC118273; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471064; EAW67858.1; -; Genomic_DNA.
DR EMBL; CH471064; EAW67861.1; -; Genomic_DNA.
DR EMBL; CH471064; EAW67857.1; -; Genomic_DNA.
DR EMBL; CH471064; EAW67859.1; -; Genomic_DNA.
DR EMBL; BC025672; AAH25672.1; -; mRNA.
DR EMBL; AF254358; AAF71358.1; -; mRNA.
DR EMBL; AF254357; AAF71357.1; -; mRNA.
DR PIR; A56881; A56881.
DR RefSeq; NP_001014986.1; NM_001014986.1.
DR RefSeq; NP_001180400.1; NM_001193471.1.
DR RefSeq; NP_001180401.1; NM_001193472.1.
DR RefSeq; NP_001180402.1; NM_001193473.1.
DR RefSeq; NP_004467.1; NM_004476.1.
DR UniGene; Hs.654487; -.
DR PDB; 1Z8L; X-ray; 3.50 A; A/B/C/D=56-750.
DR PDB; 2C6C; X-ray; 2.00 A; A=44-750.
DR PDB; 2C6G; X-ray; 2.20 A; A=44-750.
DR PDB; 2C6P; X-ray; 2.39 A; A=44-750.
DR PDB; 2CIJ; X-ray; 2.40 A; A=44-750.
DR PDB; 2JBJ; X-ray; 2.19 A; A=44-750.
DR PDB; 2JBK; X-ray; 2.99 A; A=44-750.
DR PDB; 2OOT; X-ray; 1.64 A; A=44-750.
DR PDB; 2OR4; X-ray; 1.62 A; A=44-750.
DR PDB; 2PVV; X-ray; 2.11 A; A=44-750.
DR PDB; 2PVW; X-ray; 1.71 A; A=44-750.
DR PDB; 2XEF; X-ray; 1.59 A; A=44-750.
DR PDB; 2XEG; X-ray; 1.59 A; A=44-750.
DR PDB; 2XEI; X-ray; 1.69 A; A=44-750.
DR PDB; 2XEJ; X-ray; 1.78 A; A=44-750.
DR PDB; 3BHX; X-ray; 1.60 A; A=44-750.
DR PDB; 3BI0; X-ray; 1.67 A; A=44-750.
DR PDB; 3BI1; X-ray; 1.50 A; A=44-750.
DR PDB; 3BXM; X-ray; 1.71 A; A=44-750.
DR PDB; 3D7D; X-ray; 1.69 A; A=44-750.
DR PDB; 3D7F; X-ray; 1.54 A; A=44-750.
DR PDB; 3D7G; X-ray; 1.75 A; A=44-750.
DR PDB; 3D7H; X-ray; 1.55 A; A=44-750.
DR PDB; 3IWW; X-ray; 2.30 A; A=44-750.
DR PDB; 3RBU; X-ray; 1.60 A; A=44-750.
DR PDB; 3SJE; X-ray; 1.70 A; A=44-750.
DR PDB; 3SJF; X-ray; 1.65 A; A=44-750.
DR PDB; 3SJG; X-ray; 1.65 A; A=44-750.
DR PDB; 3SJX; X-ray; 1.66 A; A=44-750.
DR PDBsum; 1Z8L; -.
DR PDBsum; 2C6C; -.
DR PDBsum; 2C6G; -.
DR PDBsum; 2C6P; -.
DR PDBsum; 2CIJ; -.
DR PDBsum; 2JBJ; -.
DR PDBsum; 2JBK; -.
DR PDBsum; 2OOT; -.
DR PDBsum; 2OR4; -.
DR PDBsum; 2PVV; -.
DR PDBsum; 2PVW; -.
DR PDBsum; 2XEF; -.
DR PDBsum; 2XEG; -.
DR PDBsum; 2XEI; -.
DR PDBsum; 2XEJ; -.
DR PDBsum; 3BHX; -.
DR PDBsum; 3BI0; -.
DR PDBsum; 3BI1; -.
DR PDBsum; 3BXM; -.
DR PDBsum; 3D7D; -.
DR PDBsum; 3D7F; -.
DR PDBsum; 3D7G; -.
DR PDBsum; 3D7H; -.
DR PDBsum; 3IWW; -.
DR PDBsum; 3RBU; -.
DR PDBsum; 3SJE; -.
DR PDBsum; 3SJF; -.
DR PDBsum; 3SJG; -.
DR PDBsum; 3SJX; -.
DR ProteinModelPortal; Q04609; -.
DR SMR; Q04609; 55-750.
DR IntAct; Q04609; 4.
DR MINT; MINT-3025010; -.
DR BindingDB; Q04609; -.
DR ChEMBL; CHEMBL1892; -.
