Reviewed, UniProtKB/Swiss-Prot P50747 (BPL1_HUMAN)

Names and origin

Protein names

Recommended name:
    Biotin--protein ligase
    EC=6.3.4.-
Alternative name(s):
    Biotin apo-protein ligase
Including the following 4 domains:
    1- Recommended name:
            Biotin--[methylmalonyl-CoA-carboxytransferase] ligase
              EC=6.3.4.9
    2- Recommended name:
            Biotin--[propionyl-CoA-carboxylase [ATP-hydrolyzing]] ligase
              EC=6.3.4.10
        Alternative name(s):
            Holocarboxylase synthetase
              Short name=HCS
    3- Recommended name:
            Biotin--[methylcrotonoyl-CoA-carboxylase] ligase
              EC=6.3.4.11
    4- Recommended name:
            Biotin--[acetyl-CoA-carboxylase] ligase
              EC=6.3.4.15

Gene names

Name:

HLCS

Organism

Homo sapiens (Human) [Complete proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	726 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	Post-translational modification of specific protein by attachment of biotin. Acts on various carboxylases such as acetyl-CoA-carboxylase, pyruvate carboxylase, propionyl CoA carboxylase, and 3-methylcrotonyl CoA carboxylase.
Catalytic activity	ATP + biotin + apo-[methylmalonyl-CoA:pyruvate carboxytransferase] = AMP + diphosphate + [methylmalonyl-CoA:pyruvate carboxytransferase]. ATP + biotin + apo-[propionyl-CoA:carbon-dioxide ligase (ADP-forming)] = AMP + diphosphate + [propionyl-CoA:carbon-dioxide ligase (ADP-forming)]. ATP + biotin + apo-[3-methylcrotonoyl-CoA:carbon-dioxide ligase (ADP-forming)] = AMP + diphosphate + [3-methylcrotonoyl-CoA:carbon-dioxide ligase (ADP-forming)]. ATP + biotin + apo-[acetyl-CoA:carbon-dioxide ligase (ADP-forming)] = AMP + diphosphate + [acetyl-CoA:carbon-dioxide ligase (ADP-forming)].
Subunit structure	Monomer.
Subcellular location	Cytoplasm. Mitochondrion.
Tissue specificity	Mostly expressed in muscle, placenta, in lesser extent in the brain, kidney, pancreas, liver and lung.
Involvement in disease	Defects in HLCS are the cause of holocarboxylase synthetase deficiency (HLCS deficiency) [MIM:253270]; also known as biotin-responsive multiple carboxylase deficiency. HLCS deficiency is a neonatal form of multiple carboxylase deficiency, an autosomal recessive disorder characterized by metabolic ketoacidosis, hyperammonemia, excretion of abnormal organic acid metabolites and dermatitis. Clinical and biochemical symptoms improve dramatically with administration of biotin.
Sequence similarities	Belongs to the biotin--protein ligase family.
Biophysicochemical properties	Kinetic parameters: KM=224 nM for biotin Vmax=143.9 pmol/min/mg enzyme

