ID CAH4_HUMAN Reviewed; 312 AA.
AC P22748; B4DQA4; Q6FHI7;
DT 01-AUG-1991, integrated into UniProtKB/Swiss-Prot.
DT 01-AUG-1992, sequence version 2.
DT 24-JAN-2024, entry version 223.
DE RecName: Full=Carbonic anhydrase 4;
DE EC=4.2.1.1 {ECO:0000269|PubMed:15563508, ECO:0000269|PubMed:16686544, ECO:0000269|PubMed:16807956, ECO:0000269|PubMed:17127057, ECO:0000269|PubMed:17652713, ECO:0000269|PubMed:17705204, ECO:0000269|PubMed:7625839};
DE AltName: Full=Carbonate dehydratase IV;
DE AltName: Full=Carbonic anhydrase IV;
DE Short=CA-IV;
DE Flags: Precursor;
GN Name=CA4 {ECO:0000312|HGNC:HGNC:1375};
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 [MRNA] (ISOFORM 1).
RX PubMed=1311094; DOI=10.1073/pnas.89.4.1315;
RA Okuyama T., Sato S., Zhu X.L., Waheed A., Sly W.S.;
RT "Human carbonic anhydrase IV: cDNA cloning, sequence comparison, and
RT expression in COS cell membranes.";
RL Proc. Natl. Acad. Sci. U.S.A. 89:1315-1319(1992).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=8325641; DOI=10.1006/geno.1993.1247;
RA Okuyama T., Batanian J.R., Sly W.S.;
RT "Genomic organization and localization of gene for human carbonic anhydrase
RT IV to chromosome 17q.";
RL Genomics 16:678-684(1993).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC TISSUE=Brain;
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 MRNA] (ISOFORM 1).
RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.;
RT "Cloning of human full open reading frames in Gateway(TM) system entry
RT vector (pDONR201).";
RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16625196; DOI=10.1038/nature04689;
RA Zody M.C., Garber M., Adams D.J., Sharpe T., Harrow J., Lupski J.R.,
RA Nicholson C., Searle S.M., Wilming L., Young S.K., Abouelleil A.,
RA Allen N.R., Bi W., Bloom T., Borowsky M.L., Bugalter B.E., Butler J.,
RA Chang J.L., Chen C.-K., Cook A., Corum B., Cuomo C.A., de Jong P.J.,
RA DeCaprio D., Dewar K., FitzGerald M., Gilbert J., Gibson R., Gnerre S.,
RA Goldstein S., Grafham D.V., Grocock R., Hafez N., Hagopian D.S., Hart E.,
RA Norman C.H., Humphray S., Jaffe D.B., Jones M., Kamal M., Khodiyar V.K.,
RA LaButti K., Laird G., Lehoczky J., Liu X., Lokyitsang T., Loveland J.,
RA Lui A., Macdonald P., Major J.E., Matthews L., Mauceli E., McCarroll S.A.,
RA Mihalev A.H., Mudge J., Nguyen C., Nicol R., O'Leary S.B., Osoegawa K.,
RA Schwartz D.C., Shaw-Smith C., Stankiewicz P., Steward C., Swarbreck D.,
RA Venkataraman V., Whittaker C.A., Yang X., Zimmer A.R., Bradley A.,
RA Hubbard T., Birren B.W., Rogers J., Lander E.S., Nusbaum C.;
RT "DNA sequence of human chromosome 17 and analysis of rearrangement in the
RT human lineage.";
RL Nature 440:1045-1049(2006).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Brain, and Placenta;
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 [8]
RP PROTEIN SEQUENCE OF 19-35; 113-123 AND 233-239.
RC TISSUE=Lung;
RX PubMed=2111324; DOI=10.1016/s0021-9258(19)38958-6;
RA Zhu X.L., Sly W.S.;
RT "Carbonic anhydrase IV from human lung. Purification, characterization, and
RT comparison with membrane carbonic anhydrase from human kidney.";
RL J. Biol. Chem. 265:8795-8801(1990).
RN [9]
RP DISULFIDE BONDS.
RX PubMed=8809084; DOI=10.1006/abbi.1996.0412;
RA Waheed A., Okuyama T., Heyduk T., Sly W.S.;
RT "Carbonic anhydrase IV: purification of a secretory form of the recombinant
RT human enzyme and identification of the positions and importance of its
RT disulfide bonds.";
RL Arch. Biochem. Biophys. 333:432-438(1996).
