P11498 (PYC_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Pyruvate carboxylase, mitochondrial
EC=6.4.1.1

Alternative name(s):
Pyruvic carboxylase
Short name=PCB

Gene names

Name:

PC

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	1178 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence 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 process	Gluconeogenesis Lipid biosynthesis Lipid metabolism
Cellular component	Mitochondrion
Coding sequence diversity	Polymorphism
Disease	Disease mutation
Domain	Transit peptide
Ligand	ATP-binding Biotin Manganese Metal-binding Nucleotide-binding Pyruvate
Molecular function	Ligase
PTM	Acetylation
Technical term	3D-structure Complete proteome Multifunctional enzyme Reference proteome
Gene Ontology (GO)
Biological_process	gluconeogenesis Traceable author statement. Source: Reactome lipid metabolic process Inferred from electronic annotation. Source: UniProtKB-KW oxaloacetate metabolic process Inferred from electronic annotation. Source: Compara pyruvate metabolic process Inferred from electronic annotation. Source: Compara small molecule metabolic process Traceable author statement. Source: Reactome
Cellular_component	mitochondrial inner membrane Inferred from electronic annotation. Source: Compara mitochondrial matrix Traceable author statement. Source: Reactome
Molecular_function	ATP 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 key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Transit peptide

1 – 20

20

Mitochondrion Potential

Chain

21 – 1178

1158

Pyruvate carboxylase, mitochondrial

PRO_0000002840

Regions

Domain

36 – 486

451

Biotin carboxylation

Domain

156 – 353

198

ATP-grasp

Domain

563 – 832

270

Carboxyltransferase

Domain

1110 – 1177

68

Biotinyl-binding

Region

571 – 575

5

Substrate binding

Sites

Active site

328

1

By similarity

Metal binding

572

1

Manganese

Metal binding

741

1

Manganese; via carbamate group

Metal binding

771

1

Manganese

Metal binding

773

1

Manganese

Binding site

152

1

ATP By similarity

Binding site

236

1

ATP By similarity

Binding site

271

1

ATP By similarity

Binding site

644

1

Substrate

Binding site

908

1

Substrate

Amino acid modifications

Modified residue

741

1

N6-carboxylysine

Modified residue

1090

1

N6-acetyllysine Ref.7

Modified residue

1144

1

N6-biotinyllysine

Natural variations

Natural variant

76

1

H → L.
Corresponds to variant rs7104156 [ dbSNP | Ensembl ].

VAR_048416

Natural variant

145

1

V → A in PC deficiency; mild. Ref.11 Ref.12
Corresponds to variant rs28940591 [ dbSNP | Ensembl ].

VAR_015199

Natural variant

156

1

R → Q in PC deficiency. Ref.12

VAR_058957

Natural variant

270

1

R → W in PC deficiency. Ref.12

VAR_058958

Natural variant

304

1

Y → C in PC deficiency. Ref.12

VAR_058959

Natural variant

451

1

R → C in PC deficiency; mild. Ref.11 Ref.12

VAR_015200

Natural variant

583

1

R → L in PC deficiency. Ref.12

VAR_058960

Natural variant

610

1

A → T in PC deficiency; mild. Ref.10 Ref.12
Corresponds to variant rs28940589 [ dbSNP | Ensembl ].

VAR_008095

Natural variant

631

1

R → Q in PC deficiency. Ref.12

VAR_058961

Natural variant

743

1

M → I in PC deficiency; mild. Ref.10 Ref.12
Corresponds to variant rs28940590 [ dbSNP | Ensembl ].

VAR_008096

Natural variant

1131 – 1133

3

Missing in PC deficiency.

VAR_058962

Experimental info

Mutagenesis

1077

1

F → A or E: Loss of tetramerization and enzyme activity, resulting in an inactive homodimer. Ref.9

Sequence conflict

225 – 226

2

LA → WP in AAB31500. Ref.2

Sequence conflict

352

1

A → S in AAA82937. Ref.3

Sequence conflict

385 – 386

2

RS → PT in AAB31500. Ref.2

Sequence conflict

486 – 487

2

EL → DV in AAB31500. Ref.2

Sequence conflict

638

1

P → R in AAB31500. Ref.2

Sequence conflict

729

1

E → A in AAB31500. Ref.2

Sequence conflict

774 – 775

2

DT → AP in AAB31500. Ref.2

Secondary structure

1

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1178

Helix Strand Turn

Details...