DR DrugBank; DB00089; Capromab.
DR DrugBank; DB00142; L-Glutamic Acid.
DR MEROPS; M28.010; -.
DR PhosphoSite; Q04609; -.
DR DMDM; 548615; -.
DR PaxDb; Q04609; -.
DR PRIDE; Q04609; -.
DR DNASU; 2346; -.
DR Ensembl; ENST00000256999; ENSP00000256999; ENSG00000086205.
DR Ensembl; ENST00000340334; ENSP00000344131; ENSG00000086205.
DR Ensembl; ENST00000343844; ENSP00000344086; ENSG00000086205.
DR Ensembl; ENST00000356696; ENSP00000349129; ENSG00000086205.
DR Ensembl; ENST00000533034; ENSP00000431463; ENSG00000086205.
DR GeneID; 2346; -.
DR KEGG; hsa:2346; -.
DR UCSC; uc001ngy.3; human.
DR CTD; 2346; -.
DR GeneCards; GC11M049168; -.
DR H-InvDB; HIX0129475; -.
DR HGNC; HGNC:3788; FOLH1.
DR HPA; CAB001451; -.
DR HPA; HPA010593; -.
DR MIM; 600934; gene.
DR neXtProt; NX_Q04609; -.
DR PharmGKB; PA28205; -.
DR eggNOG; NOG74799; -.
DR HOVERGEN; HBG051639; -.
DR KO; K14592; -.
DR OMA; QDFDKSN; -.
DR OrthoDB; EOG7QK0BC; -.
DR PhylomeDB; Q04609; -.
DR EvolutionaryTrace; Q04609; -.
DR GeneWiki; Glutamate_carboxypeptidase_II; -.
DR GenomeRNAi; 2346; -.
DR NextBio; 9513; -.
DR PRO; PR:Q04609; -.
DR ArrayExpress; Q04609; -.
DR Bgee; Q04609; -.
DR CleanEx; HS_FOLH1; -.
DR Genevestigator; Q04609; -.
DR GO; GO:0005737; C:cytoplasm; IDA:HPA.
DR GO; GO:0005887; C:integral to plasma membrane; TAS:ProtInc.
DR GO; GO:0005634; C:nucleus; IDA:HPA.
DR GO; GO:0004180; F:carboxypeptidase activity; IEA:UniProtKB-KW.
DR GO; GO:0016805; F:dipeptidase activity; IEA:UniProtKB-KW.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0008237; F:metallopeptidase activity; IEA:UniProtKB-KW.
DR GO; GO:0008233; F:peptidase activity; NAS:UniProtKB.
DR GO; GO:0006760; P:folic acid-containing compound metabolic process; IEA:Ensembl.
DR GO; GO:0006508; P:proteolysis; NAS:UniProtKB.
DR Gene3D; 1.20.930.40; -; 1.
DR InterPro; IPR007484; Peptidase_M28.
DR InterPro; IPR003137; Protease-assoc_domain.
DR InterPro; IPR007365; TFR-like_dimer_dom.
DR Pfam; PF02225; PA; 1.
DR Pfam; PF04389; Peptidase_M28; 1.
DR Pfam; PF04253; TFR_dimer; 1.
DR SUPFAM; SSF47672; SSF47672; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Calcium; Carboxypeptidase;
KW Cell membrane; Complete proteome; Cytoplasm; Dipeptidase;
KW Direct protein sequencing; Glycoprotein; Hydrolase; Membrane;
KW Metal-binding; Metalloprotease; Multifunctional enzyme; Polymorphism;
KW Protease; Reference proteome; Signal-anchor; Transmembrane;
KW Transmembrane helix; Zinc.
FT CHAIN 1 750 Glutamate carboxypeptidase 2.
FT /FTId=PRO_0000174117.
FT TOPO_DOM 1 19 Cytoplasmic (Probable).
FT TRANSMEM 20 43 Helical; Signal-anchor for type II
FT membrane protein; (Probable).
FT TOPO_DOM 44 750 Extracellular (Probable).
FT REGION 274 587 NAALADase.
FT REGION 534 536 Substrate binding.
FT REGION 699 700 Substrate binding.
FT COMPBIAS 146 149 Poly-Pro.
FT ACT_SITE 424 424 For NAALADase activity.
FT ACT_SITE 628 628 Charge relay system (Potential).
FT ACT_SITE 666 666 Charge relay system (Potential).
FT ACT_SITE 689 689 Charge relay system (Potential).
FT METAL 269 269 Calcium.
FT METAL 272 272 Calcium; via carbonyl oxygen.
FT METAL 377 377 Zinc 1.
FT METAL 387 387 Zinc 1.
FT METAL 387 387 Zinc 2.
