BPL1_HUMAN
ID BPL1_HUMAN Reviewed; 726 AA.
AC P50747; B2RAH1; D3DSG6; Q99451;
DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
DT 01-OCT-1996, sequence version 1.
DT 03-AUG-2022, entry version 201.
DE RecName: Full=Biotin--protein ligase;
DE EC=6.3.4.- {ECO:0000305|PubMed:10590022};
DE AltName: Full=Biotin apo-protein ligase;
DE Includes:
DE RecName: Full=Biotin--[methylmalonyl-CoA-carboxytransferase] ligase;
DE EC=6.3.4.9 {ECO:0000305|PubMed:10590022};
DE Includes:
DE RecName: Full=Biotin--[propionyl-CoA-carboxylase [ATP-hydrolyzing]] ligase;
DE EC=6.3.4.10 {ECO:0000269|PubMed:7753853};
DE AltName: Full=Holocarboxylase synthetase;
DE Short=HCS;
DE Includes:
DE RecName: Full=Biotin--[methylcrotonoyl-CoA-carboxylase] ligase;
DE EC=6.3.4.11 {ECO:0000305|PubMed:10590022};
DE Includes:
DE RecName: Full=Biotin--[acetyl-CoA-carboxylase] ligase;
DE EC=6.3.4.15 {ECO:0000305|PubMed:10590022};
GN Name=HLCS {ECO:0000312|HGNC:HGNC:4976};
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], VARIANT HLCS DEFICIENCY PRO-237, FUNCTION,
RP SUBUNIT, SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RC TISSUE=Liver;
RX PubMed=7842009; DOI=10.1038/ng1094-122;
RA Suzuki Y., Aoki Y., Ishida Y., Chiba Y., Iwamatsu A., Kishino T.,
RA Niikawa N., Matsubara Y., Narisawa K.;
RT "Isolation and characterization of mutations in the human holocarboxylase
RT synthetase cDNA.";
RL Nat. Genet. 8:122-128(1994).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Bone marrow;
RX PubMed=9037601; DOI=10.1101/gr.7.1.47;
RA Ohira M., Seki N., Nagase T., Suzuki E., Nomura N., Ohara O., Hattori M.,
RA Sakaki Y., Eki T., Murakami Y., Saito T., Ichikawa H., Ohki M.;
RT "Gene identification in 1.6-Mb region of the Down syndrome region on
RT chromosome 21.";
RL Genome Res. 7:47-58(1997).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RA Shibuya K., Kudoh J., Minoshima S., Kawasaki K., Nakatoh E., Shintani A.,
RA Asakawa S., Shimizu N.;
RT "Genomic sequencing of 1.2-Mb region on human chromosome 21q22.2.";
RL Submitted (NOV-1999) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANTS HLCS DEFICIENCY ASP-42;
RP PRO-237; GLU-333; SER-360; CYS-456; SER-470; TRP-508; GLY-547; MET-550;
RP SER-581; THR-610 DEL AND TYR-634, AND CHARACTERIZATION OF VARIANTS HLCS
RP DEFICIENCY ASP-42; SER-360; CYS-456; SER-470; GLY-547 AND TYR-634.
RX PubMed=11735028; DOI=10.1007/s004390100603;
RA Yang X., Aoki Y., Li X., Sakamoto O., Hiratsuka M., Kure S., Taheri S.,
RA Christensen E., Inui K., Kubota M., Ohira M., Ohki M., Kudoh J.,
RA Kawasaki K., Shibuya K., Shintani A., Asakawa S., Minoshima S., Shimizu N.,
RA Narisawa K., Matsubara Y., Suzuki Y.;
RT "Structure of human holocarboxylase synthetase gene and mutation spectrum
RT of holocarboxylase synthetase deficiency.";
RL Hum. Genet. 109:526-534(2001).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Thalamus, and Tongue;
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 [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=10830953; DOI=10.1038/35012518;
RA Hattori M., Fujiyama A., Taylor T.D., Watanabe H., Yada T., Park H.-S.,
RA Toyoda A., Ishii K., Totoki Y., Choi D.-K., Groner Y., Soeda E., Ohki M.,
RA Takagi T., Sakaki Y., Taudien S., Blechschmidt K., Polley A., Menzel U.,
RA Delabar J., Kumpf K., Lehmann R., Patterson D., Reichwald K., Rump A.,
RA Schillhabel M., Schudy A., Zimmermann W., Rosenthal A., Kudoh J.,
RA Shibuya K., Kawasaki K., Asakawa S., Shintani A., Sasaki T., Nagamine K.,
RA Mitsuyama S., Antonarakis S.E., Minoshima S., Shimizu N., Nordsiek G.,
RA Hornischer K., Brandt P., Scharfe M., Schoen O., Desario A., Reichelt J.,
RA Kauer G., Bloecker H., Ramser J., Beck A., Klages S., Hennig S.,
RA Riesselmann L., Dagand E., Wehrmeyer S., Borzym K., Gardiner K.,
RA Nizetic D., Francis F., Lehrach H., Reinhardt R., Yaspo M.-L.;
RT "The DNA sequence of human chromosome 21.";
RL Nature 405:311-319(2000).
