CAH6_HUMAN
ID CAH6_HUMAN Reviewed; 308 AA.
AC P23280; E7EMQ1; Q5FBW3; Q5FC00; Q96QX8; Q9UF03;
DT 01-NOV-1991, integrated into UniProtKB/Swiss-Prot.
DT 17-OCT-2006, sequence version 3.
DT 03-AUG-2022, entry version 194.
DE RecName: Full=Carbonic anhydrase 6;
DE EC=4.2.1.1;
DE AltName: Full=Carbonate dehydratase VI;
DE AltName: Full=Carbonic anhydrase VI;
DE Short=CA-VI;
DE AltName: Full=Salivary carbonic anhydrase;
DE AltName: Full=Secreted carbonic anhydrase;
DE Flags: Precursor;
GN Name=CA6;
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), AND VARIANT GLY-90.
RX PubMed=1899030; DOI=10.1021/bi00216a035;
RA Aldred P., Fu P., Barrett G., Penschow J.D., Wright R., Coghlan J.P.,
RA Fernley R.T.;
RT "Human secreted carbonic anhydrase: cDNA cloning, nucleotide sequence, and
RT hybridization histochemistry.";
RL Biochemistry 30:569-575(1991).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT GLY-90.
RA Grubb D.J.;
RL Submitted (FEB-1999) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 2 AND 3), AND VARIANT GLY-90.
RA Tabata Y., Hayashi A., Sameshima E., Iida K., Mitsuyama M., Kanai S.,
RA Furuya T., Saito T.;
RT "CA6 mRNA, nirs splice variant 1.";
RL Submitted (FEB-2003) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16710414; DOI=10.1038/nature04727;
RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A.,
RA Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C.,
RA Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K.,
RA Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C.,
RA Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W.,
RA Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J.,
RA Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J.,
RA Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y.,
RA Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J.,
RA Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S.,
RA Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K.,
RA Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R.,
RA Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M.,
RA Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S.,
RA Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J.,
RA Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W.,
RA McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S.,
RA Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M.,
RA White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H.,
RA Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E.,
RA Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G.,
RA Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence and biological annotation of human chromosome 1.";
RL Nature 441:315-321(2006).
RN [5]
RP ACTIVITY REGULATION.
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 [6]
RP ACTIVITY REGULATION.
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 [7]
RP ACTIVITY REGULATION.
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 [8]
RP ACTIVITY REGULATION.
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 [9]
RP X-RAY CRYSTALLOGRAPHY (1.90 ANGSTROMS) OF 21-290 IN COMPLEX WITH MAGNESIUM
RP ION.
RX PubMed=4628675; DOI=10.1101/sqb.1972.036.01.030;
RA Kannan K.K., Liljas A., Waara I., Bergsten P.C., Loevgren S.,
RA Strandberg B., Bengtsson U., Carlbom U., Fridborg K., Jaerup L., Petef M.;
RT "Crystal structure of human erythrocyte carbonic anhydrase C. VI. The
RT three-dimensional structure at high resolution in relation to other
RT mammalian carbonic anhydrases.";
RL Cold Spring Harb. Symp. Quant. Biol. 36:221-231(1972).
CC -!- FUNCTION: Reversible hydration of carbon dioxide. Its role in saliva is
CC unknown.
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;
CC -!- COFACTOR:
CC Name=Zn(2+); Xref=ChEBI:CHEBI:29105;
CC Evidence={ECO:0000250|UniProtKB:P23589};
CC -!- ACTIVITY REGULATION: Inhibited by coumarins, sulfonamide derivatives
CC such as acetazolamide (AZA), saccharin and Foscarnet (phosphonoformate
CC trisodium salt). {ECO:0000269|PubMed:17314045,
CC ECO:0000269|PubMed:17705204, ECO:0000269|PubMed:19186056,
CC ECO:0000269|PubMed:19206230}.
CC -!- SUBCELLULAR LOCATION: Secreted.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=P23280-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P23280-2; Sequence=VSP_045435;
CC Name=3;
CC IsoId=P23280-3; Sequence=VSP_046668;
CC -!- TISSUE SPECIFICITY: Major constituent of saliva.