RN [10]
RP GPI-ANCHOR AT SER-284, MUTAGENESIS OF SER-284, CATALYTIC ACTIVITY, AND
RP FUNCTION.
RX PubMed=7625839; DOI=10.1016/0003-9861(95)90015-2;
RA Okuyama T., Waheed A., Kusumoto W., Zhu X.L., Sly W.S.;
RT "Carbonic anhydrase IV: role of removal of C-terminal domain in
RT glycosylphosphatidylinositol anchoring and realization of enzyme
RT activity.";
RL Arch. Biochem. Biophys. 320:315-322(1995).
RN [11]
RP ACTIVITY REGULATION, CATALYTIC ACTIVITY, AND FUNCTION.
RX PubMed=16807956; DOI=10.1002/chem.200600159;
RA Temperini C., Scozzafava A., Vullo D., Supuran C.T.;
RT "Carbonic anhydrase activators. Activation of isozymes I, II, IV, VA, VII,
RT and XIV with l- and d-histidine and crystallographic analysis of their
RT adducts with isoform II: engineering proton-transfer processes within the
RT active site of an enzyme.";
RL Chemistry 12:7057-7066(2006).
RN [12]
RP ACTIVITY REGULATION, FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=16686544; DOI=10.1021/jm0603320;
RA Temperini C., Scozzafava A., Vullo D., Supuran C.T.;
RT "Carbonic anhydrase activators. Activation of isoforms I, II, IV, VA, VII,
RT and XIV with L- and D-phenylalanine and crystallographic analysis of their
RT adducts with isozyme II: stereospecific recognition within the active site
RT of an enzyme and its consequences for the drug design.";
RL J. Med. Chem. 49:3019-3027(2006).
RN [13]
RP ACTIVITY REGULATION, FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=17705204; DOI=10.1002/anie.200701189;
RA Koehler K., Hillebrecht A., Schulze Wischeler J., Innocenti A., Heine A.,
RA Supuran C.T., Klebe G.;
RT "Saccharin inhibits carbonic anhydrases: possible explanation for its
RT unpleasant metallic aftertaste.";
RL Angew. Chem. Int. Ed. Engl. 46:7697-7699(2007).
RN [14]
RP ACTIVITY REGULATION, FUNCTION, CATALYTIC ACTIVITY, AND ALTERNATIVE
RP SPLICING.
RX PubMed=17127057; DOI=10.1016/j.bmcl.2006.11.027;
RA Temperini C., Innocenti A., Scozzafava A., Mastrolorenzo A., Supuran C.T.;
RT "Carbonic anhydrase activators: L-Adrenaline plugs the active site entrance
RT of isozyme II, activating better isoforms I, IV, VA, VII, and XIV.";
RL Bioorg. Med. Chem. Lett. 17:628-635(2007).
RN [15]
RP ACTIVITY REGULATION, FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=17314045; DOI=10.1016/j.bmcl.2007.01.113;
RA Temperini C., Innocenti A., Guerri A., Scozzafava A., Rusconi S.,
RA Supuran C.T.;
RT "Phosph(on)ate as a zinc-binding group in metalloenzyme inhibitors: X-ray
RT crystal structure of the antiviral drug foscarnet complexed to human
RT carbonic anhydrase I.";
RL Bioorg. Med. Chem. Lett. 17:2210-2215(2007).
RN [16]
RP ACTIVITY REGULATION, AND CATALYTIC ACTIVITY.
RX PubMed=19186056; DOI=10.1016/j.bmcl.2009.01.038;
RA Crocetti L., Maresca A., Temperini C., Hall R.A., Scozzafava A.,
RA Muehlschlegel F.A., Supuran C.T.;
RT "A thiabendazole sulfonamide shows potent inhibitory activity against
RT mammalian and nematode alpha-carbonic anhydrases.";
RL Bioorg. Med. Chem. Lett. 19:1371-1375(2009).