RN [7]
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 [8]
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 [9]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1-92.
RC TISSUE=Brain;
RX PubMed=9503011; DOI=10.1006/geno.1997.5146;
RA Dahmane N., Ait-Ghezala G., Gosset P., Chamoun Z., Dufresne-Zacharia M.-C.,
RA Lopes C., Rabatel N., Gassanova-Maugenre S., Chettouh Z., Abramowski V.,
RA Fayet E., Yaspo M.-L., Korn B., Blouin J.-L., Lehrach H., Poustka A.,
RA Antonarakis S.E., Sinet P.-M., Creau N., Delabar J.-M.;
RT "Transcriptional map of the 2.5-Mb CBR-ERG region of chromosome 21 involved
RT in Down syndrome.";
RL Genomics 48:12-23(1998).
RN [10]
RP FUNCTION, CATALYTIC ACTIVITY, AND TISSUE SPECIFICITY.
RX PubMed=7753853; DOI=10.1073/pnas.92.10.4626;
RA Leon-Del-Rio A., Leclerc D., Akerman B., Wakamatsu N., Gravel R.A.;
RT "Isolation of a cDNA encoding human holocarboxylase synthetase by
RT functional complementation of a biotin auxotroph of Escherichia coli.";
RL Proc. Natl. Acad. Sci. U.S.A. 92:4626-4630(1995).
RN [11]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-147, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [12]
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 [13]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-299, AND IDENTIFICATION BY
RP 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 [14]
RP IDENTIFICATION BY 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).
RN [15]
RP VARIANT HLCS DEFICIENCY PRO-237.
RX PubMed=8541348; DOI=10.1016/0925-4439(95)00082-8;
RA Aoki Y., Suzuki Y., Sakamoto O., Li X., Takahashi K., Ohtake A., Sakuta R.,
RA Ohura T., Miyabayashi S., Narisawa K.;
RT "Molecular analysis of holocarboxylase synthetase deficiency: a missense
RT mutation and a single base deletion are predominant in Japanese patients.";
RL Biochim. Biophys. Acta 1272:168-174(1995).
RN [16]
RP VARIANTS HLCS DEFICIENCY ARG-216; ASP-363; TRP-508; GLU-518; MET-550 AND
RP ASN-571.
RX PubMed=8817339; DOI=10.1093/hmg/5.7.1011;
RA Dupuis L., Leon-Del-Rio A., Leclerc D., Campeau E., Sweetman L.,
RA Saudubray J.-M., Herman G., Gibson K.M., Gravel R.A.;
RT "Clustering of mutations in the biotin-binding region of holocarboxylase
RT synthetase in biotin-responsive multiple carboxylase deficiency.";
RL Hum. Mol. Genet. 5:1011-1016(1996).
RN [17]
RP VARIANTS HLCS DEFICIENCY PRO-237 AND MET-550.
RX PubMed=9396568; DOI=10.1203/00006450-199712000-00021;
RA Aoki Y., Suzuki Y., Li X., Sakamoto O., Chikaoka H., Takita S.,
RA Narisawa K.;
RT "Characterization of mutant holocarboxylase synthetase (HCS): a Km for
RT biotin was not elevated in a patient with HCS deficiency.";
RL Pediatr. Res. 42:849-854(1997).
RN [18]
RP VARIANTS HLCS DEFICIENCY GLU-333; ILE-462; ASN-571; SER-581 AND THR-610
RP DEL.
RX PubMed=10190325; DOI=10.1007/s004390050927;
RA Aoki Y., Li X., Sakamoto O., Hiratsuka M., Akaishi H., Xu L., Briones P.,
RA Suormala T., Baumgartner E.R., Suzuki Y., Narisawa K.;
RT "Identification and characterization of mutations in patients with
RT holocarboxylase synthetase deficiency.";
RL Hum. Genet. 104:143-148(1999).
RN [19]
RP VARIANTS HLCS DEFICIENCY PRO-183; ARG-216; PRO-237; GLU-333; ASP-363;
RP SER-581 AND THR-610 DEL, CHARACTERIZATION OF VARIANTS HLCS DEFICIENCY
RP PRO-183; ARG-216; PRO-237; GLU-333; ASP-363; SER-581 AND THR-610 DEL,
RP FUNCTION, CATALYTIC ACTIVITY, AND BIOPHYSICOCHEMICAL PROPERTIES.