FT METAL 425 425 Zinc 2.
FT METAL 433 433 Calcium.
FT METAL 436 436 Calcium.
FT METAL 453 453 Zinc 1.
FT METAL 553 553 Zinc 2.
FT BINDING 210 210 Substrate.
FT BINDING 257 257 Substrate.
FT BINDING 519 519 Substrate.
FT BINDING 552 552 Substrate.
FT CARBOHYD 51 51 N-linked (GlcNAc...).
FT CARBOHYD 76 76 N-linked (GlcNAc...).
FT CARBOHYD 121 121 N-linked (GlcNAc...).
FT CARBOHYD 140 140 N-linked (GlcNAc...).
FT CARBOHYD 153 153 N-linked (GlcNAc...).
FT CARBOHYD 195 195 N-linked (GlcNAc...).
FT CARBOHYD 336 336 N-linked (GlcNAc...).
FT CARBOHYD 459 459 N-linked (GlcNAc...).
FT CARBOHYD 476 476 N-linked (GlcNAc...).
FT CARBOHYD 638 638 N-linked (GlcNAc...).
FT VAR_SEQ 1 585 Missing (in isoform PSMA-3).
FT /FTId=VSP_040242.
FT VAR_SEQ 1 308 Missing (in isoform 10).
FT /FTId=VSP_044287.
FT VAR_SEQ 1 159 Missing (in isoform PSMA-4).
FT /FTId=VSP_040241.
FT VAR_SEQ 1 57 Missing (in isoform PSMA').
FT /FTId=VSP_005336.
FT VAR_SEQ 1 39 MWNLLHETDSAVATARRPRWLCAGALVLAGGFFLLGFLF
FT -> MTAGSSYPLFLAAYACTGCLAERL (in isoform
FT PSMA-7 and isoform PSMA-9).
FT /FTId=VSP_038058.
FT VAR_SEQ 214 243 VKNAQLAGAKGVILYSDPADYFAPGVKSYP -> NMLIGVE
FT LQRLLVFQVFLFIQLDTMMHRSS (in isoform PSMA-
FT 4).
FT /FTId=VSP_040243.
FT VAR_SEQ 244 750 Missing (in isoform PSMA-4).
FT /FTId=VSP_040244.
FT VAR_SEQ 657 750 NPIVLRMMNDQLMFLERAFIDPLGLPDRPFYRHVIYAPSSH
FT NKYAGESFPGIYDALFDIESKVDPSKAWGEVKRQIYVAAFT
FT VQAAAETLSEVA -> MSSMLQAATTSMQGSHSQEFMMLCL
FT ILKAKWTLPRPGEK (in isoform PSMA-3).
FT /FTId=VSP_040245.
FT VAR_SEQ 657 688 NPIVLRMMNDQLMFLERAFIDPLGLPDRPFYR -> K (in
FT isoform PSMA-8 and isoform PSMA-9).
FT /FTId=VSP_038059.
FT VARIANT 23 23 A -> T (in a colorectal cancer sample;
FT somatic mutation).
FT /FTId=VAR_036398.
FT VARIANT 75 75 Y -> H (in dbSNP:rs202676).
FT /FTId=VAR_024592.
FT VARIANT 475 475 H -> Y (can be associated with lower
FT folate and higher homocysteine levels;
FT dbSNP:rs61886492).
FT /FTId=VAR_012736.
FT VARIANT 627 627 V -> L (in dbSNP:rs2988342).
FT /FTId=VAR_028882.
FT MUTAGEN 51 51 N->A: Loss of glycosylation. Reduces
FT enzyme activity.
FT MUTAGEN 76 76 N->A: Loss of glycosylation. Reduces
FT enzyme activity.
FT MUTAGEN 121 121 N->A: Loss of glycosylation. Severely
FT reduced enzyme activity.
FT MUTAGEN 140 140 N->A: Loss of glycosylation. Severely
FT reduced enzyme activity.
FT MUTAGEN 153 153 N->A: Loss of glycosylation. Severely
FT reduced enzyme activity.
FT MUTAGEN 195 195 N->A: Loss of glycosylation. Severely
FT reduced enzyme activity.
FT MUTAGEN 336 336 N->A: Loss of glycosylation. Reduces
FT enzyme activity.
FT MUTAGEN 377 377 H->A,G,Q: Complete loss of activity.
FT MUTAGEN 379 379 D->E,N: Complete loss of activity.
FT MUTAGEN 387 387 D->E,L: Complete loss of activity.
FT MUTAGEN 387 387 D->N: No effect on enzyme activity.
FT MUTAGEN 388 388 P->A: No effect on enzyme activity.
FT MUTAGEN 424 424 E->A: Complete loss of activity.
