EST3_HUMAN
ID EST3_HUMAN Reviewed; 571 AA.
AC Q6UWW8; B2Z3W9; F5H242; Q7Z6J1; Q9H6X7;
DT 02-OCT-2007, integrated into UniProtKB/Swiss-Prot.
DT 05-JUL-2004, sequence version 1.
DT 03-AUG-2022, entry version 146.
DE RecName: Full=Carboxylesterase 3;
DE EC=3.1.1.1;
DE AltName: Full=Liver carboxylesterase 31 homolog;
DE Flags: Precursor;
GN Name=CES3; ORFNames=UNQ869/PRO1887;
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), GLYCOSYLATION, TISSUE SPECIFICITY,
RP AND BIOPHYSICOCHEMICAL PROPERTIES.
RC TISSUE=Liver;
RX PubMed=15100172; DOI=10.1124/dmd.32.5.505;
RA Sanghani S.P., Quinney S.K., Fredenburg T.B., Davis W.I., Murry D.J.,
RA Bosron W.F.;
RT "Hydrolysis of irinotecan and its oxidative metabolites, 7-ethyl-10-[4-N-
RT (5-aminopentanoic acid)-1-piperidino] carbonyloxycamptothecin and 7-ethyl-
RT 10-[4-(1-piperidino)-1-amino]-carbonyloxycamptothecin, by human
RT carboxylesterases CES1A1, CES2, and a newly expressed carboxylesterase
RT isoenzyme, CES3.";
RL Drug Metab. Dispos. 32:505-511(2004).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RX PubMed=12975309; DOI=10.1101/gr.1293003;
RA Clark H.F., Gurney A.L., Abaya E., Baker K., Baldwin D.T., Brush J.,
RA Chen J., Chow B., Chui C., Crowley C., Currell B., Deuel B., Dowd P.,
RA Eaton D., Foster J.S., Grimaldi C., Gu Q., Hass P.E., Heldens S., Huang A.,
RA Kim H.S., Klimowski L., Jin Y., Johnson S., Lee J., Lewis L., Liao D.,
RA Mark M.R., Robbie E., Sanchez C., Schoenfeld J., Seshagiri S., Simmons L.,
RA Singh J., Smith V., Stinson J., Vagts A., Vandlen R.L., Watanabe C.,
RA Wieand D., Woods K., Xie M.-H., Yansura D.G., Yi S., Yu G., Yuan J.,
RA Zhang M., Zhang Z., Goddard A.D., Wood W.I., Godowski P.J., Gray A.M.;
RT "The secreted protein discovery initiative (SPDI), a large-scale effort to
RT identify novel human secreted and transmembrane proteins: a bioinformatics
RT assessment.";
RL Genome Res. 13:2265-2270(2003).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Colon mucosa;
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 [GENOMIC DNA], AND VARIANTS ILE-129; THR-151; HIS-160;
RP LYS-191; ASN-213; TRP-367; VAL-523 AND VAL-555.
RG NIEHS SNPs program;
RL Submitted (MAR-2008) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15616553; DOI=10.1038/nature03187;
RA Martin J., Han C., Gordon L.A., Terry A., Prabhakar S., She X., Xie G.,
RA Hellsten U., Chan Y.M., Altherr M., Couronne O., Aerts A., Bajorek E.,
RA Black S., Blumer H., Branscomb E., Brown N.C., Bruno W.J., Buckingham J.M.,
RA Callen D.F., Campbell C.S., Campbell M.L., Campbell E.W., Caoile C.,
RA Challacombe J.F., Chasteen L.A., Chertkov O., Chi H.C., Christensen M.,
RA Clark L.M., Cohn J.D., Denys M., Detter J.C., Dickson M.,
RA Dimitrijevic-Bussod M., Escobar J., Fawcett J.J., Flowers D., Fotopulos D.,
RA Glavina T., Gomez M., Gonzales E., Goodstein D., Goodwin L.A., Grady D.L.,
RA Grigoriev I., Groza M., Hammon N., Hawkins T., Haydu L., Hildebrand C.E.,
RA Huang W., Israni S., Jett J., Jewett P.B., Kadner K., Kimball H.,
RA Kobayashi A., Krawczyk M.-C., Leyba T., Longmire J.L., Lopez F., Lou Y.,
RA Lowry S., Ludeman T., Manohar C.F., Mark G.A., McMurray K.L., Meincke L.J.,
RA Morgan J., Moyzis R.K., Mundt M.O., Munk A.C., Nandkeshwar R.D.,
RA Pitluck S., Pollard M., Predki P., Parson-Quintana B., Ramirez L., Rash S.,
RA Retterer J., Ricke D.O., Robinson D.L., Rodriguez A., Salamov A.,
RA Saunders E.H., Scott D., Shough T., Stallings R.L., Stalvey M.,
RA Sutherland R.D., Tapia R., Tesmer J.G., Thayer N., Thompson L.S., Tice H.,
RA Torney D.C., Tran-Gyamfi M., Tsai M., Ulanovsky L.E., Ustaszewska A.,
RA Vo N., White P.S., Williams A.L., Wills P.L., Wu J.-R., Wu K., Yang J.,
RA DeJong P., Bruce D., Doggett N.A., Deaven L., Schmutz J., Grimwood J.,
RA Richardson P., Rokhsar D.S., Eichler E.E., Gilna P., Lucas S.M.,
RA Myers R.M., Rubin E.M., Pennacchio L.A.;
RT "The sequence and analysis of duplication-rich human chromosome 16.";
RL Nature 432:988-994(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Eye;
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 TISSUE SPECIFICITY.