RX PubMed=10590022; DOI=10.1203/00006450-199912000-00004;
RA Sakamoto O., Suzuki Y., Li X., Aoki Y., Hiratsuka M., Suormala T.,
RA Baumgartner E.R., Gibson K.M., Narisawa K.;
RT "Relationship between kinetic properties of mutant enzyme and biochemical
RT and clinical responsiveness to biotin in holocarboxylase synthetase
RT deficiency.";
RL Pediatr. Res. 46:671-676(1999).
RN [20]
RP VARIANTS HLCS DEFICIENCY ARG-216; LYS-511; SER-581 AND ARG-582.
RX PubMed=12124727; DOI=10.1002/ajmg.10532;
RA Morrone A., Malvagia S., Donati M.A., Funghini S., Ciani F., Pela I.,
RA Boneh A., Peters H., Pasquini E., Zammarchi E.;
RT "Clinical findings and biochemical and molecular analysis of four patients
RT with holocarboxylase synthetase deficiency.";
RL Am. J. Med. Genet. 111:10-18(2002).
RN [21]
RP VARIANTS HLCS DEFICIENCY TRP-508; MET-550 AND ASN-634.
RX PubMed=12633764; DOI=10.1016/s0009-9120(02)00432-0;
RA Tang N.L.S., Hui J., Yong C.K.K., Wong L.T.K., Applegarth D.A.,
RA Vallance H.D., Law L.K., Fung S.L.M., Mak T.W.L., Sung Y.M., Cheung K.L.,
RA Fok T.F.;
RT "A genomic approach to mutation analysis of holocarboxylase synthetase gene
RT in three Chinese patients with late-onset holocarboxylase synthetase
RT deficiency.";
RL Clin. Biochem. 36:145-149(2003).
RN [22]
RP VARIANTS HLCS DEFICIENCY TYR-615 AND GLY-715.
RX PubMed=16134170; DOI=10.1002/humu.20204;
RA Suzuki Y., Yang X., Aoki Y., Kure S., Matsubara Y.;
RT "Mutations in the holocarboxylase synthetase gene HLCS.";
RL Hum. Mutat. 26:285-290(2005).
RN [23]
RP VARIANT [LARGE SCALE ANALYSIS] ASP-42.
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., Buckhaults P.,
RA Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V.,
RA Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H.,
RA Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W.,
RA Velculescu V.E.;
RT "The consensus coding sequences of human breast and colorectal cancers.";
RL Science 314:268-274(2006).
RN [24]
RP CHARACTERIZATION OF VARIANT HLCS DEFICIENCY ARG-216.
RX PubMed=18429047; DOI=10.1002/humu.20766;
RA Bailey L.M., Ivanov R.A., Jitrapakdee S., Wilson C.J., Wallace J.C.,
RA Polyak S.W.;
RT "Reduced half-life of holocarboxylase synthetase from patients with severe
RT multiple carboxylase deficiency.";
RL Hum. Mutat. 29:E47-E57(2008).
RN [25]
RP VARIANTS HLCS DEFICIENCY ARG-505 AND TRP-508.
RX PubMed=20095979; DOI=10.1111/j.1399-0004.2009.01357.x;
RA Tammachote R., Janklat S., Tongkobpetch S., Suphapeetiporn K.,
RA Shotelersuk V.;
RT "Holocarboxylase synthetase deficiency: novel clinical and molecular
RT findings.";
RL Clin. Genet. 78:88-93(2010).
RN [26]
RP VARIANT HLCS DEFICIENCY TRP-241.
RX PubMed=25690727; DOI=10.1007/8904_2014_367;
RA De Castro M., Zand D.J., Lichter-Konecki U., Kirmse B.;
RT "Severe neonatal holocarboxylase synthetase deficiency in west african
RT siblings.";
RL JIMD Rep. 20:1-4(2015).