FT MUTAGEN 424 424 E->D: Reduces enzyme activity.
FT MUTAGEN 424 424 E->Q: Reduces enzyme activity.
FT MUTAGEN 425 425 E->Q,D: Complete loss of activity.
FT MUTAGEN 453 453 D->N,L: Complete loss of activity.
FT MUTAGEN 453 453 D->Q: Reduces enzyme activity.
FT MUTAGEN 454 454 S->A: Reduces enzyme activity.
FT MUTAGEN 459 459 N->A: Loss of glycosylation. Reduces
FT enzyme activity.
FT MUTAGEN 476 476 N->A: Loss of glycosylation. Reduces
FT enzyme activity.
FT MUTAGEN 638 638 N->A: Loss of glycosylation. Abolishes
FT enzyme activity.
FT MUTAGEN 640 640 T->A: Abolishes enzyme activity.
FT CONFLICT 194 194 I -> V (in Ref. 9; AAZ66619).
FT CONFLICT 354 354 R -> K (in Ref. 1; AA sequence).
FT CONFLICT 398 398 I -> N (in Ref. 8; ABO93402).
FT HELIX 58 64
FT HELIX 67 77
FT STRAND 78 80
FT HELIX 87 103
FT STRAND 106 119
FT STRAND 122 124
FT STRAND 127 131
FT STRAND 137 140
FT TURN 149 151
FT HELIX 154 156
FT STRAND 174 176
FT HELIX 182 190
FT STRAND 200 204
FT HELIX 210 219
FT STRAND 223 228
FT HELIX 231 234
FT STRAND 244 247
FT STRAND 269 272
FT HELIX 283 285
FT STRAND 294 297
FT HELIX 299 306
FT HELIX 317 319
FT STRAND 322 325
FT STRAND 330 333
FT HELIX 335 337
FT STRAND 341 346
FT STRAND 349 362
FT STRAND 365 377
FT STRAND 381 383
FT TURN 385 388
FT HELIX 389 407
FT STRAND 413 423
FT HELIX 424 426
FT HELIX 429 445
FT STRAND 446 451
FT STRAND 455 457
FT STRAND 459 466
FT HELIX 468 470
FT HELIX 471 479
FT STRAND 480 482
FT TURN 486 490
FT HELIX 493 500
FT STRAND 504 506
FT STRAND 517 519
FT HELIX 521 526
FT STRAND 531 538
FT STRAND 541 543
FT TURN 545 547
FT TURN 550 553
FT HELIX 559 565
FT HELIX 571 589
FT HELIX 597 615
FT HELIX 619 624
FT HELIX 630 652
FT HELIX 658 673
FT STRAND 684 686
FT STRAND 689 695
FT STRAND 698 705
FT HELIX 706 712
FT HELIX 715 717
FT HELIX 721 744
SQ SEQUENCE 750 AA; 84331 MW; AD8C0A7DBF47901A CRC64;
MWNLLHETDS AVATARRPRW LCAGALVLAG GFFLLGFLFG WFIKSSNEAT NITPKHNMKA
FLDELKAENI KKFLYNFTQI PHLAGTEQNF QLAKQIQSQW KEFGLDSVEL AHYDVLLSYP
NKTHPNYISI INEDGNEIFN TSLFEPPPPG YENVSDIVPP FSAFSPQGMP EGDLVYVNYA
RTEDFFKLER DMKINCSGKI VIARYGKVFR GNKVKNAQLA GAKGVILYSD PADYFAPGVK
SYPDGWNLPG GGVQRGNILN LNGAGDPLTP GYPANEYAYR RGIAEAVGLP SIPVHPIGYY
DAQKLLEKMG GSAPPDSSWR GSLKVPYNVG PGFTGNFSTQ KVKMHIHSTN EVTRIYNVIG
TLRGAVEPDR YVILGGHRDS WVFGGIDPQS GAAVVHEIVR SFGTLKKEGW RPRRTILFAS
WDAEEFGLLG STEWAEENSR LLQERGVAYI NADSSIEGNY TLRVDCTPLM YSLVHNLTKE
LKSPDEGFEG KSLYESWTKK SPSPEFSGMP RISKLGSGND FEVFFQRLGI ASGRARYTKN
WETNKFSGYP LYHSVYETYE LVEKFYDPMF KYHLTVAQVR GGMVFELANS IVLPFDCRDY
AVVLRKYADK IYSISMKHPQ EMKTYSVSFD SLFSAVKNFT EIASKFSERL QDFDKSNPIV
LRMMNDQLMF LERAFIDPLG LPDRPFYRHV IYAPSSHNKY AGESFPGIYD ALFDIESKVD
PSKAWGEVKR QIYVAAFTVQ AAAETLSEVA
//
MIM
600934
*RECORD*
*FIELD* NO
600934
*FIELD* TI
*600934 FOLATE HYDROLASE 1; FOLH1
;;FOLH;;
GLUTAMATE CARBOXYPEPTIDASE II; GCP2;;
PROSTATE-SPECIFIC MEMBRANE ANTIGEN; PSM; PSMA;;
read moreN-ACETYLATED ALPHA-LINKED ACIDIC DIPEPTIDASE 1; NAALAD1;;
NAALADase I
*FIELD* TX
CLONING
Dietary folates are a mixture of polyglutamylated folates which are
digested to monoglutamyl folates by the action of folylpoly-glutamate
carboxypeptidase (FGCP), an enzyme that is anchored to the intestinal
brush border membrane and is expressed by the glutamate carboxypepidase
II (GCP2) gene. Devlin et al. (2000) cloned GCP2 cDNA from human
intestine and confirmed its identity to PSM (prostate-specific membrane
antigen), which had been found to encode a type II transmembrane protein
with folate hydrolase and N-acetylated-alpha-linked-acidic dipeptidase
(NAALADase) activity (O'Keefe et al., 1998). Devlin et al. (2000)
identified both a full-length GCP2 transcript and a 93 bp shorter
transcript lacking exon 18, consistent with the presence of a splice
variant.
