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Protein

Biotin--protein ligase

Gene

HLCS

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

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 activityi

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 + [biotin carboxyl-carrier protein]-L-lysine = AMP + diphosphate + [biotin carboxyl-carrier protein]-N6-biotinyl-L-lysine.

Kineticsi

  1. KM=224 nM for biotin1 Publication
  1. Vmax=143.9 pmol/min/mg enzyme1 Publication

GO - Molecular functioni

GO - Biological processi

  • biotin metabolic process Source: Reactome
  • cell proliferation Source: UniProtKB
  • histone biotinylation Source: UniProtKB
  • histone modification Source: UniProtKB
  • protein biotinylation Source: UniProtKB
  • response to biotin Source: UniProtKB

Keywordsi

Molecular functionLigase, Multifunctional enzyme
LigandATP-binding, Nucleotide-binding

Enzyme and pathway databases

ReactomeiR-HSA-196780 Biotin transport and metabolism
R-HSA-3371599 Defective HLCS causes multiple carboxylase deficiency
SABIO-RKiP50747

Names & Taxonomyi

Protein namesi
Recommended name:
Biotin--protein ligase (EC:6.3.4.-)
Alternative name(s):
Biotin apo-protein ligase
Including the following 4 domains:
Biotin--[methylmalonyl-CoA-carboxytransferase] ligase (EC:6.3.4.9)
Biotin--[propionyl-CoA-carboxylase [ATP-hydrolyzing]] ligase (EC:6.3.4.10)
Alternative name(s):
Holocarboxylase synthetase
Short name:
HCS
Biotin--[methylcrotonoyl-CoA-carboxylase] ligase (EC:6.3.4.11)
Biotin--[acetyl-CoA-carboxylase] ligase (EC:6.3.4.15)
Gene namesi
Name:HLCS
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 21

Organism-specific databases

EuPathDBiHostDB:ENSG00000159267.14
HGNCiHGNC:4976 HLCS
MIMi609018 gene
neXtProtiNX_P50747

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Cytoplasm, Mitochondrion

Pathology & Biotechi

Involvement in diseasei

Holocarboxylase synthetase deficiency (HLCS deficiency)12 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA neonatal form of multiple carboxylase deficiency, an autosomal recessive disorder of biotin metabolism, characterized by ketoacidosis, hyperammonemia, excretion of abnormal organic acid metabolites, and dermatitis. In holocarboxylase synthetase deficiency, clinical and biochemical symptoms improve dramatically with administration of biotin.
See also OMIM:253270
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_046507183R → P in HLCS deficiency; has normal or low KM values for biotin (non-KM mutant). 1 Publication1
Natural variantiVAR_021218216L → 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. 4 PublicationsCorresponds to variant dbSNP:rs28934602Ensembl.1
Natural variantiVAR_005084237L → P in HLCS deficiency; has normal or low KM values for biotin (non-KM mutant). 5 PublicationsCorresponds to variant dbSNP:rs119103227Ensembl.1
Natural variantiVAR_073074241G → W in HLCS deficiency. 1 Publication1
Natural variantiVAR_009196333V → E in HLCS deficiency; <10% activity; has normal or low KM values for biotin (non-KM mutant). 3 Publications1
Natural variantiVAR_046508360R → S in HLCS deficiency; 22% activity; shows elevated KM values for biotin (KM mutant) compared with that of the wild-type form. 1 Publication1
Natural variantiVAR_046509363V → D in HLCS deficiency; has normal or low KM values for biotin (non-KM mutant). 2 PublicationsCorresponds to variant dbSNP:rs769499327Ensembl.1
Natural variantiVAR_046510456Y → C in HLCS deficiency; 0.2% activity. 1 PublicationCorresponds to variant dbSNP:rs781603756Ensembl.1
Natural variantiVAR_009197462T → I in HLCS deficiency; <10% activity. 1 Publication1
Natural variantiVAR_046511470L → S in HLCS deficiency; 4.3% activity. 1 Publication1
Natural variantiVAR_073075505G → R in HLCS deficiency. 1 Publication1
Natural variantiVAR_013009508R → W in HLCS deficiency. 4 PublicationsCorresponds to variant dbSNP:rs119103229Ensembl.1
Natural variantiVAR_021219511N → K in HLCS deficiency. 1 Publication1
Natural variantiVAR_046512518G → E in HLCS deficiency. 1 Publication1
Natural variantiVAR_046513547V → G in HLCS deficiency; 3.4% activity. 1 Publication1
Natural variantiVAR_009198550V → M in HLCS deficiency. 4 PublicationsCorresponds to variant dbSNP:rs119103231Ensembl.1
Natural variantiVAR_009199571D → N in HLCS deficiency; almost no activity. 2 PublicationsCorresponds to variant dbSNP:rs119103228Ensembl.1
Natural variantiVAR_009200581G → S in HLCS deficiency; <10% activity. 4 PublicationsCorresponds to variant dbSNP:rs119103230Ensembl.1
Natural variantiVAR_021220582G → R in HLCS deficiency. 1 PublicationCorresponds to variant dbSNP:rs376899782Ensembl.1
Natural variantiVAR_009201610Missing in HLCS deficiency; 14% of activity; shows elevated KM values for biotin (KM mutant) compared with that of the wild-type form. 3 Publications1
Natural variantiVAR_046514615D → Y in HLCS deficiency. 1 Publication1
Natural variantiVAR_046515634D → N in HLCS deficiency. 1 PublicationCorresponds to variant dbSNP:rs149399432Ensembl.1
Natural variantiVAR_046516634D → Y in HLCS deficiency; 12% activity. 1 Publication1
Natural variantiVAR_046517715D → G in HLCS deficiency. 1 Publication1