RN [17]
RP ACTIVITY REGULATION, FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=19206230; DOI=10.1021/ja809683v;
RA Maresca A., Temperini C., Vu H., Pham N.B., Poulsen S.-A., Scozzafava A.,
RA Quinn R.J., Supuran C.T.;
RT "Non-zinc mediated inhibition of carbonic anhydrases: coumarins are a new
RT class of suicide inhibitors.";
RL J. Am. Chem. Soc. 131:3057-3062(2009).
RN [18]
RP CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, ACTIVITY REGULATION, AND
RP FUNCTION.
RX PubMed=18618712; DOI=10.1002/prot.22144;
RA Di Fiore A., Monti S.M., Hilvo M., Parkkila S., Romano V., Scaloni A.,
RA Pedone C., Scozzafava A., Supuran C.T., De Simone G.;
RT "Crystal structure of human carbonic anhydrase XIII and its complex with
RT the inhibitor acetazolamide.";
RL Proteins 74:164-175(2009).
RN [19]
RP X-RAY CRYSTALLOGRAPHY (2.80 ANGSTROMS) OF 19-284 IN COMPLEX WITH ZINC ION.
RX PubMed=8942978; DOI=10.1073/pnas.93.24.13589;
RA Stams T., Nair S.K., Okuyama T., Waheed A., Sly W.S., Christianson D.W.;
RT "Crystal structure of the secretory form of membrane-associated human
RT carbonic anhydrase IV at 2.8-A resolution.";
RL Proc. Natl. Acad. Sci. U.S.A. 93:13589-13594(1996).
RN [20]
RP X-RAY CRYSTALLOGRAPHY (2.00 ANGSTROMS) OF 19-284 IN COMPLEX WITH
RP INHIBITORS.
RX PubMed=20363633; DOI=10.1016/j.bmc.2010.03.014;
RA Vernier W.F., Chong W., Rewolinski D., Greasley S., Pauly T.A., Shaw M.,
RA Dinh D.M., Ferre R.A.A., Meador J.W. III, Nukui S., Ornelas M., Paz R.L.,
RA Reyner E.;
RT "Thioether benzenesulfonamide inhibitors of carbonic anhydrases II and IV:
RT structure-based drug design, synthesis, and biological evaluation.";
RL Bioorg. Med. Chem. 18:3307-3319(2010).
RN [21]
RP INVOLVEMENT IN RP17, VARIANTS RP17 TRP-14 AND SER-219, FUNCTION, CATALYTIC
RP ACTIVITY, TISSUE SPECIFICITY, INTERACTION WITH SLC4A4, AND SUBCELLULAR
RP LOCATION.
RX PubMed=15563508; DOI=10.1093/hmg/ddi023;
RA Yang Z., Alvarez B.V., Chakarova C., Jiang L., Karan G., Frederick J.M.,
RA Zhao Y., Sauve Y., Li X., Zrenner E., Wissinger B., Den Hollander A.I.,
RA Katz B., Baehr W., Cremers F.P., Casey J.R., Bhattacharya S.S., Zhang K.;
RT "Mutant carbonic anhydrase 4 impairs pH regulation and causes retinal
RT photoreceptor degeneration.";
RL Hum. Mol. Genet. 14:255-265(2005).
RN [22]
RP INTERACTION WITH SLC4A4, VARIANT RP17 HIS-69, VARIANT LYS-177,
RP CHARACTERIZATION OF VARIANT RP17 HIS-69, FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=17652713; DOI=10.1167/iovs.06-1515;
RA Alvarez B.V., Vithana E.N., Yang Z., Koh A.H., Yeung K., Yong V.,
RA Shandro H.J., Chen Y., Kolatkar P., Palasingam P., Zhang K., Aung T.,
RA Casey J.R.;
RT "Identification and characterization of a novel mutation in the carbonic
RT anhydrase IV gene that causes retinitis pigmentosa.";
RL Invest. Ophthalmol. Vis. Sci. 48:3459-3468(2007).
RN [23]
RP VARIANT RP17 THR-12.
RX PubMed=20450258; DOI=10.3109/02713680903503512;
RA Tian Y., Tang L., Cui J., Zhu X.;
RT "Screening for the carbonic anhydrase IV gene mutations in Chinese
RT retinitis pigmentosa patients.";
RL Curr. Eye Res. 35:440-444(2010).