Israeli et al. (1993) cloned a 2.65-kb cDNA for a prostate-specific
membrane antigen detected with a monoclonal antibody raised against the
human prostatic carcinoma cell line LNCaP. The PSM gene encodes a
750-amino acid protein that has an apparent molecular weight of 100 kD
(due to posttranslational modification) and is expressed by normal and
neoplastic prostate cells.
Using RT-PCR, Pangalos et al. (1999) found that NAALAD1 expression was
highest in prostate, followed by liver, kidney, small intestine, brain,
and spleen. Variable expression was detected in all specific brain
regions examined.
By PCR using primers spanning exons 10 to 16 of the PSMA gene, O'Keefe
et al. (2004) cloned PSMA from a liver cDNA library. The deduced protein
shares 97% amino acid identity with PSMAL (609020). Northern blot
analysis detected a 2.7-kb PSMA transcript in prostate, brain, kidney,
small intestine, liver, spleen, trachea, spinal cord, and fetal liver
and kidney. Expression was highest in prostate. Western blot analysis
detected PSMA in the hippocampus and amygdala, as well as in a prostate
cancer cell line.
GENE STRUCTURE
O'Keefe et al. (1998) screened a P1 library using primers based on the
cDNA sequence reported by Israeli et al. (1993) and isolated a genomic
clone of the PSMA gene. O'Keefe et al. (1998) reported that the PSMA
gene contains 19 exons spanning approximately 60 kb of genomic DNA. They
identified a 1.2-kb promoter in the 5-prime region of the PSMA gene.
Lee et al. (2003) identified an enhancer element (PSME) within intron 3
of the PSMA gene. PSME contains 2 direct repeat regions and a partial
Alu repeat sequence. Functional studies identified an activator
protein-3 (AP3) site within PSME that sustained basal but not enhanced
transcriptional activity. NFATC1 (600489) bound to the AP3 site in vivo.
Furthermore, a calcium ionophore and phorbol ester augmented the
enhancer activity of PSME.
GENE FUNCTION
Glutamate excitotoxicity has been implicated as a mechanism of motor
neuron death in both sporadic and familial amyotrophic lateral sclerosis
(ALS1; 105400). Ghadge et al. (2003) tested whether a neuroprotective
strategy involving potent and selective inhibitors of GCP2, which
converts the abundant neuropeptide N-acetylaspartylglutamate to
glutamate, could protect motor neurons in an in vitro and animal model
of familial ALS. These data suggested that the GCP2 inhibitors prevented
motor neuron cell death in both of these systems because of the
resultant decrease in glutamate levels. They suggested that GCP2
inhibition may represent a new therapeutic approach in the treatment of
ALS.
MAPPING
Rinker-Schaeffer et al. (1995) mapped the PSM gene to 11q14 by
fluorescence in situ hybridization using a cosmid containing the gene.
Leek et al. (1995) mapped an FOLH-containing YAC to 11p11.2. A tumor
suppressor gene involved in prostate cancer, KAI1 (600623), had
previously been mapped to this region but was situated distal to the
FOLH gene and was not present in the YAC that was mapped by Leek et al.
(1995). The conflicting assignments to 11p11.2 and 11q14 raised the
possibility of more than one FOLH-type gene in man. Maraj et al. (1998)
demonstrated tight linkage of the FOLH gene to D11S1326 at 11p11.2. They
suggested that the most likely location of FOLH is 11p but that there
may be a duplication on 11q and that a second PSM gene may lie at 11q14.
