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P11498 (PYC_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 166. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (7) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·Web links·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Pyruvate carboxylase, mitochondrial

EC=6.4.1.1
Alternative name(s):
Pyruvic carboxylase
Short name=PCB
Gene names
Name:PC
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length1178 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Pyruvate carboxylase catalyzes a 2-step reaction, involving the ATP-dependent carboxylation of the covalently attached biotin in the first step and the transfer of the carboxyl group to pyruvate in the second. Catalyzes in a tissue specific manner, the initial reactions of glucose (liver, kidney) and lipid (adipose tissue, liver, brain) synthesis from pyruvate.

Catalytic activity

ATP + pyruvate + HCO3- = ADP + phosphate + oxaloacetate.

Cofactor

Biotin.

Binds 1 manganese ion per subunit.

Pathway

Carbohydrate biosynthesis; gluconeogenesis.

Subunit structure

Homotetramer. Ref.9

Subcellular location

Mitochondrion matrix.

Involvement in disease

Pyruvate carboxylase deficiency (PC deficiency) [MIM:266150]: Leads to lactic acidosis, mental retardation and death. It occurs in three forms: mild or type A, severe neonatal or type B, and a very mild lacticacidemia.
Note: The disease is caused by mutations affecting the gene represented in this entry.

Sequence similarities

Contains 1 ATP-grasp domain.

Contains 1 biotin carboxylation domain.

Contains 1 biotinyl-binding domain.

Contains 1 carboxyltransferase domain.

Ontologies

Keywords
   Biological processGluconeogenesis
Lipid biosynthesis
Lipid metabolism
   Cellular componentMitochondrion
   Coding sequence diversityPolymorphism
   DiseaseDisease mutation
   DomainTransit peptide
   LigandATP-binding
Biotin
Manganese
Metal-binding
Nucleotide-binding
Pyruvate
   Molecular functionLigase
   PTMAcetylation
   Technical term3D-structure
Complete proteome
Multifunctional enzyme
Reference proteome
Gene Ontology (GO)
   Biological_processbiotin metabolic process

Traceable author statement. Source: Reactome

carbohydrate metabolic process

Traceable author statement. Source: Reactome

gluconeogenesis

Traceable author statement. Source: Reactome

glucose metabolic process

Traceable author statement. Source: Reactome

lipid metabolic process

Inferred from electronic annotation. Source: UniProtKB-KW

oxaloacetate metabolic process

Inferred from electronic annotation. Source: Ensembl

pyruvate metabolic process

Inferred from electronic annotation. Source: Ensembl

small molecule metabolic process

Traceable author statement. Source: Reactome

vitamin metabolic process

Traceable author statement. Source: Reactome

water-soluble vitamin metabolic process

Traceable author statement. Source: Reactome

   Cellular_componentcytosol

Traceable author statement. Source: Reactome

mitochondrial inner membrane

Inferred from electronic annotation. Source: Ensembl

mitochondrial matrix

Traceable author statement. Source: Reactome

mitochondrion

Inferred from direct assay. Source: HPA

   Molecular_functionATP binding

Traceable author statement Ref.2. Source: ProtInc

DNA binding

Inferred from electronic annotation. Source: InterPro

biotin binding

Traceable author statement Ref.2. Source: ProtInc

biotin carboxylase activity

Inferred from electronic annotation. Source: InterPro

metal ion binding

Inferred from electronic annotation. Source: UniProtKB-KW

pyruvate carboxylase activity

Traceable author statement. Source: Reactome

Complete GO annotation...