Ontologies

Keywords
Cellular component	Cytoplasm Mitochondrion
Coding sequence diversity	Polymorphism
Disease	Disease mutation
Ligand	ATP-binding Nucleotide-binding
Molecular function	Ligase
PTM	Phosphoprotein
Technical term	Complete proteome Multifunctional enzyme
Gene Ontology (GO)
Biological process	protein modification process Inferred from electronic annotation. Source: InterPro
Cellular component	cytosol Inferred from direct assay. Source: UniProtKB mitochondrion Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW biotin-[acetyl-CoA-carboxylase] ligase activity Inferred from electronic annotation. Source: EC biotin-[methylcrotonoyl-CoA-carboxylase] ligase activity Inferred from electronic annotation. Source: EC biotin-[methylmalonyl-CoA-carboxytransferase] ligase activity Inferred from electronic annotation. Source: EC biotin-[propionyl-CoA-carboxylase (ATP-hydrolyzing)] ligase activity Ref.1 Traceable author statement. Source: ProtInc
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 726	726	Biotin--protein ligase		PRO_0000064979
Amino acid modifications
	Modified residue	147	1	Phosphoserine Ref.8
Natural variations
	Natural variant	42	1	E → D in HLCS deficiency and a breast cancer sample; somatic mutation; conserves enzynatic wild-type activity; could be a polymorphism. Ref.4 Ref.18		VAR_035800
	Natural variant	183	1	R → P in HLCS deficiency; has normal or low KM values for biotin (non-KM mutant). Ref.14		VAR_046507
	Natural variant	216	1	L → R in HLCS deficiency; has normal or low KM values for biotin (non-KM mutant); growth of patients' fibroblasts is compromised compared with normal fibroblasts; patients cells are not sensitive to biotin-depletion from the media; growth rates cannot be restored by re-administration of biotin; enzyme activity is severely compromised and cannot be increased by additional biotin; turn-over rate for the mutant protein is double that of wild-type enzyme. dbSNP rs28934602. Ref.14 Ref.11 Ref.15 Ref.19		VAR_021218
	Natural variant	237	1	L → P in HLCS deficiency; has normal or low KM values for biotin (non-KM mutant). Ref.4 Ref.14 Ref.1 Ref.10 Ref.12		VAR_005084
	Natural variant	333	1	V → E in HLCS deficiency; <10% activity; has normal or low KM values for biotin (non-KM mutant). Ref.4 Ref.14 Ref.13		VAR_009196
	Natural variant	360	1	R → S in HLCS deficiency; 22% activity; shows elevated KM values for biotin (KM mutant) compared with that of the wild-type form. Ref.4		VAR_046508
	Natural variant	363	1	V → D in HLCS deficiency; has normal or low KM values for biotin (non-KM mutant). Ref.14 Ref.11		VAR_046509
	Natural variant	456	1	Y → C in HLCS deficiency; 0.2% activity. Ref.4		VAR_046510
	Natural variant	462	1	T → I in HLCS deficiency; <10% activity. Ref.13		VAR_009197
	Natural variant	470	1	L → S in HLCS deficiency; 4.3% activity. Ref.4		VAR_046511
	Natural variant	508	1	R → W in HLCS deficiency. Ref.4 Ref.11 Ref.16		VAR_013009
	Natural variant	511	1	N → K in HLCS deficiency. Ref.15		VAR_021219
	Natural variant	518	1	G → E in HLCS deficiency. Ref.11		VAR_046512
	Natural variant	547	1	V → G in HLCS deficiency; 3.4% activity. Ref.4		VAR_046513
	Natural variant	550	1	V → M in HLCS deficiency. Ref.4 Ref.11 Ref.12 Ref.16		VAR_009198
	Natural variant	571	1	D → N in HLCS deficiency; almost no activity. Ref.11 Ref.13		VAR_009199
	Natural variant	581	1	G → S in HLCS deficiency; <10% activity. Ref.4 Ref.14 Ref.15 Ref.13		VAR_009200
	Natural variant	582	1	G → R in HLCS deficiency. Ref.15		VAR_021220
	Natural variant	610	1	Missing in HLCS deficiency; 14% of activity; shows elevated KM values for biotin (KM mutant) compared with that of the wild-type form.		VAR_009201
	Natural variant	615	1	D → Y in HLCS deficiency. Ref.17		VAR_046514
	Natural variant	634	1	D → N in HLCS deficiency. Ref.16		VAR_046515
	Natural variant	634	1	D → Y in HLCS deficiency; 12% activity. Ref.4		VAR_046516
	Natural variant	715	1	D → G in HLCS deficiency. Ref.17		VAR_046517
Experimental info
	Sequence conflict	558	1	E → K in BAA13332. Ref.2

Sequences

	Sequence		Length	Mass (Da)
	P50747-1 [UniParc]. Last modified October 1, 1996. Version 1. Checksum: 855B8E52106D675F	FASTA	726	80,760
	10 20 30 40 50 60 MEDRLHMDNG LVPQKIVSVH LQDSTLKEVK DQVSNKQAQI LEPKPEPSLE IKPEQDGMEH 70 80 90 100 110 120 VGRDDPKALG EEPKQRRGSA SGSEPAGDSD RGGGPVEHYH LHLSSCHECL ELENSTIESV 130 140 150 160 170 180 KFASAENIPD LPYDYSSSLE SVADETSPER EGRRVNLTGK APNILLYVGS DSQEALGRFH 190 200 210 220 230 240 EVRSVLADCV DIDSYILYHL LEDSALRDPW TDNCLLLVIA TRESIPEDLY QKFMAYLSQG 250 260 270 280 290 300 GKVLGLSSSF TFGGFQVTSK GALHKTVQNL VFSKADQSEV KLSVLSSGCR YQEGPVRLSP 310 320 330 340 350 360 GRLQGHLENE DKDRMIVHVP FGTRGGEAVL CQVHLELPPS SNIVQTPEDF NLLKSSNFRR 370 380 390 400 410 420 YEVLREILTT LGLSCDMKQV PALTPLYLLS AAEEIRDPLM QWLGKHVDSE GEIKSGQLSL 430 440 450 460 470 480 RFVSSYVSEV EITPSCIPVV TNMEAFSSEH FNLEIYRQNL QTKQLGKVIL FAEVTPTTMR 490 500 510 520 530 540 LLDGLMFQTP QEMGLIVIAA RQTEGKGRGG NVWLSPVGCA LSTLLISIPL RSQLGQRIPF 550 560 570 580 590 600 VQHLMSVAVV EAVRSIPEYQ DINLRVKWPN DIYYSDLMKI GGVLVNSTLM GETFYILIGC 610 620 630 640 650 660 GFNVTNSNPT ICINDLITEY NKQHKAELKP LRADYLIARV VTVLEKLIKE FQDKGPNSVL 670 680 690 700 710 720 PLYYRYWVHS GQQVHLGSAE GPKVSIVGLD DSGFLQVHQE GGEVVTVHPD GNSFDMLRNL ILPKRR