CC -!- FUNCTION: Catalyzes the reversible hydration of carbon dioxide into
CC bicarbonate and protons and thus is essential to maintaining
CC intracellular and extracellular pH (PubMed:15563508, PubMed:17652713,
CC PubMed:7625839, PubMed:16807956, PubMed:16686544, PubMed:17705204,
CC PubMed:17127057, PubMed:17314045, PubMed:19186056, PubMed:19206230,
CC PubMed:18618712). May stimulate the sodium/bicarbonate transporter
CC activity of SLC4A4 that acts in pH homeostasis (PubMed:15563508). It is
CC essential for acid overload removal from the retina and retina
CC epithelium, and acid release in the choriocapillaris in the choroid
CC (PubMed:15563508). {ECO:0000269|PubMed:15563508,
CC ECO:0000269|PubMed:16686544, ECO:0000269|PubMed:16807956,
CC ECO:0000269|PubMed:17127057, ECO:0000269|PubMed:17314045,
CC ECO:0000269|PubMed:17652713, ECO:0000269|PubMed:17705204,
CC ECO:0000269|PubMed:18618712, ECO:0000269|PubMed:19186056,
CC ECO:0000269|PubMed:19206230, ECO:0000269|PubMed:7625839}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H(+) + hydrogencarbonate = CO2 + H2O; Xref=Rhea:RHEA:10748,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:16526,
CC ChEBI:CHEBI:17544; EC=4.2.1.1; Evidence={ECO:0000269|PubMed:15563508,
CC ECO:0000269|PubMed:16686544, ECO:0000269|PubMed:16807956,
CC ECO:0000269|PubMed:17127057, ECO:0000269|PubMed:17314045,
CC ECO:0000269|PubMed:17652713, ECO:0000269|PubMed:17705204,
CC ECO:0000269|PubMed:18618712, ECO:0000269|PubMed:19186056,
CC ECO:0000269|PubMed:19206230, ECO:0000269|PubMed:7625839};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:10749;
CC Evidence={ECO:0000305|PubMed:17652713};
CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:10750;
CC Evidence={ECO:0000305|PubMed:17652713};
CC -!- COFACTOR:
CC Name=Zn(2+); Xref=ChEBI:CHEBI:29105;
CC Evidence={ECO:0000269|PubMed:8942978};
CC -!- ACTIVITY REGULATION: Activated by histamine, L-adrenaline, D-
CC phenylalanine, L- and D-histidine. Inhibited by coumarins, saccharin,
CC sulfonamide derivatives such as acetazolamide and Foscarnet
CC (phosphonoformate trisodium salt). {ECO:0000269|PubMed:16686544,
CC ECO:0000269|PubMed:16807956, ECO:0000269|PubMed:17127057,
CC ECO:0000269|PubMed:17314045, ECO:0000269|PubMed:17705204,
CC ECO:0000269|PubMed:18618712, ECO:0000269|PubMed:19186056,
CC ECO:0000269|PubMed:19206230}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=21.5 mM for CO(2) {ECO:0000269|PubMed:18618712};
CC -!- SUBUNIT: Interacts with SLC4A4. {ECO:0000269|PubMed:15563508,
CC ECO:0000269|PubMed:17652713, ECO:0000269|PubMed:20363633,
CC ECO:0000269|PubMed:8942978}.
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:15563508};
CC Lipid-anchor, GPI-anchor {ECO:0000269|PubMed:7625839}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=P22748-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P22748-2; Sequence=VSP_055973, VSP_055974;
CC -!- TISSUE SPECIFICITY: Expressed in the endothelium of the
CC choriocapillaris in eyes (at protein level). Not expressed in the
CC retinal epithelium at detectable levels. {ECO:0000269|PubMed:15563508}.
CC -!- DISEASE: Retinitis pigmentosa 17 (RP17) [MIM:600852]: A retinal
CC dystrophy belonging to the group of pigmentary retinopathies. Retinitis
CC pigmentosa is characterized by retinal pigment deposits visible on
CC fundus examination and primary loss of rod photoreceptor cells followed
CC by secondary loss of cone photoreceptors. Patients typically have night
CC vision blindness and loss of midperipheral visual field. As their
CC condition progresses, they lose their far peripheral visual field and
CC eventually central vision as well. {ECO:0000269|PubMed:15563508,
CC ECO:0000269|PubMed:17652713, ECO:0000269|PubMed:20450258}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry. Defective acid overload removal from retina and retinal
CC epithelium, due to mutant CA4, is responsible for photoreceptor
CC degeneration, indicating that impaired pH homeostasis is the most
CC likely cause underlying the RP17 phenotype.