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Transit peptide1 – 2020Mitochondrion Potential
Chain21 – 11781158Pyruvate carboxylase, mitochondrial
PRO_0000002840

Regions

Domain36 – 486451Biotin carboxylation
Domain156 – 353198ATP-grasp
Domain563 – 832270Carboxyltransferase
Domain1110 – 117768Biotinyl-binding
Region571 – 5755Substrate binding

Sites

Active site3281 By similarity
Metal binding5721Manganese
Metal binding7411Manganese; via carbamate group
Metal binding7711Manganese
Metal binding7731Manganese
Binding site1521ATP By similarity
Binding site2361ATP By similarity
Binding site2711ATP By similarity
Binding site6441Substrate
Binding site9081Substrate

Amino acid modifications

Modified residue791N6-acetyllysine; alternate By similarity
Modified residue791N6-succinyllysine; alternate By similarity
Modified residue2971N6-acetyllysine By similarity
Modified residue3191N6-acetyllysine By similarity
Modified residue4341N6-acetyllysine By similarity
Modified residue4421N6-succinyllysine By similarity
Modified residue6611N6-acetyllysine By similarity
Modified residue7411N6-carboxylysine
Modified residue7481N6-acetyllysine By similarity
Modified residue9921N6-acetyllysine By similarity
Modified residue10611N6-acetyllysine By similarity
Modified residue10901N6-acetyllysine Ref.7
Modified residue11241N6-acetyllysine By similarity
Modified residue11441N6-biotinyllysine

Natural variations

Natural variant761H → L.
Corresponds to variant rs7104156 [ dbSNP | Ensembl ].
VAR_048416
Natural variant1451V → A in PC deficiency; mild. Ref.11 Ref.12
Corresponds to variant rs28940591 [ dbSNP | Ensembl ].
VAR_015199
Natural variant1561R → Q in PC deficiency. Ref.12
VAR_058957
Natural variant2701R → W in PC deficiency. Ref.12
VAR_058958
Natural variant3041Y → C in PC deficiency. Ref.12
VAR_058959
Natural variant4511R → C in PC deficiency; mild. Ref.11 Ref.12
VAR_015200
Natural variant5831R → L in PC deficiency. Ref.12
VAR_058960
Natural variant6101A → T in PC deficiency; mild. Ref.10 Ref.12
Corresponds to variant rs28940589 [ dbSNP | Ensembl ].
VAR_008095
Natural variant6311R → Q in PC deficiency. Ref.12
VAR_058961
Natural variant7431M → I in PC deficiency; mild. Ref.10 Ref.12
Corresponds to variant rs28940590 [ dbSNP | Ensembl ].
VAR_008096
Natural variant1131 – 11333Missing in PC deficiency.
VAR_058962

Experimental info

Mutagenesis10771F → A or E: Loss of tetramerization and enzyme activity, resulting in an inactive homodimer. Ref.9
Sequence conflict225 – 2262LA → WP in AAB31500. Ref.2
Sequence conflict3521A → S in AAA82937. Ref.3
Sequence conflict385 – 3862RS → PT in AAB31500. Ref.2
Sequence conflict486 – 4872EL → DV in AAB31500. Ref.2
Sequence conflict6381P → R in AAB31500. Ref.2
Sequence conflict7291E → A in AAB31500. Ref.2
Sequence conflict774 – 7752DT → AP in AAB31500. Ref.2

Secondary structure

.......................................................................................................... 1178
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
P11498 [UniParc].

Last modified October 1, 1996. Version 2.
Checksum: 381F527553A20095

FASTA1,178129,634
        10         20         30         40         50         60 
MLKFRTVHGG LRLLGIRRTS TAPAASPNVR RLEYKPIKKV MVANRGEIAI RVFRACTELG 

        70         80         90        100        110        120 
IRTVAIYSEQ DTGQMHRQKA DEAYLIGRGL APVQAYLHIP DIIKVAKENN VDAVHPGYGF 

       130        140        150        160        170        180 
LSERADFAQA CQDAGVRFIG PSPEVVRKMG DKVEARAIAI AAGVPVVPGT DAPITSLHEA 

       190        200        210        220        230        240 
HEFSNTYGFP IIFKAAYGGG GRGMRVVHSY EELEENYTRA YSEALAAFGN GALFVEKFIE 

       250        260        270        280        290        300 
KPRHIEVQIL GDQYGNILHL YERDCSIQRR HQKVVEIAPA AHLDPQLRTR LTSDSVKLAK 