CC -!- FUNCTION: Biotin--protein ligase catalyzing the biotinylation of the 4
CC biotin-dependent carboxylases acetyl-CoA-carboxylase, pyruvate
CC carboxylase, propionyl-CoA carboxylase, and methylcrotonyl-CoA
CC carboxylase. {ECO:0000269|PubMed:10590022, ECO:0000269|PubMed:7753853,
CC ECO:0000269|PubMed:7842009}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=apo-[methylmalonyl-CoA:pyruvate carboxytransferase] + ATP +
CC biotin = AMP + diphosphate + H(+) + holo-[methylmalonyl-CoA:pyruvate
CC carboxytransferase]; Xref=Rhea:RHEA:23668, Rhea:RHEA-COMP:10508,
CC Rhea:RHEA-COMP:10509, ChEBI:CHEBI:15378, ChEBI:CHEBI:29969,
CC ChEBI:CHEBI:30616, ChEBI:CHEBI:33019, ChEBI:CHEBI:57586,
CC ChEBI:CHEBI:83144, ChEBI:CHEBI:456215; EC=6.3.4.9;
CC Evidence={ECO:0000305|PubMed:10590022};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:23669;
CC Evidence={ECO:0000305|PubMed:10590022};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=apo-[propionyl-CoA:carbon-dioxide ligase (ADP-forming)] + ATP
CC + biotin = AMP + diphosphate + H(+) + holo-[propionyl-CoA:carbon-
CC dioxide ligase (ADP-forming)]; Xref=Rhea:RHEA:11204, Rhea:RHEA-
CC COMP:10511, Rhea:RHEA-COMP:10512, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:29969, ChEBI:CHEBI:30616, ChEBI:CHEBI:33019,
CC ChEBI:CHEBI:57586, ChEBI:CHEBI:83144, ChEBI:CHEBI:456215;
CC EC=6.3.4.10; Evidence={ECO:0000269|PubMed:7753853};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:11205;
CC Evidence={ECO:0000269|PubMed:7753853};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=apo-[3-methylcrotonoyl-CoA:carbon-dioxide ligase (ADP-
CC forming)] + ATP + biotin = AMP + diphosphate + H(+) + holo-[3-
CC methylcrotonoyl-CoA:carbon-dioxide ligase (ADP-forming)];
CC Xref=Rhea:RHEA:24376, Rhea:RHEA-COMP:10514, Rhea:RHEA-COMP:10515,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:29969, ChEBI:CHEBI:30616,
CC ChEBI:CHEBI:33019, ChEBI:CHEBI:57586, ChEBI:CHEBI:83144,
CC ChEBI:CHEBI:456215; EC=6.3.4.11;
CC Evidence={ECO:0000305|PubMed:10590022};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:24377;
CC Evidence={ECO:0000269|PubMed:7753853};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + biotin + L-lysyl-[protein] = AMP + diphosphate + H(+) +
CC N(6)-biotinyl-L-lysyl-[protein]; Xref=Rhea:RHEA:11756, Rhea:RHEA-
CC COMP:9752, Rhea:RHEA-COMP:10505, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:29969, ChEBI:CHEBI:30616, ChEBI:CHEBI:33019,
CC ChEBI:CHEBI:57586, ChEBI:CHEBI:83144, ChEBI:CHEBI:456215;
CC EC=6.3.4.15; Evidence={ECO:0000305|PubMed:10590022};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:11757;
CC Evidence={ECO:0000269|PubMed:7753853};
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=224 nM for biotin {ECO:0000269|PubMed:10590022};
CC Vmax=143.9 pmol/min/mg enzyme {ECO:0000269|PubMed:10590022};
CC -!- SUBUNIT: Monomer. {ECO:0000305|PubMed:7842009}.
CC -!- INTERACTION:
CC P50747; O00763: ACACB; NbExp=4; IntAct=EBI-3915568, EBI-2211739;
CC P50747; Q8N6D5: ANKRD29; NbExp=3; IntAct=EBI-3915568, EBI-17439331;
CC P50747; P26371: KRTAP5-9; NbExp=3; IntAct=EBI-3915568, EBI-3958099;
CC P50747; A0JLT2-2: MED19; NbExp=3; IntAct=EBI-3915568, EBI-13288755;
CC P50747; Q9NUX5: POT1; NbExp=2; IntAct=EBI-3915568, EBI-752420;
CC P50747; Q5T0L3: SPATA46; NbExp=4; IntAct=EBI-3915568, EBI-750105;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000305|PubMed:7842009}.
CC Mitochondrion {ECO:0000305|PubMed:7842009}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=P50747-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P50747-2; Sequence=VSP_061442;
CC -!- TISSUE SPECIFICITY: Widely expressed (PubMed:7842009, PubMed:7753853).
CC Mostly expressed in muscle, placenta and to a lower extent in the
CC brain, kidney, pancreas, liver and lung (PubMed:7842009).
CC {ECO:0000269|PubMed:7753853, ECO:0000269|PubMed:7842009}.
CC -!- DISEASE: Holocarboxylase synthetase deficiency (HLCS deficiency)
CC [MIM:253270]: A neonatal form of multiple carboxylase deficiency, an
CC autosomal recessive disorder of biotin metabolism, characterized by
CC ketoacidosis, hyperammonemia, excretion of abnormal organic acid
CC metabolites, and dermatitis. In holocarboxylase synthetase deficiency,
CC clinical and biochemical symptoms improve dramatically with
CC administration of biotin. {ECO:0000269|PubMed:10190325,
CC ECO:0000269|PubMed:10590022, ECO:0000269|PubMed:11735028,
CC ECO:0000269|PubMed:12124727, ECO:0000269|PubMed:12633764,
CC ECO:0000269|PubMed:16134170, ECO:0000269|PubMed:20095979,
CC ECO:0000269|PubMed:25690727, ECO:0000269|PubMed:7842009,
CC ECO:0000269|PubMed:8541348, ECO:0000269|PubMed:8817339,
CC ECO:0000269|PubMed:9396568}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the biotin--protein ligase family.