CC -!- SIMILARITY: Belongs to the alpha-carbonic anhydrase family.
CC {ECO:0000305}.
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DR EMBL; M57892; AAA51892.1; -; mRNA.
DR EMBL; AF128418; AAF22565.1; -; Genomic_DNA.
DR EMBL; AF128411; AAF22565.1; JOINED; Genomic_DNA.
DR EMBL; AF128412; AAF22565.1; JOINED; Genomic_DNA.
DR EMBL; AF128413; AAF22565.1; JOINED; Genomic_DNA.
DR EMBL; AF128414; AAF22565.1; JOINED; Genomic_DNA.
DR EMBL; AF128415; AAF22565.1; JOINED; Genomic_DNA.
DR EMBL; AF128416; AAF22565.1; JOINED; Genomic_DNA.
DR EMBL; AF128417; AAF22565.1; JOINED; Genomic_DNA.
DR EMBL; AB102863; BAD89397.1; -; mRNA.
DR EMBL; AB103091; BAD89434.1; -; mRNA.
DR EMBL; AL139415; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR CCDS; CCDS30578.1; -. [P23280-1]
DR CCDS; CCDS57970.1; -. [P23280-2]
DR CCDS; CCDS57971.1; -. [P23280-3]
DR PIR; A37917; CRHU6.
DR RefSeq; NP_001206.2; NM_001215.3. [P23280-1]
DR RefSeq; NP_001257429.1; NM_001270500.1. [P23280-2]
DR RefSeq; NP_001257430.1; NM_001270501.1. [P23280-3]
DR PDB; 3FE4; X-ray; 1.90 A; A/B=21-290.
DR PDBsum; 3FE4; -.
DR AlphaFoldDB; P23280; -.
DR SMR; P23280; -.
DR BioGRID; 107220; 86.
DR IntAct; P23280; 1.
DR STRING; 9606.ENSP00000366654; -.
DR BindingDB; P23280; -.
DR ChEMBL; CHEMBL3025; -.
DR DrugBank; DB00562; Benzthiazide.
DR DrugBank; DB00606; Cyclothiazide.
DR DrugBank; DB08846; Ellagic acid.
DR DrugBank; DB06795; Mafenide.
DR DrugBank; DB00909; Zonisamide.
DR DrugCentral; P23280; -.
DR GlyConnect; 1924; 10 N-Linked glycans (3 sites).
DR GlyGen; P23280; 3 sites, 11 N-linked glycans (3 sites).
DR BioMuta; CA6; -.
DR DMDM; 116241278; -.
DR jPOST; P23280; -.
DR MassIVE; P23280; -.
DR PaxDb; P23280; -.
DR PeptideAtlas; P23280; -.
DR PRIDE; P23280; -.
DR ProteomicsDB; 16991; -.
DR ProteomicsDB; 54077; -. [P23280-1]
DR ProteomicsDB; 62797; -.
DR TopDownProteomics; P23280-1; -. [P23280-1]
DR Antibodypedia; 27596; 354 antibodies from 29 providers.
DR DNASU; 765; -.
DR Ensembl; ENST00000377436.6; ENSP00000366654.3; ENSG00000131686.15. [P23280-2]
DR Ensembl; ENST00000377442.3; ENSP00000366661.2; ENSG00000131686.15. [P23280-3]
DR Ensembl; ENST00000377443.7; ENSP00000366662.2; ENSG00000131686.15. [P23280-1]
DR GeneID; 765; -.
DR KEGG; hsa:765; -.
DR MANE-Select; ENST00000377443.7; ENSP00000366662.2; NM_001215.4; NP_001206.2.
DR UCSC; uc001apm.5; human. [P23280-1]
DR CTD; 765; -.
DR DisGeNET; 765; -.
DR GeneCards; CA6; -.
DR HGNC; HGNC:1380; CA6.
DR HPA; ENSG00000131686; Tissue enriched (salivary).
DR MIM; 114780; gene.
DR neXtProt; NX_P23280; -.
DR OpenTargets; ENSG00000131686; -.
DR PharmGKB; PA25995; -.
DR VEuPathDB; HostDB:ENSG00000131686; -.