By radiation hybrid analysis, O'Keefe et al. (1998) mapped the gene
encoding PSMA to 11p12-p11. O'Keefe et al. (1998) determined that the
gene on 11q14, PSMAL, is homologous but not identical to PSMA and that
the duplication and divergence of the genes occurred 22 million years
ago.
MOLECULAR GENETICS
Devlin et al. (2000) identified a his475-to-tyr (H475Y) polymorphism in
GCP2 in DNA samples from 75 healthy Caucasian individuals. Membranes of
transfected COS-7 cells expressing the H475Y variant GCP2 cDNA had 53%
less FGCP activity than did cells expressing wildtype GCP2. The presence
of the H475Y GCP2 allele was significantly associated with lower folate
and higher homocysteine levels in this population. These data suggested
that the presence of the H475Y GCP2 allele impairs the intestinal
absorption of dietary folates, resulting in relatively low blood folate
levels and consequent hyperhomocysteinemia. Hyperhomocysteinemia has
been associated with increased risk for cardiovascular disease, neural
tube defects, and cognitive deficits.
*FIELD* RF
1. Devlin, A. M.; Ling, E.; Peerson, J. M.; Fernando, S.; Clarke,
R.; Smith, A. D.; Halsted, C. H.: Glutamate carboxypeptidase II:
a polymorphism associated with lower levels of serum folate and hyperhomocysteinemia. Hum.
Molec. Genet. 9: 2837-2844, 2000.
2. Ghadge, G. D.; Slusher, B. S.; Bodner, A.; Dal Canto, M.; Wozniak,
K.; Thomas, A. G.; Rojas, C.; Tsukamoto, T.; Majer, P.; Miller, R.
J.; Monti, A. L.; Roos, R. P.: Glutamate carboxypeptidase II inhibition
protects motor neurons from death in familial amyotrophic lateral
sclerosis models. Proc. Nat. Acad. Sci. 100: 9554-9559, 2003.
3. Israeli, R. S.; Powell, C. T.; Fair, W. R.; Heston, W. D. W.:
Molecular cloning of a complementary DNA encoding a prostate-specific
membrane antigen. Cancer Res. 53: 227-230, 1993.
4. Lee, S.-J.; Lee, K.; Yang, X.; Jung, C.; Gardner, T.; Kim, H.-S.;
Jeng, M.-H.; Kao, C.: NAFTc1 with AP-3 site binding specificity mediates
gene expression of prostate-specific-membrane-antigen. J. Molec.
Biol. 330: 749-760, 2003.
5. Leek, J.; Lench, N.; Maraj, B.; Bailey, A.; Carr, I. M.; Andersen,
S.; Cross, J.; Whelan, P.; MacLennan, K. A.; Meredith, D. M.; Markham,
A. F.: Prostate-specific membrane antigen: evidence for the existence
of a second related human gene. Brit. J. Cancer 72: 583-588, 1995.
6. Maraj, B. H.; Leek, J. P.; Karayi, M.; Ali, M.; Lench, N. J.; Markham,
A. F.: Detailed genetic mapping around a putative prostate-specific
membrane antigen locus on human chromosome 11p11.2. Cytogenet. Cell
Genet. 81: 3-9, 1998.
7. O'Keefe, D. S.; Bacich, D. J.; Heston, W. D. W.: Comparative analysis
of prostate-specific membrane antigen (PSMA) versus a prostate-specific
membrane antigen-like gene. Prostate 58: 200-210, 2004.
8. O'Keefe, D. S.; Su, S. L.; Bacich, D. J.; Horiguchi, Y.; Luo, Y.;
Powell, C. T.; Zandvliet, D.; Russell, P. J.; Molloy, P. L.; Nowak,
N. J.; Shows, T. B.; Mullins, C.; Vonder Haar, R. A.; Fair, W. R.;
Heston, W. D. W.: Mapping, genomic organization and promoter analysis
of the human prostate-specific membrane antigen gene. Biochim. Biophys.
Acta 1443: 113-127, 1998.
9. Pangalos, M. N.; Neefs, J.-M.; Somers, M.; Verhasselt, P.; Bekkers,
M.; van der Helm, L.; Fraiponts, E.; Ashton, D.; Gordon, R. D.: Isolation
and expression of novel human glutamate carboxypeptidases with N-acetylated
alpha-linked acidic dipeptidase and dipeptidyl peptidase IV activity. J.
Biol. Chem. 274: 8470-8483, 1999.
10. Rinker-Schaeffer, C. W.; Hawkins, A. L.; Su, S. L.; Israeli, R.
S.; Griffin, C. A.; Isaacs, J. T.; Heston, W. D. W.: Localization
and physical mapping of the prostate-specific membrane antigen (PSM)
gene to human chromosome 11. Genomics 30: 105-108, 1995.