CC {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AK307940; Type=Frameshift; Evidence={ECO:0000305};
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DR EMBL; D23672; BAA04902.1; -; mRNA.
DR EMBL; D87328; BAA13332.1; -; mRNA.
DR EMBL; AP000697; BAA89434.1; -; Genomic_DNA.
DR EMBL; AP000703; BAA89434.1; JOINED; Genomic_DNA.
DR EMBL; AP000701; BAA89434.1; JOINED; Genomic_DNA.
DR EMBL; AP000698; BAA89434.1; JOINED; Genomic_DNA.
DR EMBL; AB063285; BAB68550.1; -; Genomic_DNA.
DR EMBL; AK307940; -; NOT_ANNOTATED_CDS; mRNA.
DR EMBL; AK314189; BAG36868.1; -; mRNA.
DR EMBL; AP001726; BAA95510.1; -; Genomic_DNA.
DR EMBL; AP001727; BAA95511.1; -; Genomic_DNA.
DR EMBL; CH471079; EAX09731.1; -; Genomic_DNA.
DR EMBL; CH471079; EAX09732.1; -; Genomic_DNA.
DR EMBL; BC060787; AAH60787.1; -; mRNA.
DR EMBL; AJ001864; CAA05056.1; -; mRNA.
DR CCDS; CCDS13647.1; -. [P50747-1]
DR PIR; S50833; S50833.
DR RefSeq; NP_000402.3; NM_000411.6.
DR RefSeq; NP_001229713.1; NM_001242784.1.
DR RefSeq; NP_001229714.1; NM_001242785.1.
DR RefSeq; XP_005261012.1; XM_005260955.3.
DR RefSeq; XP_005261013.1; XM_005260956.3.
DR RefSeq; XP_006724057.1; XM_006723994.2.
DR RefSeq; XP_006724058.1; XM_006723995.1.
DR RefSeq; XP_011527840.1; XM_011529538.1.
DR RefSeq; XP_011527841.1; XM_011529539.2.
DR RefSeq; XP_011527843.1; XM_011529541.2.
DR RefSeq; XP_016883819.1; XM_017028330.1.
DR AlphaFoldDB; P50747; -.
DR SMR; P50747; -.
DR BioGRID; 109386; 35.
DR IntAct; P50747; 18.
DR MINT; P50747; -.
DR STRING; 9606.ENSP00000382071; -.
DR BindingDB; P50747; -.
DR ChEMBL; CHEMBL2062354; -.
DR DrugBank; DB00121; Biotin.
DR iPTMnet; P50747; -.
DR PhosphoSitePlus; P50747; -.
DR BioMuta; HLCS; -.
DR DMDM; 1705499; -.
DR EPD; P50747; -.
DR jPOST; P50747; -.
DR MassIVE; P50747; -.
DR MaxQB; P50747; -.
DR PaxDb; P50747; -.
DR PeptideAtlas; P50747; -.
DR PRIDE; P50747; -.
DR ProteomicsDB; 56260; -.
DR Antibodypedia; 8381; 162 antibodies from 23 providers.
DR DNASU; 3141; -.
DR Ensembl; ENST00000336648.8; ENSP00000338387.3; ENSG00000159267.17. [P50747-1]
DR Ensembl; ENST00000399120.5; ENSP00000382071.1; ENSG00000159267.17. [P50747-1]
DR Ensembl; ENST00000612277.4; ENSP00000479939.1; ENSG00000159267.17. [P50747-1]
DR Ensembl; ENST00000674895.3; ENSP00000502087.2; ENSG00000159267.17. [P50747-2]
DR Ensembl; ENST00000675307.1; ENSP00000501750.1; ENSG00000159267.17. [P50747-1]
DR GeneID; 3141; -.
DR KEGG; hsa:3141; -.
DR MANE-Select; ENST00000674895.3; ENSP00000502087.2; NM_001352514.2; NP_001339443.1. [P50747-2]
DR UCSC; uc002yvs.4; human. [P50747-1]
DR CTD; 3141; -.
DR DisGeNET; 3141; -.
DR GeneCards; HLCS; -.
DR HGNC; HGNC:4976; HLCS.
DR HPA; ENSG00000159267; Low tissue specificity.
DR MalaCards; HLCS; -.
