CMBL_HUMAN
ID CMBL_HUMAN Reviewed; 245 AA.
AC Q96DG6; D3DTC7; Q8TED6;
DT 23-OCT-2007, integrated into UniProtKB/Swiss-Prot.
DT 01-DEC-2001, sequence version 1.
DT 03-AUG-2022, entry version 159.
DE RecName: Full=Carboxymethylenebutenolidase homolog;
DE EC=3.1.-.-;
GN Name=CMBL;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Skeletal muscle;
RA Ievolella C., Zara I., Millino C., Faulkner G., Lanfranchi G.;
RT "Full length sequencing of some human and murine muscular transcripts
RT (Telethon Italy project B41).";
RL Submitted (MAY-2000) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Adipose tissue;
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 [3]
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 (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=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 [5]
RP PROTEIN SEQUENCE OF 2-31; 150-168; 206-217 AND 236-245, CLEAVAGE OF
RP INITIATOR METHIONINE, ACETYLATION AT ALA-2, AND IDENTIFICATION BY MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RA Bienvenut W.V., Calvo F., Kolch W.;
RL Submitted (MAR-2008) to UniProtKB.
RN [6]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-36, AND IDENTIFICATION BY MASS
RP SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T.C.,
RA Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [7]
RP FUNCTION, TISSUE SPECIFICITY, SUBCELLULAR LOCATION, BIOPHYSICOCHEMICAL
RP PROPERTIES, MUTAGENESIS OF CYS-132, AND IDENTIFICATION BY MASS
RP SPECTROMETRY.
RX PubMed=20177059; DOI=10.1074/jbc.m109.072629;
RA Ishizuka T., Fujimori I., Kato M., Noji-Sakikawa C., Saito M., Yoshigae Y.,
RA Kubota K., Kurihara A., Izumi T., Ikeda T., Okazaki O.;
RT "Human carboxymethylenebutenolidase as a bioactivating hydrolase of
RT olmesartan medoxomil in liver and intestine.";
RL J. Biol. Chem. 285:11892-11902(2010).
RN [8]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [9]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Erythroleukemia;
RX PubMed=23186163; DOI=10.1021/pr300630k;
RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA Mohammed S.;
RT "Toward a comprehensive characterization of a human cancer cell
RT phosphoproteome.";
RL J. Proteome Res. 12:260-271(2013).
RN [10]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-223, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA Ye M., Zou H.;
RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT phosphoproteome.";
RL J. Proteomics 96:253-262(2014).
CC -!- FUNCTION: Cysteine hydrolase. Can convert the prodrug olmesartan
CC medoxomil into its pharmacologically active metabolite olmerstatan, an
CC angiotensin receptor blocker, in liver and intestine. May also activate
CC beta-lactam antibiotics faropenem medoxomil and lenampicillin.
CC {ECO:0000269|PubMed:20177059}.
CC -!- ACTIVITY REGULATION: Strongly inhibited by p-chloromercuribenzoate
CC (PCMB). Partially inhibited by bis-p-nitrophenylphosphate (BNPP). Not
CC inhibited by DFP, PMSF, eserine or EDTA.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=170 uM for olmesartan medoxomil {ECO:0000269|PubMed:20177059};
CC KM=283 uM for faropenem medoxomil {ECO:0000269|PubMed:20177059};
CC KM=63.4 uM for lenampicillin {ECO:0000269|PubMed:20177059};
CC Vmax=24.6 nmol/min/mg enzyme toward olmesartan medoxomil
CC {ECO:0000269|PubMed:20177059};
CC Vmax=16.4 nmol/min/mg enzyme toward faropenem medoxomil
CC {ECO:0000269|PubMed:20177059};
CC Vmax=4 nmol/min/mg enzyme toward lenampicillin
CC {ECO:0000269|PubMed:20177059};
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol {ECO:0000269|PubMed:20177059}.
CC -!- TISSUE SPECIFICITY: Widely expressed, with highest levels in liver,
CC followed by kidney, small intestine and colon. Present in liver and
CC intestine (at protein level). {ECO:0000269|PubMed:20177059}.
CC -!- SIMILARITY: Belongs to the dienelactone hydrolase family.
CC {ECO:0000305}.
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DR EMBL; AJ278125; CAC81950.1; -; mRNA.
DR EMBL; AK074197; BAB85014.1; -; mRNA.
DR EMBL; CH471102; EAX08070.1; -; Genomic_DNA.
DR EMBL; CH471102; EAX08071.1; -; Genomic_DNA.
DR EMBL; BC001573; AAH01573.1; -; mRNA.
DR CCDS; CCDS3878.1; -.
DR RefSeq; NP_620164.1; NM_138809.3.
DR RefSeq; XP_016864523.1; XM_017009034.1.
DR RefSeq; XP_016864524.1; XM_017009035.1.
DR AlphaFoldDB; Q96DG6; -.
DR SMR; Q96DG6; -.
DR BioGRID; 126387; 50.
DR IntAct; Q96DG6; 29.
DR MINT; Q96DG6; -.
DR STRING; 9606.ENSP00000296658; -.
DR ESTHER; human-CMBL; CMBL.
DR CarbonylDB; Q96DG6; -.
DR GlyGen; Q96DG6; 1 site, 1 O-linked glycan (1 site).