RX PubMed=14581373;
RA Sanghani S.P., Quinney S.K., Fredenburg T.B., Sun Z., Davis W.I.,
RA Murry D.J., Cummings O.W., Seitz D.E., Bosron W.F.;
RT "Carboxylesterases expressed in human colon tumor tissue and their role in
RT CPT-11 hydrolysis.";
RL Clin. Cancer Res. 9:4983-4991(2003).
RN [9]
RP TISSUE SPECIFICITY.
RX PubMed=15687373; DOI=10.1124/jpet.104.081265;
RA Quinney S.K., Sanghani S.P., Davis W.I., Hurley T.D., Sun Z., Murry D.J.,
RA Bosron W.F.;
RT "Hydrolysis of capecitabine to 5'-deoxy-5-fluorocytidine by human
RT carboxylesterases and inhibition by loperamide.";
RL J. Pharmacol. Exp. Ther. 313:1011-1016(2005).
RN [10]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-105.
RC TISSUE=Liver;
RX PubMed=19159218; DOI=10.1021/pr8008012;
RA Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H.;
RT "Glycoproteomics analysis of human liver tissue by combination of multiple
RT enzyme digestion and hydrazide chemistry.";
RL J. Proteome Res. 8:651-661(2009).
CC -!- FUNCTION: Involved in the detoxification of xenobiotics and in the
CC activation of ester and amide prodrugs. Shows low catalytic efficiency
CC for hydrolysis of CPT-11 (7-ethyl-10-[4-(1-piperidino)-1-piperidino]-
CC carbonyloxycamptothecin), a prodrug for camptothecin used in cancer
CC therapeutics.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=a carboxylic ester + H2O = a carboxylate + an alcohol + H(+);
CC Xref=Rhea:RHEA:21164, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:29067, ChEBI:CHEBI:30879, ChEBI:CHEBI:33308; EC=3.1.1.1;
CC Evidence={ECO:0000255|PROSITE-ProRule:PRU10039};
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=137 uM for 7-ethyl-10-[4-(1-piperidino)-1-piperidino]-
CC carbonyloxycamptothecin {ECO:0000269|PubMed:15100172};
CC KM=460 uM for 7-ethyl-10-[4-(1-piperidino)-1-amino]-
CC carbonyloxycamptothecin {ECO:0000269|PubMed:15100172};
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum lumen {ECO:0000250}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q6UWW8-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q6UWW8-2; Sequence=VSP_044994;
CC -!- TISSUE SPECIFICITY: Expressed in liver, colon and small intestine.
CC {ECO:0000269|PubMed:14581373, ECO:0000269|PubMed:15100172,
CC ECO:0000269|PubMed:15687373}.
CC -!- PTM: N-glycosylated. {ECO:0000269|PubMed:15100172,
CC ECO:0000269|PubMed:19159218}.
CC -!- SIMILARITY: Belongs to the type-B carboxylesterase/lipase family.
CC {ECO:0000305}.
CC -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC URL="http://egp.gs.washington.edu/data/ces3/";
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DR EMBL; AY358609; AAQ88972.1; -; mRNA.
DR EMBL; AK025389; BAB15123.1; -; mRNA.
DR EMBL; EU595874; ACD11491.1; -; Genomic_DNA.
DR EMBL; AC009084; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471092; EAW83060.1; -; Genomic_DNA.
DR EMBL; BC053670; AAH53670.1; -; mRNA.