DR eggNOG; KOG0382; Eukaryota.
DR GeneTree; ENSGT00940000160409; -.
DR HOGENOM; CLU_039326_1_0_1; -.
DR InParanoid; P23280; -.
DR OMA; PPTMRMT; -.
DR OrthoDB; 1377476at2759; -.
DR PhylomeDB; P23280; -.
DR TreeFam; TF316425; -.
DR BRENDA; 4.2.1.1; 2681.
DR PathwayCommons; P23280; -.
DR Reactome; R-HSA-1475029; Reversible hydration of carbon dioxide.
DR SignaLink; P23280; -.
DR BioGRID-ORCS; 765; 12 hits in 1076 CRISPR screens.
DR ChiTaRS; CA6; human.
DR EvolutionaryTrace; P23280; -.
DR GeneWiki; Carbonic_anhydrase_VI; -.
DR GenomeRNAi; 765; -.
DR Pharos; P23280; Tclin.
DR PRO; PR:P23280; -.
DR Proteomes; UP000005640; Chromosome 1.
DR RNAct; P23280; protein.
DR Bgee; ENSG00000131686; Expressed in parotid gland and 92 other tissues.
DR ExpressionAtlas; P23280; baseline and differential.
DR Genevisible; P23280; HS.
DR GO; GO:0005829; C:cytosol; IEA:Ensembl.
DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB.
DR GO; GO:0005576; C:extracellular region; TAS:Reactome.
DR GO; GO:0005615; C:extracellular space; IDA:UniProtKB.
DR GO; GO:0004089; F:carbonate dehydratase activity; IBA:GO_Central.
DR GO; GO:0016836; F:hydro-lyase activity; IBA:GO_Central.
DR GO; GO:0008270; F:zinc ion binding; IEA:InterPro.
DR GO; GO:0001580; P:detection of chemical stimulus involved in sensory perception of bitter taste; IDA:UniProtKB.
DR GO; GO:0006730; P:one-carbon metabolic process; IBA:GO_Central.
DR DisProt; DP02680; -.
DR Gene3D; 3.10.200.10; -; 1.
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 InterPro; IPR018428; Carbonic_anhydrase_CA6.
DR PANTHER; PTHR18952; PTHR18952; 1.
DR PANTHER; PTHR18952:SF110; PTHR18952:SF110; 1.
DR Pfam; PF00194; Carb_anhydrase; 1.
DR SMART; SM01057; Carb_anhydrase; 1.
DR SUPFAM; SSF51069; SSF51069; 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; Disulfide bond; Glycoprotein; Lyase;
KW Metal-binding; Reference proteome; Secreted; Signal; Zinc.
FT SIGNAL 1..17
FT /evidence="ECO:0000255"
FT CHAIN 18..308
FT /note="Carbonic anhydrase 6"
FT /id="PRO_0000004241"
FT DOMAIN 21..278
FT /note="Alpha-carbonic anhydrase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01134"
FT ACT_SITE 85
FT /note="Proton donor/acceptor"
FT /evidence="ECO:0000250|UniProtKB:P00918"
FT BINDING 111
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000305|PubMed:4628675"
FT BINDING 113
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000305|PubMed:4628675"
FT BINDING 138
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000305|PubMed:4628675"
FT BINDING 220..221
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P00918"
FT CARBOHYD 67
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 256
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 42..224
FT /evidence="ECO:0000255"
FT VAR_SEQ 27..86