*FIELD* CN
Patricia A. Hartz - updated: 11/27/2007
Patricia A. Hartz - updated: 11/8/2004
Victor A. McKusick - updated: 9/8/2003
George E. Tiller - updated: 1/29/2001
Joanna S. Amberger - updated: 10/23/2000
Victor A. McKusick - updated: 9/9/1998
*FIELD* CD
Alan F. Scott: 11/9/1995
*FIELD* ED
mgross: 11/28/2007
terry: 11/27/2007
mgross: 11/8/2004
terry: 11/8/2004
alopez: 7/23/2004
cwells: 9/10/2003
terry: 9/8/2003
carol: 1/29/2001
terry: 10/24/2000
joanna: 10/23/2000
alopez: 9/10/1998
terry: 9/9/1998
carol: 8/20/1998
mark: 7/30/1997
mark: 4/21/1997
terry: 2/6/1996
mark: 11/9/1995
*RECORD*
*FIELD* NO
600934
*FIELD* TI
*600934 FOLATE HYDROLASE 1; FOLH1
;;FOLH;;
GLUTAMATE CARBOXYPEPTIDASE II; GCP2;;
PROSTATE-SPECIFIC MEMBRANE ANTIGEN; PSM; PSMA;;
read moreN-ACETYLATED ALPHA-LINKED ACIDIC DIPEPTIDASE 1; NAALAD1;;
NAALADase I
*FIELD* TX
CLONING
Dietary folates are a mixture of polyglutamylated folates which are
digested to monoglutamyl folates by the action of folylpoly-glutamate
carboxypeptidase (FGCP), an enzyme that is anchored to the intestinal
brush border membrane and is expressed by the glutamate carboxypepidase
II (GCP2) gene. Devlin et al. (2000) cloned GCP2 cDNA from human
intestine and confirmed its identity to PSM (prostate-specific membrane
antigen), which had been found to encode a type II transmembrane protein
with folate hydrolase and N-acetylated-alpha-linked-acidic dipeptidase
(NAALADase) activity (O'Keefe et al., 1998). Devlin et al. (2000)
identified both a full-length GCP2 transcript and a 93 bp shorter
transcript lacking exon 18, consistent with the presence of a splice
variant.
Israeli et al. (1993) cloned a 2.65-kb cDNA for a prostate-specific
membrane antigen detected with a monoclonal antibody raised against the
human prostatic carcinoma cell line LNCaP. The PSM gene encodes a
750-amino acid protein that has an apparent molecular weight of 100 kD
(due to posttranslational modification) and is expressed by normal and
neoplastic prostate cells.
Using RT-PCR, Pangalos et al. (1999) found that NAALAD1 expression was
highest in prostate, followed by liver, kidney, small intestine, brain,
and spleen. Variable expression was detected in all specific brain
regions examined.
By PCR using primers spanning exons 10 to 16 of the PSMA gene, O'Keefe
et al. (2004) cloned PSMA from a liver cDNA library. The deduced protein
shares 97% amino acid identity with PSMAL (609020). Northern blot
analysis detected a 2.7-kb PSMA transcript in prostate, brain, kidney,
small intestine, liver, spleen, trachea, spinal cord, and fetal liver
and kidney. Expression was highest in prostate. Western blot analysis
detected PSMA in the hippocampus and amygdala, as well as in a prostate
cancer cell line.
GENE STRUCTURE
O'Keefe et al. (1998) screened a P1 library using primers based on the
cDNA sequence reported by Israeli et al. (1993) and isolated a genomic
clone of the PSMA gene. O'Keefe et al. (1998) reported that the PSMA
gene contains 19 exons spanning approximately 60 kb of genomic DNA. They
identified a 1.2-kb promoter in the 5-prime region of the PSMA gene.
Lee et al. (2003) identified an enhancer element (PSME) within intron 3
of the PSMA gene. PSME contains 2 direct repeat regions and a partial
Alu repeat sequence. Functional studies identified an activator
protein-3 (AP3) site within PSME that sustained basal but not enhanced
transcriptional activity. NFATC1 (600489) bound to the AP3 site in vivo.
Furthermore, a calcium ionophore and phorbol ester augmented the
enhancer activity of PSME.
GENE FUNCTION
Glutamate excitotoxicity has been implicated as a mechanism of motor
neuron death in both sporadic and familial amyotrophic lateral sclerosis
(ALS1; 105400). Ghadge et al. (2003) tested whether a neuroprotective
strategy involving potent and selective inhibitors of GCP2, which
converts the abundant neuropeptide N-acetylaspartylglutamate to
glutamate, could protect motor neurons in an in vitro and animal model
of familial ALS. These data suggested that the GCP2 inhibitors prevented
motor neuron cell death in both of these systems because of the
resultant decrease in glutamate levels. They suggested that GCP2
inhibition may represent a new therapeutic approach in the treatment of
ALS.