DR CCDS; CCDS10826.1; -. [Q6UWW8-1]
DR CCDS; CCDS54023.1; -. [Q6UWW8-2]
DR RefSeq; NP_001172105.1; NM_001185176.1. [Q6UWW8-2]
DR RefSeq; NP_001172106.1; NM_001185177.1.
DR RefSeq; NP_079198.2; NM_024922.5. [Q6UWW8-1]
DR AlphaFoldDB; Q6UWW8; -.
DR SMR; Q6UWW8; -.
DR BioGRID; 117043; 17.
DR IntAct; Q6UWW8; 6.
DR STRING; 9606.ENSP00000304782; -.
DR ESTHER; human-CES3; Carb_B_Chordata.
DR MEROPS; S09.958; -.
DR GlyGen; Q6UWW8; 1 site.
DR iPTMnet; Q6UWW8; -.
DR PhosphoSitePlus; Q6UWW8; -.
DR BioMuta; CES3; -.
DR DMDM; 74758561; -.
DR EPD; Q6UWW8; -.
DR jPOST; Q6UWW8; -.
DR MassIVE; Q6UWW8; -.
DR MaxQB; Q6UWW8; -.
DR PaxDb; Q6UWW8; -.
DR PeptideAtlas; Q6UWW8; -.
DR PRIDE; Q6UWW8; -.
DR ProteomicsDB; 25850; -.
DR ProteomicsDB; 67533; -. [Q6UWW8-1]
DR Antibodypedia; 29363; 155 antibodies from 25 providers.
DR DNASU; 23491; -.
DR Ensembl; ENST00000303334.9; ENSP00000304782.4; ENSG00000172828.13. [Q6UWW8-1]
DR Ensembl; ENST00000543856.1; ENSP00000445559.1; ENSG00000172828.13. [Q6UWW8-2]
DR GeneID; 23491; -.
DR KEGG; hsa:23491; -.
DR MANE-Select; ENST00000303334.9; ENSP00000304782.4; NM_024922.6; NP_079198.2.
DR UCSC; uc002eqt.4; human. [Q6UWW8-1]
DR CTD; 23491; -.
DR DisGeNET; 23491; -.
DR GeneCards; CES3; -.
DR HGNC; HGNC:1865; CES3.
DR HPA; ENSG00000172828; Tissue enhanced (intestine, liver, skeletal muscle).
DR MIM; 605279; gene.
DR neXtProt; NX_Q6UWW8; -.
DR OpenTargets; ENSG00000172828; -.
DR PharmGKB; PA26418; -.
DR VEuPathDB; HostDB:ENSG00000172828; -.
DR eggNOG; KOG1516; Eukaryota.
DR GeneTree; ENSGT00940000155200; -.
DR HOGENOM; CLU_006586_2_1_1; -.
DR InParanoid; Q6UWW8; -.
DR OMA; IFFYEFQ; -.
DR OrthoDB; 754103at2759; -.
DR PhylomeDB; Q6UWW8; -.
DR TreeFam; TF315470; -.
DR BioCyc; MetaCyc:HS10576-MON; -.
DR PathwayCommons; Q6UWW8; -.
DR Reactome; R-HSA-211945; Phase I - Functionalization of compounds.
DR Reactome; R-HSA-8964038; LDL clearance.
DR SABIO-RK; Q6UWW8; -.
DR SignaLink; Q6UWW8; -.
DR BioGRID-ORCS; 23491; 11 hits in 1074 CRISPR screens.
DR GeneWiki; Carboxylesterase_3; -.
DR GenomeRNAi; 23491; -.
DR Pharos; Q6UWW8; Tbio.
DR PRO; PR:Q6UWW8; -.
DR Proteomes; UP000005640; Chromosome 16.
DR RNAct; Q6UWW8; protein.
DR Bgee; ENSG00000172828; Expressed in mucosa of transverse colon and 105 other tissues.
DR ExpressionAtlas; Q6UWW8; baseline and differential.
DR Genevisible; Q6UWW8; HS.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005788; C:endoplasmic reticulum lumen; IEA:UniProtKB-SubCell.
DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB.
DR GO; GO:0052689; F:carboxylic ester hydrolase activity; TAS:Reactome.
DR GO; GO:0080030; F:methyl indole-3-acetate esterase activity; IEA:UniProtKB-EC.
DR GO; GO:0034383; P:low-density lipoprotein particle clearance; TAS:Reactome.
DR GO; GO:0006805; P:xenobiotic metabolic process; TAS:Reactome.