Keywords - Diseasei

Disease mutation

Organism-specific databases

DisGeNETi3141
MalaCardsiHLCS
MIMi253270 phenotype
OpenTargetsiENSG00000159267
Orphaneti79242 Holocarboxylase synthetase deficiency
PharmGKBiPA29310

Chemistry databases

ChEMBLiCHEMBL2062354
DrugBankiDB00121 Biotin

Polymorphism and mutation databases

BioMutaiHLCS
DMDMi1705499

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000649791 – 726Biotin--protein ligaseAdd BLAST726

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei147PhosphoserineCombined sources1
Modified residuei299PhosphoserineCombined sources1

Keywords - PTMi

Phosphoprotein

Proteomic databases

EPDiP50747
MaxQBiP50747
PaxDbiP50747
PeptideAtlasiP50747
PRIDEiP50747

PTM databases

iPTMnetiP50747
PhosphoSitePlusiP50747

Expressioni

Tissue specificityi

Mostly expressed in muscle, placenta, in lesser extent in the brain, kidney, pancreas, liver and lung.

Gene expression databases

BgeeiENSG00000159267
CleanExiHS_HLCS
ExpressionAtlasiP50747 baseline and differential
GenevisibleiP50747 HS

Organism-specific databases

HPAiHPA017379

Interactioni

Subunit structurei

Monomer.

Binary interactionsi

Show more details

GO - Molecular functioni

  • enzyme binding Source: UniProtKB
  • protein homodimerization activity Source: Ensembl

Protein-protein interaction databases

BioGridi109386, 9 interactors
IntActiP50747, 10 interactors
MINTiP50747
STRINGi9606.ENSP00000338387

Chemistry databases

BindingDBiP50747

Structurei

3D structure databases

ProteinModelPortaliP50747
SMRiP50747
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini463 – 652BPL/LPL catalyticPROSITE-ProRule annotationAdd BLAST190

Sequence similaritiesi

Belongs to the biotin--protein ligase family.Curated

Phylogenomic databases

eggNOGiKOG1536 Eukaryota
COG0340 LUCA
GeneTreeiENSGT00390000002960
HOGENOMiHOG000095254
HOVERGENiHBG004872
InParanoidiP50747
KOiK01942
OMAiRDPLMQW
OrthoDBiEOG091G0G5R
PhylomeDBiP50747
TreeFamiTF105860

Family and domain databases

CDDicd16442 BPL, 1 hit
InterProiView protein in InterPro
IPR019197 Biotin-prot_ligase_N
IPR004408 Biotin_CoA_COase_ligase
IPR003142 BPL_C
IPR004143 BPL_LPL_catalytic
PANTHERiPTHR12835:SF5 PTHR12835:SF5, 2 hits
PfamiView protein in Pfam
PF02237 BPL_C, 1 hit
PF03099 BPL_LplA_LipB, 1 hit
PF09825 BPL_N, 1 hit
TIGRFAMsiTIGR00121 birA_ligase, 1 hit
PROSITEiView protein in PROSITE
PS51733 BPL_LPL_CATALYTIC, 1 hit

Sequencei

Sequence statusi: Complete.