CC -!- SIMILARITY: Belongs to the alpha-carbonic anhydrase family.
CC {ECO:0000305}.
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DR EMBL; M83670; AAA35630.1; -; mRNA.
DR EMBL; L10955; AAA35625.1; ALT_SEQ; Genomic_DNA.
DR EMBL; L10951; AAA35625.1; JOINED; Genomic_DNA.
DR EMBL; L10953; AAA35625.1; JOINED; Genomic_DNA.
DR EMBL; L10954; AAA35625.1; JOINED; Genomic_DNA.
DR EMBL; L10955; AAA35626.1; ALT_SEQ; Genomic_DNA.
DR EMBL; L10954; AAA35626.1; JOINED; Genomic_DNA.
DR EMBL; AK289715; BAF82404.1; -; mRNA.
DR EMBL; AK298710; BAG60866.1; -; mRNA.
DR EMBL; CR541766; CAG46565.1; -; mRNA.
DR EMBL; AC025048; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471109; EAW94362.1; -; Genomic_DNA.
DR EMBL; BC057792; AAH57792.1; -; mRNA.
DR EMBL; BC069649; AAH69649.1; -; mRNA.
DR EMBL; BC074768; AAH74768.1; -; mRNA.
DR CCDS; CCDS11624.1; -. [P22748-1]
DR PIR; A45745; CRHU4.
DR RefSeq; NP_000708.1; NM_000717.4. [P22748-1]
DR RefSeq; XP_016880501.1; XM_017025012.1.
DR PDB; 1ZNC; X-ray; 2.80 A; A/B=19-284.
DR PDB; 3F7B; X-ray; 2.05 A; A/B=19-284.
DR PDB; 3F7U; X-ray; 2.00 A; A/B/C/D=19-284.
DR PDB; 3FW3; X-ray; 1.72 A; A/B=19-284.
DR PDB; 5IPZ; X-ray; 2.10 A; A/B/C/D=19-284.
DR PDB; 5JN8; X-ray; 1.85 A; A/B/C/D=19-284.
DR PDB; 5JN9; X-ray; 2.10 A; A/B/C/D=19-284.
DR PDB; 5JNA; X-ray; 2.00 A; A/B/C/D=19-284.
DR PDB; 5JNC; X-ray; 2.00 A; A/B/C/D=19-284.
DR PDB; 5KU6; X-ray; 1.80 A; A/B/C/D=19-284.
DR PDBsum; 1ZNC; -.
DR PDBsum; 3F7B; -.
DR PDBsum; 3F7U; -.
DR PDBsum; 3FW3; -.
DR PDBsum; 5IPZ; -.
DR PDBsum; 5JN8; -.
DR PDBsum; 5JN9; -.
DR PDBsum; 5JNA; -.
DR PDBsum; 5JNC; -.
DR PDBsum; 5KU6; -.
DR AlphaFoldDB; P22748; -.
DR SMR; P22748; -.
DR BioGRID; 107217; 11.
DR IntAct; P22748; 6.
DR STRING; 9606.ENSP00000300900; -.
DR BindingDB; P22748; -.
DR ChEMBL; CHEMBL3729; -.
DR DrugBank; DB00819; Acetazolamide.
DR DrugBank; DB00436; Bendroflumethiazide.
DR DrugBank; DB00562; Benzthiazide.
DR DrugBank; DB01194; Brinzolamide.
DR DrugBank; DB00606; Cyclothiazide.
DR DrugBank; DB01144; Diclofenamide.
DR DrugBank; DB00869; Dorzolamide.
DR DrugBank; DB08846; Ellagic acid.
DR DrugBank; DB00311; Ethoxzolamide.
DR DrugBank; DB00774; Hydroflumethiazide.
DR DrugBank; DB00703; Methazolamide.
DR DrugBank; DB00232; Methyclothiazide.
DR DrugBank; DB09460; Sodium carbonate.
DR DrugBank; DB00273; Topiramate.