DR iPTMnet; Q96DG6; -.
DR PhosphoSitePlus; Q96DG6; -.
DR BioMuta; CMBL; -.
DR DMDM; 74731452; -.
DR CPTAC; CPTAC-45; -.
DR CPTAC; CPTAC-46; -.
DR EPD; Q96DG6; -.
DR jPOST; Q96DG6; -.
DR MassIVE; Q96DG6; -.
DR MaxQB; Q96DG6; -.
DR PaxDb; Q96DG6; -.
DR PeptideAtlas; Q96DG6; -.
DR PRIDE; Q96DG6; -.
DR ProteomicsDB; 76287; -.
DR Antibodypedia; 22459; 130 antibodies from 20 providers.
DR DNASU; 134147; -.
DR Ensembl; ENST00000296658.4; ENSP00000296658.3; ENSG00000164237.9.
DR GeneID; 134147; -.
DR KEGG; hsa:134147; -.
DR MANE-Select; ENST00000296658.4; ENSP00000296658.3; NM_138809.4; NP_620164.1.
DR UCSC; uc003jes.4; human.
DR CTD; 134147; -.
DR GeneCards; CMBL; -.
DR HGNC; HGNC:25090; CMBL.
DR HPA; ENSG00000164237; Tissue enhanced (kidney, liver, skeletal muscle).
DR MIM; 613379; gene.
DR neXtProt; NX_Q96DG6; -.
DR OpenTargets; ENSG00000164237; -.
DR PharmGKB; PA162382521; -.
DR VEuPathDB; HostDB:ENSG00000164237; -.
DR eggNOG; KOG3043; Eukaryota.
DR GeneTree; ENSGT00390000000183; -.
DR HOGENOM; CLU_054590_8_2_1; -.
DR InParanoid; Q96DG6; -.
DR OMA; HIKAYVV; -.
DR OrthoDB; 1275897at2759; -.
DR PhylomeDB; Q96DG6; -.
DR TreeFam; TF331795; -.
DR BRENDA; 3.1.1.45; 2681.
DR PathwayCommons; Q96DG6; -.
DR Reactome; R-HSA-211945; Phase I - Functionalization of compounds.
DR SignaLink; Q96DG6; -.
DR BioGRID-ORCS; 134147; 14 hits in 1078 CRISPR screens.
DR ChiTaRS; CMBL; human.
DR GenomeRNAi; 134147; -.
DR Pharos; Q96DG6; Tbio.
DR PRO; PR:Q96DG6; -.
DR Proteomes; UP000005640; Chromosome 5.
DR RNAct; Q96DG6; protein.
DR Bgee; ENSG00000164237; Expressed in kidney epithelium and 188 other tissues.
DR Genevisible; Q96DG6; HS.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB.
DR GO; GO:0016787; F:hydrolase activity; 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; IPR042946; CMBL.
DR InterPro; IPR002925; Dienelactn_hydro.
DR PANTHER; PTHR46812; PTHR46812; 1.
DR Pfam; PF01738; DLH; 1.
DR SUPFAM; SSF53474; SSF53474; 1.
PE 1: Evidence at protein level;
KW Acetylation; Cytoplasm; Direct protein sequencing; Hydrolase;
KW Phosphoprotein; Reference proteome.
FT INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0000269|Ref.5"
FT CHAIN 2..245
FT /note="Carboxymethylenebutenolidase homolog"
FT /id="PRO_0000308188"
FT ACT_SITE 132
FT ACT_SITE 179
FT /evidence="ECO:0000250"
FT ACT_SITE 212
FT /evidence="ECO:0000250"
FT MOD_RES 2
FT /note="N-acetylalanine"
FT /evidence="ECO:0000269|Ref.5"
FT MOD_RES 36
FT /note="N6-acetyllysine"
FT /evidence="ECO:0007744|PubMed:19608861"
FT MOD_RES 223
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:24275569"
FT VARIANT 155
FT /note="Y -> C (in dbSNP:rs35489000)"
FT /id="VAR_036751"
FT MUTAGEN 132
FT /note="C->A: 97% inhibition of enzymatic activity."
FT /evidence="ECO:0000269|PubMed:20177059"
FT MUTAGEN 132
FT /note="C->S: 70% inhibition of enzymatic activity."
FT /evidence="ECO:0000269|PubMed:20177059"
FT CONFLICT 99
FT /note="K -> N (in Ref. 2; BAB85014)"
FT /evidence="ECO:0000305"
FT CONFLICT 104
FT /note="Q -> H (in Ref. 2; BAB85014)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 245 AA; 28048 MW; 222A22E3AD859495 CRC64;
MANEAYPCPC DIGHRLEYGG LGREVQVEHI KAYVTKSPVD AGKAVIVIQD IFGWQLPNTR
YIADMISGNG YTTIVPDFFV GQEPWDPSGD WSIFPEWLKT RNAQKIDREI SAILKYLKQQ
CHAQKIGIVG FCWGGTAVHH LMMKYSEFRA GVSVYGIVKD SEDIYNLKNP TLFIFAENDV
VIPLKDVSLL TQKLKEHCKV EYQIKTFSGQ THGFVHRKRE DCSPADKPYI DEARRNLIEW
LNKYM