DR MIM; 253270; phenotype.
DR MIM; 609018; gene.
DR neXtProt; NX_P50747; -.
DR OpenTargets; ENSG00000159267; -.
DR Orphanet; 79242; Holocarboxylase synthetase deficiency.
DR PharmGKB; PA29310; -.
DR VEuPathDB; HostDB:ENSG00000159267; -.
DR eggNOG; KOG1536; Eukaryota.
DR GeneTree; ENSGT00390000002960; -.
DR HOGENOM; CLU_006150_2_0_1; -.
DR InParanoid; P50747; -.
DR OMA; CPEREGR; -.
DR OrthoDB; 1392751at2759; -.
DR PhylomeDB; P50747; -.
DR TreeFam; TF105860; -.
DR PathwayCommons; P50747; -.
DR Reactome; R-HSA-196780; Biotin transport and metabolism.
DR Reactome; R-HSA-3371599; Defective HLCS causes multiple carboxylase deficiency.
DR SABIO-RK; P50747; -.
DR SignaLink; P50747; -.
DR BioGRID-ORCS; 3141; 25 hits in 1082 CRISPR screens.
DR ChiTaRS; HLCS; human.
DR GenomeRNAi; 3141; -.
DR Pharos; P50747; Tchem.
DR PRO; PR:P50747; -.
DR Proteomes; UP000005640; Chromosome 21.
DR RNAct; P50747; protein.
DR Bgee; ENSG00000159267; Expressed in paraflocculus and 134 other tissues.
DR ExpressionAtlas; P50747; baseline and differential.
DR Genevisible; P50747; HS.
DR GO; GO:0000785; C:chromatin; IDA:UniProtKB.
DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR GO; GO:0005829; C:cytosol; IDA:UniProtKB.
DR GO; GO:0005739; C:mitochondrion; IEA:UniProtKB-SubCell.
DR GO; GO:0005652; C:nuclear lamina; IDA:UniProtKB.
DR GO; GO:0016363; C:nuclear matrix; IDA:UniProtKB.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0009374; F:biotin binding; IDA:UniProtKB.
DR GO; GO:0004077; F:biotin-[acetyl-CoA-carboxylase] ligase activity; IBA:GO_Central.
DR GO; GO:0004078; F:biotin-[methylcrotonoyl-CoA-carboxylase] ligase activity; IEA:UniProtKB-EC.
DR GO; GO:0004079; F:biotin-[methylmalonyl-CoA-carboxytransferase] ligase activity; IEA:UniProtKB-EC.
DR GO; GO:0004080; F:biotin-[propionyl-CoA-carboxylase (ATP-hydrolyzing)] ligase activity; IDA:UniProtKB.
DR GO; GO:0018271; F:biotin-protein ligase activity; IDA:UniProtKB.
DR GO; GO:0019899; F:enzyme binding; IPI:UniProtKB.
DR GO; GO:0006768; P:biotin metabolic process; TAS:Reactome.
DR GO; GO:0043687; P:post-translational protein modification; IDA:UniProtKB.
DR GO; GO:0070781; P:response to biotin; IDA:UniProtKB.
DR CDD; cd16442; BPL; 1.
DR Gene3D; 3.30.930.10; -; 1.
DR InterPro; IPR045864; aa-tRNA-synth_II/BPL/LPL.
DR InterPro; IPR019197; Biotin-prot_ligase_N.
DR InterPro; IPR004408; Biotin_CoA_COase_ligase.
DR InterPro; IPR003142; BPL_C.
DR InterPro; IPR004143; BPL_LPL_catalytic.
DR Pfam; PF02237; BPL_C; 1.
DR Pfam; PF03099; BPL_LplA_LipB; 1.
DR Pfam; PF09825; BPL_N; 1.
DR SUPFAM; SSF55681; SSF55681; 1.
DR TIGRFAMs; TIGR00121; birA_ligase; 1.
DR PROSITE; PS51733; BPL_LPL_CATALYTIC; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; ATP-binding; Cytoplasm; Disease variant; Ligase;
KW Mitochondrion; Multifunctional enzyme; Nucleotide-binding; Phosphoprotein;
KW Reference proteome.