DR Gene3D; 3.40.50.1820; -; 1.
DR InterPro; IPR029058; AB_hydrolase.
DR InterPro; IPR002018; CarbesteraseB.
DR InterPro; IPR019826; Carboxylesterase_B_AS.
DR Pfam; PF00135; COesterase; 1.
DR SUPFAM; SSF53474; SSF53474; 1.
DR PROSITE; PS00122; CARBOXYLESTERASE_B_1; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Disulfide bond; Endoplasmic reticulum; Glycoprotein;
KW Hydrolase; Reference proteome; Serine esterase; Signal.
FT SIGNAL 1..26
FT /evidence="ECO:0000255"
FT CHAIN 27..571
FT /note="Carboxylesterase 3"
FT /id="PRO_0000305191"
FT MOTIF 568..571
FT /note="Prevents secretion from ER"
FT /evidence="ECO:0000255"
FT ACT_SITE 229
FT /note="Acyl-ester intermediate"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10039"
FT ACT_SITE 347
FT /note="Charge relay system"
FT /evidence="ECO:0000250"
FT ACT_SITE 460
FT /note="Charge relay system"
FT /evidence="ECO:0000250"
FT CARBOHYD 105
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:19159218"
FT DISULFID 97..124
FT /evidence="ECO:0000250"
FT DISULFID 281..292
FT /evidence="ECO:0000250"
FT VAR_SEQ 1..361
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_044994"
FT VARIANT 129
FT /note="V -> I (in dbSNP:rs61745806)"
FT /evidence="ECO:0000269|Ref.4"
FT /id="VAR_060699"
FT VARIANT 151
FT /note="A -> T (in dbSNP:rs71647891)"
FT /evidence="ECO:0000269|Ref.4"
FT /id="VAR_060700"
FT VARIANT 160
FT /note="Y -> H (in dbSNP:rs71647892)"
FT /evidence="ECO:0000269|Ref.4"
FT /id="VAR_060701"
FT VARIANT 191
FT /note="E -> K (in dbSNP:rs61742964)"
FT /evidence="ECO:0000269|Ref.4"
FT /id="VAR_060702"
FT VARIANT 213
FT /note="I -> N (in dbSNP:rs71647894)"
FT /evidence="ECO:0000269|Ref.4"
FT /id="VAR_060703"
FT VARIANT 367
FT /note="R -> W (in dbSNP:rs61743167)"
FT /evidence="ECO:0000269|Ref.4"
FT /id="VAR_060704"
FT VARIANT 523
FT /note="A -> V (in dbSNP:rs71649615)"
FT /evidence="ECO:0000269|Ref.4"
FT /id="VAR_060705"
FT VARIANT 555
FT /note="I -> V (in dbSNP:rs8059252)"
FT /evidence="ECO:0000269|Ref.4"
FT /id="VAR_060706"
FT CONFLICT 372
FT /note="A -> S (in Ref. 3; BAB15123)"
FT /evidence="ECO:0000305"
FT CONFLICT 481..483
FT /note="Missing (in Ref. 7; AAH53670)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 571 AA; 62282 MW; F2200968FDE072D2 CRC64;
MERAVRVESG VLVGVVCLLL ACPATATGPE VAQPEVDTTL GRVRGRQVGV KGTDRLVNVF
LGIPFAQPPL GPDRFSAPHP AQPWEGVRDA STAPPMCLQD VESMNSSRFV LNGKQQIFSV
SEDCLVLNVY SPAEVPAGSG RPVMVWVHGG ALITGAATSY DGSALAAYGD VVVVTVQYRL
GVLGFFSTGD EHAPGNQGFL DVVAALRWVQ ENIAPFGGDL NCVTVFGGSA GGSIISGLVL
SPVAAGLFHR AITQSGVITT PGIIDSHPWP LAQKIANTLA CSSSSPAEMV QCLQQKEGEE
LVLSKKLKNT IYPLTVDGTV FPKSPKELLK EKPFHSVPFL MGVNNHEFSW LIPRGWGLLD
TMEQMSREDM LAISTPVLTS LDVPPEMMPT VIDEYLGSNS DAQAKCQAFQ EFMGDVFINV
PTVSFSRYLR DSGSPVFFYE FQHRPSSFAK IKPAWVKADH GAEGAFVFGG PFLMDESSRL
AFPEATEEEK QLSLTMMAQW THFARTGDPN SKALPPWPQF NQAEQYLEIN PVPRAGQKFR
EAWMQFWSET LPSKIQQWHQ KQKNRKAQED L