DR DrugBank; DB01021; Trichlormethiazide.
DR DrugBank; DB00909; Zonisamide.
DR DrugCentral; P22748; -.
DR GuidetoPHARMACOLOGY; 2599; -.
DR iPTMnet; P22748; -.
DR PhosphoSitePlus; P22748; -.
DR BioMuta; CA4; -.
DR DMDM; 115465; -.
DR EPD; P22748; -.
DR jPOST; P22748; -.
DR MassIVE; P22748; -.
DR PaxDb; 9606-ENSP00000300900; -.
DR PeptideAtlas; P22748; -.
DR ProteomicsDB; 54034; -. [P22748-1]
DR Antibodypedia; 2592; 361 antibodies from 33 providers.
DR DNASU; 762; -.
DR Ensembl; ENST00000300900.9; ENSP00000300900.3; ENSG00000167434.10. [P22748-1]
DR Ensembl; ENST00000586876.1; ENSP00000467465.1; ENSG00000167434.10. [P22748-2]
DR GeneID; 762; -.
DR KEGG; hsa:762; -.
DR MANE-Select; ENST00000300900.9; ENSP00000300900.3; NM_000717.5; NP_000708.1.
DR UCSC; uc002iym.5; human. [P22748-1]
DR AGR; HGNC:1375; -.
DR CTD; 762; -.
DR DisGeNET; 762; -.
DR GeneCards; CA4; -.
DR GeneReviews; CA4; -.
DR HGNC; HGNC:1375; CA4.
DR HPA; ENSG00000167434; Tissue enhanced (intestine).
DR MalaCards; CA4; -.
DR MIM; 114760; gene.
DR MIM; 600852; phenotype.
DR neXtProt; NX_P22748; -.
DR OpenTargets; ENSG00000167434; -.
DR Orphanet; 791; Retinitis pigmentosa.
DR PharmGKB; PA25991; -.
DR VEuPathDB; HostDB:ENSG00000167434; -.
DR eggNOG; KOG0382; Eukaryota.
DR GeneTree; ENSGT00940000155690; -.
DR HOGENOM; CLU_039326_2_2_1; -.
DR InParanoid; P22748; -.
DR OMA; TGSGDWC; -.
DR OrthoDB; 49814at2759; -.
DR PhylomeDB; P22748; -.
DR TreeFam; TF316425; -.
DR BRENDA; 4.2.1.1; 2681.
DR PathwayCommons; P22748; -.
DR Reactome; R-HSA-1237044; Erythrocytes take up carbon dioxide and release oxygen.
DR Reactome; R-HSA-1247673; Erythrocytes take up oxygen and release carbon dioxide.
DR Reactome; R-HSA-1475029; Reversible hydration of carbon dioxide.
DR SABIO-RK; P22748; -.
DR SignaLink; P22748; -.
DR BioGRID-ORCS; 762; 18 hits in 1156 CRISPR screens.
DR ChiTaRS; CA4; human.
DR EvolutionaryTrace; P22748; -.
DR GeneWiki; Carbonic_anhydrase_4; -.
DR GenomeRNAi; 762; -.
DR Pharos; P22748; Tclin.
DR PRO; PR:P22748; -.
DR Proteomes; UP000005640; Chromosome 17.
DR RNAct; P22748; Protein.
DR Bgee; ENSG00000167434; Expressed in mucosa of transverse colon and 178 other cell types or tissues.
DR ExpressionAtlas; P22748; baseline and differential.
DR Genevisible; P22748; HS.
DR GO; GO:0016324; C:apical plasma membrane; IDA:DFLAT.
DR GO; GO:0031526; C:brush border membrane; IDA:DFLAT.
DR GO; GO:0009986; C:cell surface; IDA:DFLAT.
DR GO; GO:0005793; C:endoplasmic reticulum-Golgi intermediate compartment; IDA:DFLAT.
DR GO; GO:0009897; C:external side of plasma membrane; IDA:DFLAT.
DR GO; GO:0070062; C:extracellular exosome; IDA:UniProtKB.
DR GO; GO:0005794; C:Golgi apparatus; IDA:DFLAT.
DR GO; GO:0016020; C:membrane; TAS:ProtInc.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; IDA:DFLAT.
DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR GO; GO:0005791; C:rough endoplasmic reticulum; IDA:DFLAT.
DR GO; GO:0030667; C:secretory granule membrane; IDA:DFLAT.
DR GO; GO:0005802; C:trans-Golgi network; IDA:DFLAT.
DR GO; GO:0030658; C:transport vesicle membrane; IDA:DFLAT.
DR GO; GO:0004089; F:carbonate dehydratase activity; IBA:GO_Central.
DR GO; GO:0008270; F:zinc ion binding; IEA:InterPro.
DR GO; GO:0015701; P:bicarbonate transport; IMP:DFLAT.
DR GO; GO:0006730; P:one-carbon metabolic process; IBA:GO_Central.
DR CDD; cd03117; alpha_CA_IV_XV_like; 1.
DR Gene3D; 3.10.200.10; Alpha carbonic anhydrase; 1.
DR InterPro; IPR041874; CA4/CA15.
DR InterPro; IPR001148; CA_dom.
DR InterPro; IPR036398; CA_dom_sf.
DR InterPro; IPR023561; Carbonic_anhydrase_a-class.
DR InterPro; IPR018338; Carbonic_anhydrase_a-class_CS.
DR PANTHER; PTHR18952; CARBONIC ANHYDRASE; 1.
DR PANTHER; PTHR18952:SF95; CARBONIC ANHYDRASE 4; 1.
DR Pfam; PF00194; Carb_anhydrase; 1.
DR SMART; SM01057; Carb_anhydrase; 1.
DR SUPFAM; SSF51069; Carbonic anhydrase; 1.
DR PROSITE; PS00162; ALPHA_CA_1; 1.
DR PROSITE; PS51144; ALPHA_CA_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Cell membrane;
KW Direct protein sequencing; Disease variant; Disulfide bond; Glycoprotein;
KW GPI-anchor; Lipoprotein; Lyase; Membrane; Metal-binding;
KW Reference proteome; Retinitis pigmentosa; Signal; Zinc.
FT SIGNAL 1..18
FT /evidence="ECO:0000269|PubMed:2111324"
FT CHAIN 19..284
FT /note="Carbonic anhydrase 4"
FT /id="PRO_0000004226"
FT PROPEP 285..312
FT /note="Removed in mature form"
FT /evidence="ECO:0000269|PubMed:7625839"
FT /id="PRO_0000004227"
FT DOMAIN 21..285
FT /note="Alpha-carbonic anhydrase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01134"
FT ACT_SITE 88
FT /note="Proton donor/acceptor"
FT /evidence="ECO:0000250|UniProtKB:P00918"
FT BINDING 115
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000269|PubMed:8942978"
FT BINDING 117
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000269|PubMed:8942978"
FT BINDING 140
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000269|PubMed:8942978"
FT BINDING 225..226
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P00918"
FT LIPID 284
FT /note="GPI-anchor amidated serine"
FT /evidence="ECO:0000269|PubMed:7625839"
FT DISULFID 24..36
FT /evidence="ECO:0000269|PubMed:8809084"
FT DISULFID 46..229
FT /evidence="ECO:0000269|PubMed:8809084"
FT VAR_SEQ 90..106
FT /note="VMMLLENKASISGGGLP -> GWNPGERGLPATGGGTV (in isoform
FT 2)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_055973"
FT VAR_SEQ 107..312
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_055974"
FT VARIANT 12
FT /note="A -> T (in RP17; dbSNP:rs1245199379)"
FT /evidence="ECO:0000269|PubMed:20450258"
FT /id="VAR_071430"
FT VARIANT 14
FT /note="R -> W (in RP17; abolishes interaction with SLC4A4;
FT impaired SLC4A4 cotransporter activity stimulation;
FT dbSNP:rs104894559)"
FT /evidence="ECO:0000269|PubMed:15563508"
FT /id="VAR_024749"
FT VARIANT 69
FT /note="R -> H (in RP17; has no effect on carbonate
FT dehydratase activity; loss of interaction with SLC4A4;
FT dbSNP:rs121434552)"
FT /evidence="ECO:0000269|PubMed:17652713"
FT /id="VAR_071431"
FT VARIANT 177
FT /note="N -> K (in dbSNP:rs185942554)"
FT /evidence="ECO:0000269|PubMed:17652713"
FT /id="VAR_071432"
FT VARIANT 219
FT /note="R -> S (in RP17; abolishes carbonate dehydratase
FT activity; impaired SLC4A4 cotransporter activity
FT stimulation; dbSNP:rs121434551)"
FT /evidence="ECO:0000269|PubMed:15563508"
FT /id="VAR_024750"
FT VARIANT 237
FT /note="V -> L (in dbSNP:rs2229178)"
FT /id="VAR_048680"
FT MUTAGEN 284
FT /note="S->F: Loss of C-terminal domain removal and
FT abolishes carbonate dehydratase activity."