FT CHAIN 1..726
FT /note="Biotin--protein ligase"
FT /id="PRO_0000064979"
FT DOMAIN 463..652
FT /note="BPL/LPL catalytic"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01067"
FT REGION 28..98
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 47..78
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 147
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648"
FT MOD_RES 299
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT VAR_SEQ 1
FT /note="M -> MLITLCYLYLWARWGRRPAELVRATVRRLRASRCSFTFCGAAAQPPG
FT ARVCLSRGGRVFCVSDSQSIEDLNKWALFLVSPFILEAEHIAFVTESIWVQSENLQRSS
FT SSETIVKWSDCCLPLACRPGDPYRLIAEASVDNFSKLGVAFM (in isoform 2)"
FT /id="VSP_061442"
FT VARIANT 42
FT /note="E -> D (in HLCS deficiency; benign variant;
FT conserves enzymatic wild-type activity; dbSNP:rs61732504)"
FT /evidence="ECO:0000269|PubMed:11735028,
FT ECO:0000269|PubMed:16959974"
FT /id="VAR_035800"
FT VARIANT 183
FT /note="R -> P (in HLCS deficiency; has normal or low KM
FT values for biotin (non-KM mutant))"
FT /evidence="ECO:0000269|PubMed:10590022"
FT /id="VAR_046507"
FT VARIANT 216
FT /note="L -> R (in HLCS deficiency; has normal or low KM
FT values for biotin (non-KM mutant); growth of patients'
FT fibroblasts is compromised compared with normal
FT fibroblasts; patients cells are not sensitive to biotin-
FT depletion from the media; growth rates cannot be restored
FT by re-administration of biotin; enzyme activity is severely
FT compromised and cannot be increased by additional biotin;
FT turn-over rate for the mutant protein is double that of
FT wild-type enzyme; dbSNP:rs28934602)"
FT /evidence="ECO:0000269|PubMed:10590022,
FT ECO:0000269|PubMed:12124727, ECO:0000269|PubMed:18429047,
FT ECO:0000269|PubMed:8817339"
FT /id="VAR_021218"
FT VARIANT 237
FT /note="L -> P (in HLCS deficiency; has normal or low KM
FT values for biotin (non-KM mutant); dbSNP:rs119103227)"
FT /evidence="ECO:0000269|PubMed:10590022,
FT ECO:0000269|PubMed:11735028, ECO:0000269|PubMed:7842009,
FT ECO:0000269|PubMed:8541348, ECO:0000269|PubMed:9396568"
FT /id="VAR_005084"
FT VARIANT 241
FT /note="G -> W (in HLCS deficiency)"
FT /evidence="ECO:0000269|PubMed:25690727"
FT /id="VAR_073074"
FT VARIANT 333
FT /note="V -> E (in HLCS deficiency; <10% activity; has
FT normal or low KM values for biotin (non-KM mutant);
FT dbSNP:rs1198548955)"
FT /evidence="ECO:0000269|PubMed:10190325,
FT ECO:0000269|PubMed:10590022, ECO:0000269|PubMed:11735028"
FT /id="VAR_009196"
FT VARIANT 360
FT /note="R -> S (in HLCS deficiency; 22% activity; shows
FT elevated KM values for biotin (KM mutant) compared with
FT that of the wild-type form; dbSNP:rs1230666123)"
FT /evidence="ECO:0000269|PubMed:11735028"
FT /id="VAR_046508"
FT VARIANT 363
FT /note="V -> D (in HLCS deficiency; has normal or low KM
FT values for biotin (non-KM mutant); dbSNP:rs769499327)"
FT /evidence="ECO:0000269|PubMed:10590022,
FT ECO:0000269|PubMed:8817339"
FT /id="VAR_046509"
FT VARIANT 456
FT /note="Y -> C (in HLCS deficiency; 0.2% activity;
FT dbSNP:rs781603756)"
FT /evidence="ECO:0000269|PubMed:11735028"
FT /id="VAR_046510"
FT VARIANT 462
FT /note="T -> I (in HLCS deficiency; <10% activity;
FT dbSNP:rs1256356959)"
FT /evidence="ECO:0000269|PubMed:10190325"
FT /id="VAR_009197"
FT VARIANT 470
FT /note="L -> S (in HLCS deficiency; 4.3% activity;
FT dbSNP:rs1261821166)"
FT /evidence="ECO:0000269|PubMed:11735028"
FT /id="VAR_046511"
FT VARIANT 505