P50747-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MEDRLHMDNG LVPQKIVSVH LQDSTLKEVK DQVSNKQAQI LEPKPEPSLE
60 70 80 90 100
IKPEQDGMEH VGRDDPKALG EEPKQRRGSA SGSEPAGDSD RGGGPVEHYH
110 120 130 140 150
LHLSSCHECL ELENSTIESV KFASAENIPD LPYDYSSSLE SVADETSPER
160 170 180 190 200
EGRRVNLTGK APNILLYVGS DSQEALGRFH EVRSVLADCV DIDSYILYHL
210 220 230 240 250
LEDSALRDPW TDNCLLLVIA TRESIPEDLY QKFMAYLSQG GKVLGLSSSF
260 270 280 290 300
TFGGFQVTSK GALHKTVQNL VFSKADQSEV KLSVLSSGCR YQEGPVRLSP
310 320 330 340 350
GRLQGHLENE DKDRMIVHVP FGTRGGEAVL CQVHLELPPS SNIVQTPEDF
360 370 380 390 400
NLLKSSNFRR YEVLREILTT LGLSCDMKQV PALTPLYLLS AAEEIRDPLM
410 420 430 440 450
QWLGKHVDSE GEIKSGQLSL RFVSSYVSEV EITPSCIPVV TNMEAFSSEH
460 470 480 490 500
FNLEIYRQNL QTKQLGKVIL FAEVTPTTMR LLDGLMFQTP QEMGLIVIAA
510 520 530 540 550
RQTEGKGRGG NVWLSPVGCA LSTLLISIPL RSQLGQRIPF VQHLMSVAVV
560 570 580 590 600
EAVRSIPEYQ DINLRVKWPN DIYYSDLMKI GGVLVNSTLM GETFYILIGC
610 620 630 640 650
GFNVTNSNPT ICINDLITEY NKQHKAELKP LRADYLIARV VTVLEKLIKE
660 670 680 690 700
FQDKGPNSVL PLYYRYWVHS GQQVHLGSAE GPKVSIVGLD DSGFLQVHQE
710 720
GGEVVTVHPD GNSFDMLRNL ILPKRR
Length:726
Mass (Da):80,760
Last modified:October 1, 1996 - v1
Checksum:i855B8E52106D675F
GO

Sequence cautioni

The sequence AK307940 differs from that shown. Reason: Frameshift at position 169.Curated