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Isolation and characterization of mutations in the human holocarboxylase synthetase cDNA." Suzuki Y., Aoki Y., Ishida Y., Chiba Y., Iwamatsu A., Kishino T., Niikawa N., Matsubara Y., Narisawa K. Nat. Genet. 8:122-128(1994) [PubMed: 7842009] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], VARIANT HLCS DEFICIENCY PRO-237. Tissue: Liver.
[2]	"Gene identification in the 1.6 Mb of the Down syndrome region on chromosome 21." Ohira M., Seki N., Nagase T., Suzuki E., Nomura N., Ohara O., Hattori M., Sakaki Y., Eki T., Murakami Y., Saito T., Ichikawa H., Ohki M. Submitted (FEB-1997) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Bone marrow.
[3]	"Genomic sequencing of 1.2-Mb region on human chromosome 21q22.2." Shibuya K., Kudoh J., Minoshima S., Kawasaki K., Nakatoh E., Shintani A., Asakawa S., Shimizu N. Submitted (NOV-1999) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[4]	"Structure of human holocarboxylase synthetase gene and mutation spectrum of holocarboxylase synthetase deficiency." Yang X., Aoki Y., Li X., Sakamoto O., Hiratsuka M., Kure S., Taheri S., Christensen E., Inui K., Kubota M., Ohira M., Ohki M., Kudoh J., Kawasaki K., Shibuya K., Shintani A., Asakawa S., Minoshima S. , Shimizu N., Narisawa K., Matsubara Y., Suzuki Y. Hum. Genet. 109:526-534(2001) [PubMed: 11735028] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANTS HLCS DEFICIENCY ASP-42; PRO-237; GLU-333; SER-360; CYS-456; SER-470; TRP-508; GLY-547; MET-550; SER-581; THR-610 DEL AND TYR-634, CHARACTERIZATION OF VARIANTS HLCS DEFICIENCY ASP-42; SER-360; CYS-456; SER-470; GLY-547 AND TYR-634.
[5]	"The DNA sequence of human chromosome 21." Hattori M., Fujiyama A., Taylor T.D., Watanabe H., Yada T., Park H.-S., Toyoda A., Ishii K., Totoki Y., Choi D.-K., Groner Y., Soeda E., Ohki M., Takagi T., Sakaki Y., Taudien S., Blechschmidt K., Polley A. , Menzel U., Delabar J., Kumpf K., Lehmann R., Patterson D., Reichwald K., Rump A., Schillhabel M., Schudy A., Zimmermann W., Rosenthal A., Kudoh J., Shibuya K., Kawasaki K., Asakawa S., Shintani A., Sasaki T., Nagamine K., Mitsuyama S., Antonarakis S.E., Minoshima S., Shimizu N., Nordsiek G., Hornischer K., Brandt P., Scharfe M., Schoen O., Desario A., Reichelt J., Kauer G., Bloecker H., Ramser J., Beck A., Klages S., Hennig S., Riesselmann L., Dagand E., Wehrmeyer S., Borzym K., Gardiner K., Nizetic D., Francis F., Lehrach H., Reinhardt R., Yaspo M.-L. Nature 405:311-319(2000) [PubMed: 10830953] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[6]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Placenta.
[7]	"Transcriptional map of the 2.5-Mb CBR-ERG region of chromosome 21 involved in Down syndrome." Dahmane N., Ait-Ghezala G., Gosset P., Chamoun Z., Dufresne-Zacharia M.-C., Lopes C., Rabatel N., Gassanova-Maugenre S., Chettouh Z., Abramowski V., Fayet E., Yaspo M.-L., Korn B., Blouin J.-L., Lehrach H., Poustka A., Antonarakis S.E., Sinet P.-M., Creau N., Delabar J.-M. Genomics 48:12-23(1998) [PubMed: 9503011] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 1-92. Tissue: Brain.
[8]	"A quantitative atlas of mitotic phosphorylation." Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., Elledge S.J., Gygi S.P. Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008) [PubMed: 18669648] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-147, MASS SPECTROMETRY.
[9]	Colinge J., Superti-Furga G., Bennett K.L. Submitted (OCT-2008) to UniProtKB Cited for: IDENTIFICATION [LARGE SCALE ANALYSIS], MASS SPECTROMETRY.