       310        320        330        340        350        360 
QVGYENAGTV EFLVDRHGKH YFIEVNSRLQ VEHTVTEEIT DVDLVHAQIH VAEGRSLPDL 

       370        380        390        400        410        420 
GLRQENIRIN GCAIQCRVTT EDPARSFQPD TGRIEVFRSG EGMGIRLDNA SAFQGAVISP 

       430        440        450        460        470        480 
HYDSLLVKVI AHGKDHPTAA TKMSRALAEF RVRGVKTNIA FLQNVLNNQQ FLAGTVDTQF 

       490        500        510        520        530        540 
IDENPELFQL RPAQNRAQKL LHYLGHVMVN GPTTPIPVKA SPSPTDPVVP AVPIGPPPAG 

       550        560        570        580        590        600 
FRDILLREGP EGFARAVRNH PGLLLMDTTF RDAHQSLLAT RVRTHDLKKI APYVAHNFSK 

       610        620        630        640        650        660 
LFSMENWGGA TFDVAMRFLY ECPWRRLQEL RELIPNIPFQ MLLRGANAVG YTNYPDNVVF 

       670        680        690        700        710        720 
KFCEVAKENG MDVFRVFDSL NYLPNMLLGM EAAGSAGGVV EAAISYTGDV ADPSRTKYSL 

       730        740        750        760        770        780 
QYYMGLAEEL VRAGTHILCI KDMAGLLKPT ACTMLVSSLR DRFPDLPLHI HTHDTSGAGV 

       790        800        810        820        830        840 
AAMLACAQAG ADVVDVAADS MSGMTSQPSM GALVACTRGT PLDTEVPMER VFDYSEYWEG 

       850        860        870        880        890        900 
ARGLYAAFDC TATMKSGNSD VYENEIPGGQ YTNLHFQAHS MGLGSKFKEV KKAYVEANQM 

       910        920        930        940        950        960 
LGDLIKVTPS SKIVGDLAQF MVQNGLSRAE AEAQAEELSF PRSVVEFLQG YIGVPHGGFP 

       970        980        990       1000       1010       1020 
EPFRSKVLKD LPRVEGRPGA SLPPLDLQAL EKELVDRHGE EVTPEDVLSA AMYPDVFAHF 

      1030       1040       1050       1060       1070       1080 
KDFTATFGPL DSLNTRLFLQ GPKIAEEFEV ELERGKTLHI KALAVSDLNR AGQRQVFFEL 

      1090       1100       1110       1120       1130       1140 
NGQLRSILVK DTQAMKEMHF HPKALKDVKG QIGAPMPGKV IDIKVVAGAK VAKGQPLCVL 