Helix

495 – 510

16

Helix

541 – 559

19

Beta strand

564 – 567

4

Turn

569 – 571

3

Helix

572 – 577

6

Helix

584 – 597

14

Beta strand

602 – 608

7

Helix

611 – 617

7

Helix

623 – 633

11

Beta strand

635 – 637

3

Beta strand

639 – 643

5

Helix

645 – 647

3

Beta strand

650 – 652

3

Helix

656 – 669

14

Beta strand

673 – 677

5

Helix

683 – 694

12

Turn

695 – 697

3

Beta strand

698 – 705

8

Helix

720 – 733

14

Beta strand

736 – 741

6

Helix

749 – 762

14

Beta strand

768 – 771

4

Helix

779 – 788

10

Beta strand

792 – 797

6

Helix

799 – 801

3

Helix

810 – 817

8

Helix

828 – 844

17

Helix

845 – 848

4

Helix

850 – 852

3

Helix

861 – 864

4

Helix

868 – 875

8

Helix

876 – 878

3

Turn

879 – 881

3

Helix

886 – 900

15

Helix

910 – 923

14

Helix

928 – 934

7

Turn

935 – 937

3

Helix

942 – 947

6

Turn

948 – 950

3

Helix

961 – 968

8

Beta strand

969 – 971

3

Helix

978 – 981

4

Helix

989 – 997

9

Helix

1004 – 1012

9

Helix

1014 – 1026

13

Helix

1035 – 1040

6

Beta strand

1047 – 1051

5

Turn

1053 – 1055

3

Beta strand

1057 – 1068

12

Beta strand

1072 – 1090

19

Helix

1092 – 1094

3

Beta strand

1108 – 1110

3

Beta strand

1118 – 1123

6

Beta strand

1138 – 1144

7

Beta strand

1146 – 1149

4

Beta strand

1164 – 1168

5

Beta strand

1173 – 1175

3

Sequences

	Sequence		Length	Mass (Da)
	P11498 [UniParc]. Last modified October 1, 1996. Version 2. Checksum: 381F527553A20095	FASTA	1,178	129,634
	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

References

	« Hide 'large scale' referencesShow '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, MASS SPECTROMETRY.
[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.

IPI

IPI00299402.

PIR

JC2460. G01933.

RefSeq

NP_000911.2. NM_000920.3.
NP_001035806.1. NM_001040716.1.
NP_071504.2. NM_022172.2.

UniGene

Hs.89890.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
3BG3	X-ray	2.80	A/B/C/D	482-1178	[»]
3BG9	X-ray	3.00	A/B/C/D	482-1178	[»]

ProteinModelPortal

P11498.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-46372N.

IntAct

P11498. 2 interactions.

MINT

MINT-3007737.

STRING

9606.ENSP00000377527.

PTM databases

PhosphoSite

P11498.

Polymorphism databases

DMDM

1709947.

Proteomic databases

PaxDb

P11498.

PeptideAtlas

P11498.

PRIDE

P11498.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000393955; ENSP00000377527; ENSG00000173599.
ENST00000393958; ENSP00000377530; ENSG00000173599.
ENST00000393960; ENSP00000377532; ENSG00000173599.

GeneID

5091.

KEGG

hsa:5091.

UCSC

uc001ojn.1. human.

Organism-specific databases

CTD

5091.

GeneCards

GC11M066615.

HGNC

HGNC:8636. PC.

HPA

CAB033742.

MIM

266150. phenotype.
608786. gene.

neXtProt

NX_P11498.

Orphanet

3008. Pyruvate carboxylase deficiency.

PharmGKB

PA32975.

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG1038.

HOGENOM

HOG000282801.

HOVERGEN

HBG008340.

InParanoid

P11498.

KO

K01958.

OrthoDB

EOG4ZCT3P.

PhylomeDB

P11498.

Enzyme and pathway databases

BioCyc

MetaCyc:HS10697-MONOMER.

BRENDA

6.4.1.1. 2681.

Reactome

REACT_111217. Metabolism.

SABIO-RK

P11498.

UniPathway

UPA00138.

Gene expression databases

ArrayExpress

P11498.

Bgee

P11498.

CleanEx

HS_PC.

Genevestigator

P11498.

GermOnline

ENSG00000173599. Homo sapiens.

Family and domain databases

Gene3D

1.10.10.60. 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.

InterPro

IPR013785. 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]

PANTHER

PTHR18866:SF10. PTHR18866:SF10. 1 hit.

Pfam

PF02785. 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]

PIRSF

PIRSF001594. Pyruv_carbox. 1 hit.

SMART

SM00878. Biotin_carb_C. 1 hit.
[Graphical view]

SUPFAM

SSF51230. Hybrid_motif. 1 hit.
SSF52440. PreATP-grasp-like. 1 hit.
SSF51246. Rudmnt_hyb_motif. 1 hit.

TIGRFAMs

TIGR01235. pyruv_carbox. 1 hit.

PROSITE

PS50975. ATP_GRASP. 1 hit.
PS50979. BC. 1 hit.
PS00188. BIOTIN. 1 hit.
PS50968. BIOTINYL_LIPOYL. 1 hit.
PS50989. COA_CT_CTER. False negative.
PS50980. COA_CT_NTER. False negative.
PS50991. PYR_CT. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

ChiTaRS

PC. human.

DrugBank

DB00121. Biotin.
DB00119. Pyruvic acid.

EvolutionaryTrace

P11498.

GenomeRNAi

5091.

NextBio

19632.

SOURCE

Search...

Entry information

Entry name

PYC_HUMAN

Accession

Primary (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:	May 29, 2013
This is version 157 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

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.