[10]	"Molecular analysis of holocarboxylase synthetase deficiency: a missense mutation and a single base deletion are predominant in Japanese patients." Aoki Y., Suzuki Y., Sakamoto O., Li X., Takahashi K., Ohtake A., Sakuta R., Ohura T., Miyabayashi S., Narisawa K. Biochim. Biophys. Acta 1272:168-174(1995) [PubMed: 8541348] [Abstract] Cited for: VARIANT HLCS DEFICIENCY PRO-237.
[11]	"Clustering of mutations in the biotin-binding region of holocarboxylase synthetase in biotin-responsive multiple carboxylase deficiency." Dupuis L., Leon-Del-Rio A., Leclerc D., Campeau E., Sweetman L., Saudubray J.-M., Herman G., Gibson K.M., Gravel R.A. Hum. Mol. Genet. 5:1011-1016(1996) [PubMed: 8817339] [Abstract] Cited for: VARIANTS HLCS DEFICIENCY ARG-216; ASP-363; TRP-508; GLU-518; MET-550 AND ASN-571.
[12]	"Characterization of mutant holocarboxylase synthetase (HCS): a Km for biotin was not elevated in a patient with HCS deficiency." Aoki Y., Suzuki Y., Li X., Sakamoto O., Chikaoka H., Takita S., Narisawa K. Pediatr. Res. 42:849-854(1997) [PubMed: 9396568] [Abstract] Cited for: VARIANTS HLCS DEFICIENCY PRO-237 AND MET-550.
[13]	"Identification and characterization of mutations in patients with holocarboxylase synthetase deficiency." Aoki Y., Li X., Sakamoto O., Hiratsuka M., Akaishi H., Xu L., Briones P., Suormala T., Baumgartner E.R., Suzuki Y., Narisawa K. Hum. Genet. 104:143-148(1999) [PubMed: 10190325] [Abstract] Cited for: VARIANTS HLCS DEFICIENCY GLU-333; ILE-462; ASN-571; SER-581 AND THR-610 DEL.
[14]	"Relationship between kinetic properties of mutant enzyme and biochemical and clinical responsiveness to biotin in holocarboxylase synthetase deficiency." Sakamoto O., Suzuki Y., Li X., Aoki Y., Hiratsuka M., Suormala T., Baumgartner E.R., Gibson K.M., Narisawa K. Pediatr. Res. 46:671-676(1999) [PubMed: 10590022] [Abstract] Cited for: BIOPHYSICOCHEMICAL PROPERTIES, VARIANTS HLCS DEFICIENCY PRO-183; ARG-216; PRO-237; GLU-333; ASP-363; SER-581 AND THR-610 DEL, CHARACTERIZATION OF VARIANTS HLCS DEFICIENCY PRO-183; ARG-216; PRO-237; GLU-333; ASP-363; SER-581 AND THR-610 DEL.
[15]	"Clinical findings and biochemical and molecular analysis of four patients with holocarboxylase synthetase deficiency." Morrone A., Malvagia S., Donati M.A., Funghini S., Ciani F., Pela I., Boneh A., Peters H., Pasquini E., Zammarchi E. Am. J. Med. Genet. 111:10-18(2002) [PubMed: 12124727] [Abstract] Cited for: VARIANTS HLCS DEFICIENCY ARG-216; LYS-511; SER-581 AND ARG-582.
[16]	"A genomic approach to mutation analysis of holocarboxylase synthetase gene in three Chinese patients with late-onset holocarboxylase synthetase deficiency." Tang N.L.S., Hui J., Yong C.K.K., Wong L.T.K., Applegarth D.A., Vallance H.D., Law L.K., Fung S.L.M., Mak T.W.L., Sung Y.M., Cheung K.L., Fok T.F. Clin. Biochem. 36:145-149(2003) [PubMed: 12633764] [Abstract] Cited for: VARIANTS HLCS DEFICIENCY TRP-508; MET-550 AND ASN-634.
[17]	"Mutations in the holocarboxylase synthetase gene HLCS." Suzuki Y., Yang X., Aoki Y., Kure S., Matsubara Y. Hum. Mutat. 26:285-290(2005) [PubMed: 16134170] [Abstract] Cited for: VARIANTS HLCS DEFICIENCY TYR-615 AND GLY-715.
[18]	"The consensus coding sequences of human breast and colorectal cancers." Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D., Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V. , Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W., Velculescu V.E. Science 314:268-274(2006) [PubMed: 16959974] [Abstract] Cited for: VARIANT [LARGE SCALE ANALYSIS] ASP-42.
[19]	"Reduced half-life of holocarboxylase synthetase from patients with severe multiple carboxylase deficiency." Bailey L.M., Ivanov R.A., Jitrapakdee S., Wilson C.J., Wallace J.C., Polyak S.W. Hum. Mutat. 29:E47-E57(2008) [PubMed: 18429047] [Abstract] Cited for: CHARACTERIZATION OF VARIANT HLCS DEFICIENCY ARG-216.
+	Additional computationally mapped references.