MAPPING
Rinker-Schaeffer et al. (1995) mapped the PSM gene to 11q14 by
fluorescence in situ hybridization using a cosmid containing the gene.
Leek et al. (1995) mapped an FOLH-containing YAC to 11p11.2. A tumor
suppressor gene involved in prostate cancer, KAI1 (600623), had
previously been mapped to this region but was situated distal to the
FOLH gene and was not present in the YAC that was mapped by Leek et al.
(1995). The conflicting assignments to 11p11.2 and 11q14 raised the
possibility of more than one FOLH-type gene in man. Maraj et al. (1998)
demonstrated tight linkage of the FOLH gene to D11S1326 at 11p11.2. They
suggested that the most likely location of FOLH is 11p but that there
may be a duplication on 11q and that a second PSM gene may lie at 11q14.
By radiation hybrid analysis, O'Keefe et al. (1998) mapped the gene
encoding PSMA to 11p12-p11. O'Keefe et al. (1998) determined that the
gene on 11q14, PSMAL, is homologous but not identical to PSMA and that
the duplication and divergence of the genes occurred 22 million years
ago.
MOLECULAR GENETICS
Devlin et al. (2000) identified a his475-to-tyr (H475Y) polymorphism in
GCP2 in DNA samples from 75 healthy Caucasian individuals. Membranes of
transfected COS-7 cells expressing the H475Y variant GCP2 cDNA had 53%
less FGCP activity than did cells expressing wildtype GCP2. The presence
of the H475Y GCP2 allele was significantly associated with lower folate
and higher homocysteine levels in this population. These data suggested
that the presence of the H475Y GCP2 allele impairs the intestinal
absorption of dietary folates, resulting in relatively low blood folate
levels and consequent hyperhomocysteinemia. Hyperhomocysteinemia has
been associated with increased risk for cardiovascular disease, neural
tube defects, and cognitive deficits.
*FIELD* RF
1. Devlin, A. M.; Ling, E.; Peerson, J. M.; Fernando, S.; Clarke,
R.; Smith, A. D.; Halsted, C. H.: Glutamate carboxypeptidase II:
a polymorphism associated with lower levels of serum folate and hyperhomocysteinemia. Hum.
Molec. Genet. 9: 2837-2844, 2000.
2. Ghadge, G. D.; Slusher, B. S.; Bodner, A.; Dal Canto, M.; Wozniak,
K.; Thomas, A. G.; Rojas, C.; Tsukamoto, T.; Majer, P.; Miller, R.
J.; Monti, A. L.; Roos, R. P.: Glutamate carboxypeptidase II inhibition
protects motor neurons from death in familial amyotrophic lateral
sclerosis models. Proc. Nat. Acad. Sci. 100: 9554-9559, 2003.
3. Israeli, R. S.; Powell, C. T.; Fair, W. R.; Heston, W. D. W.:
Molecular cloning of a complementary DNA encoding a prostate-specific
membrane antigen. Cancer Res. 53: 227-230, 1993.
4. Lee, S.-J.; Lee, K.; Yang, X.; Jung, C.; Gardner, T.; Kim, H.-S.;
Jeng, M.-H.; Kao, C.: NAFTc1 with AP-3 site binding specificity mediates
gene expression of prostate-specific-membrane-antigen. J. Molec.
Biol. 330: 749-760, 2003.
5. Leek, J.; Lench, N.; Maraj, B.; Bailey, A.; Carr, I. M.; Andersen,
S.; Cross, J.; Whelan, P.; MacLennan, K. A.; Meredith, D. M.; Markham,
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*FIELD* CN
Patricia A. Hartz - updated: 11/27/2007
Patricia A. Hartz - updated: 11/8/2004
Victor A. McKusick - updated: 9/8/2003
George E. Tiller - updated: 1/29/2001
Joanna S. Amberger - updated: 10/23/2000
Victor A. McKusick - updated: 9/9/1998
*FIELD* CD
Alan F. Scott: 11/9/1995
*FIELD* ED
mgross: 11/28/2007
terry: 11/27/2007
mgross: 11/8/2004
terry: 11/8/2004
alopez: 7/23/2004
cwells: 9/10/2003
terry: 9/8/2003
carol: 1/29/2001
terry: 10/24/2000
joanna: 10/23/2000
alopez: 9/10/1998
terry: 9/9/1998
carol: 8/20/1998
mark: 7/30/1997
mark: 4/21/1997
terry: 2/6/1996
mark: 11/9/1995