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000303|Ref.3"
FT /id="VSP_046668"
FT VAR_SEQ 282..308
FT /note="EYTLGSEFQFYLHKIEEILDYLRRALN -> GKGHGGHRGRSQNPRVQPTST
FT RHPLALGSLEA (in isoform 2)"
FT /evidence="ECO:0000303|Ref.3"
FT /id="VSP_045435"
FT VARIANT 37
FT /note="Q -> L (in dbSNP:rs34265054)"
FT /id="VAR_033712"
FT VARIANT 55
FT /note="T -> M (in dbSNP:rs2274327)"
FT /id="VAR_028268"
FT VARIANT 58
FT /note="R -> W (in dbSNP:rs58800854)"
FT /id="VAR_061093"
FT VARIANT 68
FT /note="M -> L (in dbSNP:rs2274328)"
FT /id="VAR_028269"
FT VARIANT 70
FT /note="G -> A (in dbSNP:rs2274329)"
FT /id="VAR_028270"
FT VARIANT 90
FT /note="S -> G (in dbSNP:rs2274333)"
FT /evidence="ECO:0000269|PubMed:1899030, ECO:0000269|Ref.2,
FT ECO:0000269|Ref.3"
FT /id="VAR_028271"
FT CONFLICT 103
FT /note="T -> I (in Ref. 1; AAA51892 and 4; BAD89434)"
FT /evidence="ECO:0000305"
FT CONFLICT 148
FT /note="S -> T (in Ref. 1; AAA51892, 2; AAF22565 and 4;
FT BAD89434)"
FT /evidence="ECO:0000305"
FT CONFLICT 270
FT /note="N -> K (in Ref. 1; AAA51892, 2; AAF22565 and 4;
FT BAD89434)"
FT /evidence="ECO:0000305"
FT HELIX 35..38
FT /evidence="ECO:0007829|PDB:3FE4"
FT HELIX 40..43
FT /evidence="ECO:0007829|PDB:3FE4"
FT STRAND 44..46
FT /evidence="ECO:0007829|PDB:3FE4"
FT HELIX 54..56
FT /evidence="ECO:0007829|PDB:3FE4"
FT STRAND 68..70
FT /evidence="ECO:0007829|PDB:3FE4"
FT STRAND 72..82
FT /evidence="ECO:0007829|PDB:3FE4"
FT STRAND 87..90
FT /evidence="ECO:0007829|PDB:3FE4"
FT STRAND 96..98
FT /evidence="ECO:0007829|PDB:3FE4"
FT STRAND 104..114
FT /evidence="ECO:0007829|PDB:3FE4"
FT STRAND 125..128
FT /evidence="ECO:0007829|PDB:3FE4"
FT STRAND 134..143
FT /evidence="ECO:0007829|PDB:3FE4"
FT STRAND 146..148
FT /evidence="ECO:0007829|PDB:3FE4"
FT HELIX 149..152
FT /evidence="ECO:0007829|PDB:3FE4"
FT STRAND 159..167
FT /evidence="ECO:0007829|PDB:3FE4"
FT HELIX 175..177
FT /evidence="ECO:0007829|PDB:3FE4"
FT HELIX 178..183
FT /evidence="ECO:0007829|PDB:3FE4"
FT HELIX 184..187
FT /evidence="ECO:0007829|PDB:3FE4"
FT STRAND 193..199
FT /evidence="ECO:0007829|PDB:3FE4"
FT HELIX 201..204
FT /evidence="ECO:0007829|PDB:3FE4"
FT STRAND 212..217
FT /evidence="ECO:0007829|PDB:3FE4"
FT STRAND 228..235
FT /evidence="ECO:0007829|PDB:3FE4"
FT HELIX 241..249
FT /evidence="ECO:0007829|PDB:3FE4"
FT STRAND 256..258
FT /evidence="ECO:0007829|PDB:3FE4"
FT STRAND 275..277
FT /evidence="ECO:0007829|PDB:3FE4"
SQ SEQUENCE 308 AA; 35367 MW; 6EBFF15085E7112D CRC64;
MRALVLLLSL FLLGGQAQHV SDWTYSEGAL DEAHWPQHYP ACGGQRQSPI NLQRTKVRYN
PSLKGLNMTG YETQAGEFPM VNNGHTVQIS LPSTMRMTVA DGTVYIAQQM HFHWGGASSE
ISGSEHTVDG IRHVIEIHIV HYNSKYKSYD IAQDAPDGLA VLAAFVEVKN YPENTYYSNF
ISHLANIKYP GQRTTLTGLD VQDMLPRNLQ HYYTYHGSLT TPPCTENVHW FVLADFVKLS
RTQVWKLENS LLDHRNKTIH NDYRRTQPLN HRVVESNFPN QEYTLGSEFQ FYLHKIEEIL
DYLRRALN