FT /evidence="ECO:0000269|PubMed:7625839"
FT CONFLICT 24
FT /note="C -> E (in Ref. 8; AA sequence)"
FT /evidence="ECO:0000305"
FT HELIX 26..29
FT /evidence="ECO:0007829|PDB:3FW3"
FT HELIX 39..41
FT /evidence="ECO:0007829|PDB:3FW3"
FT TURN 44..47
FT /evidence="ECO:0007829|PDB:3FW3"
FT STRAND 48..50
FT /evidence="ECO:0007829|PDB:3FW3"
FT HELIX 58..60
FT /evidence="ECO:0007829|PDB:3FW3"
FT STRAND 61..63
FT /evidence="ECO:0007829|PDB:3FW3"
FT STRAND 70..77
FT /evidence="ECO:0007829|PDB:3FW3"
FT STRAND 82..85
FT /evidence="ECO:0007829|PDB:3FW3"
FT STRAND 87..93
FT /evidence="ECO:0007829|PDB:3FW3"
FT STRAND 99..102
FT /evidence="ECO:0007829|PDB:3FW3"
FT STRAND 109..118
FT /evidence="ECO:0007829|PDB:3FW3"
FT TURN 122..124
FT /evidence="ECO:0007829|PDB:5IPZ"
FT STRAND 127..130
FT /evidence="ECO:0007829|PDB:3FW3"
FT STRAND 136..145
FT /evidence="ECO:0007829|PDB:3FW3"
FT HELIX 153..157
FT /evidence="ECO:0007829|PDB:5KU6"
FT STRAND 162..175
FT /evidence="ECO:0007829|PDB:3FW3"
FT HELIX 178..180
FT /evidence="ECO:0007829|PDB:3FW3"
FT HELIX 181..186
FT /evidence="ECO:0007829|PDB:3FW3"
FT HELIX 187..189
FT /evidence="ECO:0007829|PDB:3FW3"
FT STRAND 196..198
FT /evidence="ECO:0007829|PDB:3FW3"
FT HELIX 205..207
FT /evidence="ECO:0007829|PDB:3FW3"
FT HELIX 211..214
FT /evidence="ECO:0007829|PDB:3FW3"
FT STRAND 217..222
FT /evidence="ECO:0007829|PDB:3FW3"
FT STRAND 233..240
FT /evidence="ECO:0007829|PDB:3FW3"
FT STRAND 242..245
FT /evidence="ECO:0007829|PDB:3FW3"
FT HELIX 246..255
FT /evidence="ECO:0007829|PDB:3FW3"
FT STRAND 257..259
FT /evidence="ECO:0007829|PDB:3FW3"
FT STRAND 264..266
FT /evidence="ECO:0007829|PDB:5KU6"
SQ SEQUENCE 312 AA; 35032 MW; EF5F182474ABE9B0 CRC64;
MRMLLALLAL SAARPSASAE SHWCYEVQAE SSNYPCLVPV KWGGNCQKDR QSPINIVTTK
AKVDKKLGRF FFSGYDKKQT WTVQNNGHSV MMLLENKASI SGGGLPAPYQ AKQLHLHWSD
LPYKGSEHSL DGEHFAMEMH IVHEKEKGTS RNVKEAQDPE DEIAVLAFLV EAGTQVNEGF
QPLVEALSNI PKPEMSTTMA ESSLLDLLPK EEKLRHYFRY LGSLTTPTCD EKVVWTVFRE
PIQLHREQIL AFSQKLYYDK EQTVSMKDNV RPLQQLGQRT VIKSGAPGRP LPWALPALLG
PMLACLLAGF LR
//