Web resources

GeneReviews

Cross-references

Sequence databases
EMBLGenBankDDBJ	D23672 mRNA. Translation: BAA04902.1. D87328 mRNA. Translation: BAA13332.1. AP000697 , AP000703, AP000701, AP000698 Genomic DNA. Translation: BAA89434.1. AB063285 Genomic DNA. Translation: BAB68550.1. AP001727 Genomic DNA. Translation: BAA95511.1. AP001726 Genomic DNA. Translation: BAA95510.1. BC060787 mRNA. Translation: AAH60787.1. AJ001864 mRNA. Translation: CAA05056.1.
IPI	IPI00301907.
PIR	S50833.
RefSeq	NP_000402.3.
UniGene	Hs.371350
3D structure databases
ModBase	Search...
Protein-protein interaction databases
STRING	P50747.
PTM databases
PhosphoSite	P50747.
Proteomic databases
PRIDE	P50747.
Genome annotation databases
Ensembl	ENST00000336648; ENSP00000338387; ENSG00000159267; Homo sapiens. [Genome view] ENST00000399120; ENSP00000382071; ENSG00000159267; Homo sapiens. [Genome view] ENST00000419461; ENSP00000396370; ENSG00000159267; Homo sapiens. [Genome view] ENST00000427746; ENSP00000396443; ENSG00000159267; Homo sapiens. [Genome view] ENST00000448340; ENSP00000392923; ENSG00000159267; Homo sapiens. [Genome view]
GeneID	3141.
KEGG	hsa:3141.
NMPDR	fig|9606.3.peg.20939.
UCSC	uc002yvs.1. human.
Organism-specific databases
CTD	3141.
GeneCards	GC21M037045.
H-InvDB	HIX0040887.
HGNC	HGNC:4976. HLCS.
HPA	HPA017379.
MIM	253270. phenotype. 609018. gene.
Orphanet	148. Multiple carboxylase deficiency.
PharmGKB	PA29310.
GenAtlas	Search...
Phylogenomic databases
HOGENOM	P50747.
HOVERGEN	P50747.
OMA	YWVHSGQ.
Enzyme and pathway databases
BRENDA	6.3.4.10. 247. 6.3.4.11. 247. 6.3.4.15. 247. 6.3.4.9. 247.
Gene expression databases
ArrayExpress	P50747.
Bgee	P50747.
CleanEx	HS_HLCS.
Genevestigator	P50747.
GermOnline	ENSG00000159267. Homo sapiens.
Family and domain databases
InterPro	IPR004408. Biotin_CoA_COase_ligase. IPR003142. BPL_C. IPR004143. BPL_LipA_LipB. [Graphical view]
PANTHER	PTHR12835. BirA_ligase. 1 hit.
Pfam	PF02237. BPL_C. 1 hit. PF03099. BPL_LipA_LipB. 1 hit. [Graphical view]
TIGRFAMs	TIGR00121. birA_ligase. 1 hit.
ProtoNet	Search...
Other Resources
DrugBank	DB00121. Biotin.
NextBio	12456.
SOURCE	Search...

Entry information

Entry name

BPL1_HUMAN

Accession

Primary (citable) accession number: P50747
Secondary accession number(s): Q99451

Entry history

Integrated into UniProtKB/Swiss-Prot:	October 1, 1996
Last sequence update:	October 1, 1996
Last modified:	November 3, 2009
This is version 93 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.