      1150       1160       1170 
SAMKMETVVT SPMEGTVRKV HVTKDMTLEG DDLILEIE 

« Hide

References

« Hide 'large scale' references
[1]"Primary amino acid sequence and structure of human pyruvate carboxylase."
Wexler I.D., Du Y., Lisgaris M.V., Mandal S.K., Freytag S.O., Yang B.-S., Liu T.-C., Kwon M., Patel M.S., Kerr D.S.
Biochim. Biophys. Acta 1227:46-52(1994) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
Tissue: Kidney and Liver.
[2]"cDNA cloning of human kidney pyruvate carboxylase."
Mackay N., Rigat B., Douglas C., Chen H.S., Robinson B.H.
Biochem. Biophys. Res. Commun. 202:1009-1014(1994) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
Tissue: Kidney.
[3]Walker M.E., Jitrapakdee S., Val D.L., Wallace J.C.
Submitted (JUL-1995) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
Tissue: Kidney and Liver.
[4]"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] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
Tissue: Lung.
[5]"Sequence homology around the biotin-binding site of human propionyl-CoA carboxylase and pyruvate carboxylase."
Lamhonwah A.-M., Quan F., Gravel R.A.
Arch. Biochem. Biophys. 254:631-636(1987) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 1083-1178.
[6]"Molecular cloning of a cDNA for human pyruvate carboxylase. Structural relationship to other biotin-containing carboxylases and regulation of mRNA content in differentiating preadipocytes."
Freytag S.O., Collier K.J.
J. Biol. Chem. 259:12831-12837(1984) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 1135-1178.
[7]"Lysine acetylation targets protein complexes and co-regulates major cellular functions."
Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T.C., Olsen J.V., Mann M.
Science 325:834-840(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-1090, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[8]"Initial characterization of the human central proteome."
Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.
BMC Syst. Biol. 5:17-17(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[9]"Crystal structures of human and Staphylococcus aureus pyruvate carboxylase and molecular insights into the carboxyltransfer reaction."
Xiang S., Tong L.
Nat. Struct. Mol. Biol. 15:295-302(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF 481-1178 IN COMPLEX WITH PYRUVATE; MANGANESE AND BIOTIN ANALOG, CARBAMYLATION AT LYS-741, MUTAGENESIS OF PHE-1077, SUBUNIT.
[10]"Amerindian pyruvate carboxylase deficiency is associated with two distinct missense mutations."
Carbone M.A., MacKay N., Ling M., Cole D.E.C., Douglas C., Rigat B., Feigenbaum A., Clarke J.T.R., Haworth J.C., Greenberg C.R., Seargeant L., Robinson B.H.
Am. J. Hum. Genet. 62:1312-1319(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS PC DEFICIENCY THR-610 AND ILE-743.
[11]"Molecular characterization of pyruvate carboxylase deficiency in two consanguineous families."
Wexler I.D., Kerr D.S., Du Y., Kaung M.M., Stephenson W., Lusk M.M., Wappner R.S., Higgins J.J.
Pediatr. Res. 43:579-584(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS PC DEFICIENCY ALA-145 AND CYS-451.
[12]"Structural insights on pathogenic effects of novel mutations causing pyruvate carboxylase deficiency."
Monnot S., Serre V., Chadefaux-Vekemans B., Aupetit J., Romano S., De Lonlay P., Rival J.-M., Munnich A., Steffann J., Bonnefont J.-P.
Hum. Mutat. 30:734-740(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS PC DEFICIENCY ALA-145; GLN-156; TRP-270; CYS-304; CYS-451; LEU-583; THR-610; GLN-631; ILE-743 AND 1131-VAL--LYS-1133 DEL.
+Additional computationally mapped references.

Web resources

GeneReviews
Wikipedia

Pyruvate carboxylase entry

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
U04641 mRNA. Translation: AAA99537.1.
S72370 mRNA. Translation: AAB31500.1.
U30891 mRNA. Translation: AAA82937.1.
BC011617 mRNA. Translation: AAH11617.1.
M26122 mRNA. Translation: AAA36423.1.
K02282 mRNA. Translation: AAA60033.1.
PIRJC2460. G01933.
RefSeqNP_000911.2. NM_000920.3.
NP_001035806.1. NM_001040716.1.
NP_071504.2. NM_022172.2.
XP_005274088.1. XM_005274031.2.
XP_005274089.1. XM_005274032.2.
UniGeneHs.89890.

3D structure databases

PDBe
RCSB PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
3BG3X-ray2.80A/B/C/D482-1178[»]
3BG9X-ray3.00A/B/C/D482-1178[»]
ProteinModelPortalP11498.
SMRP11498. Positions 37-488, 494-1178.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid111124. 23 interactions.
DIPDIP-46372N.
IntActP11498. 2 interactions.
MINTMINT-3007737.
STRING9606.ENSP00000377527.

Chemistry

DrugBankDB00121. Biotin.
DB00119. Pyruvic acid.

PTM databases

PhosphoSiteP11498.

Polymorphism databases

DMDM1709947.

Proteomic databases

PaxDbP11498.
PeptideAtlasP11498.
PRIDEP11498.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000393955; ENSP00000377527; ENSG00000173599.
ENST00000393958; ENSP00000377530; ENSG00000173599.
ENST00000393960; ENSP00000377532; ENSG00000173599.
GeneID5091.
KEGGhsa:5091.
UCSCuc001ojn.1. human.