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti209P → T in AK307940 (PubMed:14702039).Curated1
Sequence conflicti463K → R in BAG36868 (PubMed:14702039).Curated1
Sequence conflicti558E → K in BAA13332 (PubMed:9037601).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_03580042E → D in HLCS deficiency and a breast cancer sample; somatic mutation; conserves enzymatic wild-type activity; unknown pathological significance. 2 PublicationsCorresponds to variant dbSNP:rs61732504Ensembl.1
Natural variantiVAR_046507183R → P in HLCS deficiency; has normal or low KM values for biotin (non-KM mutant). 1 Publication1
Natural variantiVAR_021218216L → 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. 4 PublicationsCorresponds to variant dbSNP:rs28934602Ensembl.1
Natural variantiVAR_005084237L → P in HLCS deficiency; has normal or low KM values for biotin (non-KM mutant). 5 PublicationsCorresponds to variant dbSNP:rs119103227Ensembl.1
Natural variantiVAR_073074241G → W in HLCS deficiency. 1 Publication1
Natural variantiVAR_009196333V → E in HLCS deficiency; <10% activity; has normal or low KM values for biotin (non-KM mutant). 3 Publications1
Natural variantiVAR_046508360R → S in HLCS deficiency; 22% activity; shows elevated KM values for biotin (KM mutant) compared with that of the wild-type form. 1 Publication1
Natural variantiVAR_046509363V → D in HLCS deficiency; has normal or low KM values for biotin (non-KM mutant). 2 PublicationsCorresponds to variant dbSNP:rs769499327Ensembl.1
Natural variantiVAR_046510456Y → C in HLCS deficiency; 0.2% activity. 1 PublicationCorresponds to variant dbSNP:rs781603756Ensembl.1
Natural variantiVAR_009197462T → I in HLCS deficiency; <10% activity. 1 Publication1
Natural variantiVAR_046511470L → S in HLCS deficiency; 4.3% activity. 1 Publication1
Natural variantiVAR_073075505G → R in HLCS deficiency. 1 Publication1
Natural variantiVAR_013009508R → W in HLCS deficiency. 4 PublicationsCorresponds to variant dbSNP:rs119103229Ensembl.1
Natural variantiVAR_021219511N → K in HLCS deficiency. 1 Publication1
Natural variantiVAR_046512518G → E in HLCS deficiency. 1 Publication1
Natural variantiVAR_046513547V → G in HLCS deficiency; 3.4% activity. 1 Publication1
Natural variantiVAR_009198550V → M in HLCS deficiency. 4 PublicationsCorresponds to variant dbSNP:rs119103231Ensembl.1
Natural variantiVAR_009199571D → N in HLCS deficiency; almost no activity. 2 PublicationsCorresponds to variant dbSNP:rs119103228Ensembl.1
Natural variantiVAR_009200581G → S in HLCS deficiency; <10% activity. 4 PublicationsCorresponds to variant dbSNP:rs119103230Ensembl.1
Natural variantiVAR_021220582G → R in HLCS deficiency. 1 PublicationCorresponds to variant dbSNP:rs376899782Ensembl.1
Natural variantiVAR_009201610Missing in HLCS deficiency; 14% of activity; shows elevated KM values for biotin (KM mutant) compared with that of the wild-type form. 3 Publications1
Natural variantiVAR_046514615D → Y in HLCS deficiency. 1 Publication1
Natural variantiVAR_046515634D → N in HLCS deficiency. 1 PublicationCorresponds to variant dbSNP:rs149399432Ensembl.1
Natural variantiVAR_046516634D → Y in HLCS deficiency; 12% activity. 1 Publication1
Natural variantiVAR_046517715D → G in HLCS deficiency. 1 Publication1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
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
AK307940 mRNA No translation available.
AK314189 mRNA Translation: BAG36868.1
AP001726 Genomic DNA Translation: BAA95510.1
AP001727 Genomic DNA Translation: BAA95511.1
CH471079 Genomic DNA Translation: EAX09731.1
CH471079 Genomic DNA Translation: EAX09732.1
BC060787 mRNA Translation: AAH60787.1
AJ001864 mRNA Translation: CAA05056.1
CCDSiCCDS13647.1
PIRiS50833
RefSeqiNP_000402.3, NM_000411.6
NP_001229713.1, NM_001242784.1
NP_001229714.1, NM_001242785.1
XP_005261012.1, XM_005260955.3
XP_005261013.1, XM_005260956.3
XP_006724057.1, XM_006723994.2
XP_006724058.1, XM_006723995.1
XP_011527840.1, XM_011529538.1
XP_011527841.1, XM_011529539.2
XP_011527843.1, XM_011529541.2
XP_016883819.1, XM_017028330.1
UniGeneiHs.371350
Hs.732538

Genome annotation databases

EnsembliENST00000336648; ENSP00000338387; ENSG00000159267
ENST00000399120; ENSP00000382071; ENSG00000159267
ENST00000612277; ENSP00000479939; ENSG00000159267
GeneIDi3141
KEGGihsa:3141
UCSCiuc002yvs.4 human

Keywords - Coding sequence diversityi

Polymorphism

Similar proteinsi

Entry informationi

Entry nameiBPL1_HUMAN
AccessioniPrimary (citable) accession number: P50747
Secondary accession number(s): B2RAH1, D3DSG6, Q99451
Entry historyiIntegrated into UniProtKB/Swiss-Prot: October 1, 1996
Last sequence update: October 1, 1996
Last modified: April 25, 2018
This is version 173 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny 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.

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome
UniProt is an ELIXIR core data resource
Main funding by: National Institutes of Health