FT /note="G -> R (in HLCS deficiency; dbSNP:rs1555885056)"
FT /evidence="ECO:0000269|PubMed:20095979"
FT /id="VAR_073075"
FT VARIANT 508
FT /note="R -> W (in HLCS deficiency; dbSNP:rs119103229)"
FT /evidence="ECO:0000269|PubMed:11735028,
FT ECO:0000269|PubMed:12633764, ECO:0000269|PubMed:20095979,
FT ECO:0000269|PubMed:8817339"
FT /id="VAR_013009"
FT VARIANT 511
FT /note="N -> K (in HLCS deficiency)"
FT /evidence="ECO:0000269|PubMed:12124727"
FT /id="VAR_021219"
FT VARIANT 518
FT /note="G -> E (in HLCS deficiency)"
FT /evidence="ECO:0000269|PubMed:8817339"
FT /id="VAR_046512"
FT VARIANT 547
FT /note="V -> G (in HLCS deficiency; 3.4% activity)"
FT /evidence="ECO:0000269|PubMed:11735028"
FT /id="VAR_046513"
FT VARIANT 550
FT /note="V -> M (in HLCS deficiency; dbSNP:rs119103231)"
FT /evidence="ECO:0000269|PubMed:11735028,
FT ECO:0000269|PubMed:12633764, ECO:0000269|PubMed:8817339,
FT ECO:0000269|PubMed:9396568"
FT /id="VAR_009198"
FT VARIANT 571
FT /note="D -> N (in HLCS deficiency; almost no activity;
FT dbSNP:rs119103228)"
FT /evidence="ECO:0000269|PubMed:10190325,
FT ECO:0000269|PubMed:8817339"
FT /id="VAR_009199"
FT VARIANT 581
FT /note="G -> S (in HLCS deficiency; <10% activity;
FT dbSNP:rs119103230)"
FT /evidence="ECO:0000269|PubMed:10190325,
FT ECO:0000269|PubMed:10590022, ECO:0000269|PubMed:11735028,
FT ECO:0000269|PubMed:12124727"
FT /id="VAR_009200"
FT VARIANT 582
FT /note="G -> R (in HLCS deficiency; dbSNP:rs376899782)"
FT /evidence="ECO:0000269|PubMed:12124727"
FT /id="VAR_021220"
FT VARIANT 610
FT /note="Missing (in HLCS deficiency; 14% of activity; shows
FT elevated KM values for biotin (KM mutant) compared with
FT that of the wild-type form)"
FT /evidence="ECO:0000269|PubMed:10190325,
FT ECO:0000269|PubMed:10590022, ECO:0000269|PubMed:11735028"
FT /id="VAR_009201"
FT VARIANT 615
FT /note="D -> Y (in HLCS deficiency)"
FT /evidence="ECO:0000269|PubMed:16134170"
FT /id="VAR_046514"
FT VARIANT 634
FT /note="D -> N (in HLCS deficiency; dbSNP:rs149399432)"
FT /evidence="ECO:0000269|PubMed:12633764"
FT /id="VAR_046515"
FT VARIANT 634
FT /note="D -> Y (in HLCS deficiency; 12% activity)"
FT /evidence="ECO:0000269|PubMed:11735028"
FT /id="VAR_046516"
FT VARIANT 715
FT /note="D -> G (in HLCS deficiency)"
FT /evidence="ECO:0000269|PubMed:16134170"
FT /id="VAR_046517"
FT CONFLICT 209
FT /note="P -> T (in Ref. 5; AK307940)"
FT /evidence="ECO:0000305"
FT CONFLICT 463
FT /note="K -> R (in Ref. 5; BAG36868)"
FT /evidence="ECO:0000305"
FT CONFLICT 558
FT /note="E -> K (in Ref. 2; BAA13332)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 726 AA; 80760 MW; 855B8E52106D675F CRC64;
MEDRLHMDNG LVPQKIVSVH LQDSTLKEVK DQVSNKQAQI LEPKPEPSLE IKPEQDGMEH
VGRDDPKALG EEPKQRRGSA SGSEPAGDSD RGGGPVEHYH LHLSSCHECL ELENSTIESV
KFASAENIPD LPYDYSSSLE SVADETSPER EGRRVNLTGK APNILLYVGS DSQEALGRFH
EVRSVLADCV DIDSYILYHL LEDSALRDPW TDNCLLLVIA TRESIPEDLY QKFMAYLSQG
GKVLGLSSSF TFGGFQVTSK GALHKTVQNL VFSKADQSEV KLSVLSSGCR YQEGPVRLSP
GRLQGHLENE DKDRMIVHVP FGTRGGEAVL CQVHLELPPS SNIVQTPEDF NLLKSSNFRR
YEVLREILTT LGLSCDMKQV PALTPLYLLS AAEEIRDPLM QWLGKHVDSE GEIKSGQLSL
RFVSSYVSEV EITPSCIPVV TNMEAFSSEH FNLEIYRQNL QTKQLGKVIL FAEVTPTTMR
LLDGLMFQTP QEMGLIVIAA RQTEGKGRGG NVWLSPVGCA LSTLLISIPL RSQLGQRIPF
VQHLMSVAVV EAVRSIPEYQ DINLRVKWPN DIYYSDLMKI GGVLVNSTLM GETFYILIGC
GFNVTNSNPT ICINDLITEY NKQHKAELKP LRADYLIARV VTVLEKLIKE FQDKGPNSVL
PLYYRYWVHS GQQVHLGSAE GPKVSIVGLD DSGFLQVHQE GGEVVTVHPD GNSFDMLRNL
ILPKRR