Organism-specific databases

CTD5091.
GeneCardsGC11M066615.
HGNCHGNC:8636. PC.
HPACAB033742.
HPA043922.
MIM266150. phenotype.
608786. gene.
neXtProtNX_P11498.
Orphanet353320. Pyruvate carboxylase deficiency, benign type.
353308. Pyruvate carboxylase deficiency, infantile type.
353314. Pyruvate carboxylase deficiency, severe neonatal type.
PharmGKBPA32975.
GenAtlasSearch...

Phylogenomic databases

eggNOGCOG1038.
HOGENOMHOG000282801.
HOVERGENHBG008340.
InParanoidP11498.
KOK01958.
OrthoDBEOG7WT40F.
PhylomeDBP11498.
TreeFamTF300535.

Enzyme and pathway databases

BioCycMetaCyc:HS10697-MONOMER.
BRENDA6.4.1.1. 2681.
ReactomeREACT_111217. Metabolism.
REACT_116125. Disease.
SABIO-RKP11498.
UniPathwayUPA00138.

Gene expression databases

ArrayExpressP11498.
BgeeP11498.
CleanExHS_PC.
GenevestigatorP11498.

Family and domain databases

Gene3D1.10.10.60. 1 hit.
3.20.20.70. 1 hit.
3.30.1490.20. 1 hit.
3.30.470.20. 1 hit.
3.40.50.20. 1 hit.
InterProIPR013785. Aldolase_TIM.
IPR011761. ATP-grasp.
IPR013815. ATP_grasp_subdomain_1.
IPR013816. ATP_grasp_subdomain_2.
IPR001882. Biotin_BS.
IPR011764. Biotin_carboxylation_dom.
IPR005482. Biotin_COase_C.
IPR000089. Biotin_lipoyl.
IPR005481. CarbamoylP_synth_lsu_N.
IPR003379. Carboxylase_cons_dom.
IPR005479. CbamoylP_synth_lsu-like_ATP-bd.
IPR009057. Homeodomain-like.
IPR016185. PreATP-grasp_dom.
IPR000891. PYR_CT.
IPR005930. Pyruv_COase.
IPR011054. Rudment_hybrid_motif.
IPR011053. Single_hybrid_motif.
[Graphical view]
PANTHERPTHR18866:SF10. PTHR18866:SF10. 1 hit.
PfamPF02785. Biotin_carb_C. 1 hit.
PF00364. Biotin_lipoyl. 1 hit.
PF00289. CPSase_L_chain. 1 hit.
PF02786. CPSase_L_D2. 1 hit.
PF00682. HMGL-like. 1 hit.
PF02436. PYC_OADA. 1 hit.
[Graphical view]
PIRSFPIRSF001594. Pyruv_carbox. 1 hit.
SMARTSM00878. Biotin_carb_C. 1 hit.
[Graphical view]
SUPFAMSSF51230. SSF51230. 1 hit.
SSF51246. SSF51246. 1 hit.
SSF52440. SSF52440. 1 hit.
TIGRFAMsTIGR01235. pyruv_carbox. 1 hit.
PROSITEPS50975. ATP_GRASP. 1 hit.
PS50979. BC. 1 hit.
PS00188. BIOTIN. 1 hit.
PS50968. BIOTINYL_LIPOYL. 1 hit.
PS50991. PYR_CT. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

ChiTaRSPC. human.
EvolutionaryTraceP11498.
GenomeRNAi5091.
NextBio19632.
PROP11498.
SOURCESearch...

Entry information

Entry namePYC_HUMAN
AccessionPrimary (citable) accession number: P11498
Secondary accession number(s): Q16705
Entry history
Integrated into UniProtKB/Swiss-Prot: October 1, 1989
Last sequence update: October 1, 1996
Last modified: April 16, 2014
This is version 166 of the entry and version 2 of the sequence. [Complete history]
Entry statusReviewed (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.

Relevant documents

SIMILARITY comments

Index of protein domains and families

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

PATHWAY comments

Index of metabolic and biosynthesis pathways

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 11

Human chromosome 11: entries, gene names and cross-references to MIM