ID PYC_HUMAN Reviewed; 1178 AA.
AC P11498; Q16705;
DT 01-OCT-1989, integrated into UniProtKB/Swiss-Prot.
DT 01-OCT-1996, sequence version 2.
DT 01-MAY-2013, entry version 156.
DE RecName: Full=Pyruvate carboxylase, mitochondrial;
DE EC=6.4.1.1;
DE AltName: Full=Pyruvic carboxylase;
DE Short=PCB;
DE Flags: Precursor;
GN Name=PC;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Kidney, and Liver;
RX PubMed=7918683; DOI=10.1016/0925-4439(94)90105-8;
RA Wexler I.D., Du Y., Lisgaris M.V., Mandal S.K., Freytag S.O.,
RA Yang B.-S., Liu T.-C., Kwon M., Patel M.S., Kerr D.S.;
RT "Primary amino acid sequence and structure of human pyruvate
RT carboxylase.";
RL Biochim. Biophys. Acta 1227:46-52(1994).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Kidney;
RX PubMed=8048912; DOI=10.1006/bbrc.1994.2029;
RA Mackay N., Rigat B., Douglas C., Chen H.S., Robinson B.H.;
RT "cDNA cloning of human kidney pyruvate carboxylase.";
RL Biochem. Biophys. Res. Commun. 202:1009-1014(1994).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Kidney, and Liver;
RA Walker M.E., Jitrapakdee S., Val D.L., Wallace J.C.;
RL Submitted (JUL-1995) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Lung;
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
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1083-1178.
RX PubMed=3555348; DOI=10.1016/0003-9861(87)90146-9;
RA Lamhonwah A.-M., Quan F., Gravel R.A.;
RT "Sequence homology around the biotin-binding site of human propionyl-
RT CoA carboxylase and pyruvate carboxylase.";
RL Arch. Biochem. Biophys. 254:631-636(1987).
RN [6]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1135-1178.
RX PubMed=6548474;
RA Freytag S.O., Collier K.J.;
RT "Molecular cloning of a cDNA for human pyruvate carboxylase.
RT Structural relationship to other biotin-containing carboxylases and
RT regulation of mRNA content in differentiating preadipocytes.";
RL J. Biol. Chem. 259:12831-12837(1984).
RN [7]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-1090, AND MASS SPECTROMETRY.
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M.,
RA Walther T.C., Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [8]
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.,
RA Buerckstuemmer T., 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 [9]
RP X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF 481-1178 IN COMPLEX WITH
RP PYRUVATE; MANGANESE AND BIOTIN ANALOG, CARBAMYLATION AT LYS-741,
RP MUTAGENESIS OF PHE-1077, AND SUBUNIT.
RX PubMed=18297087; DOI=10.1038/nsmb.1393;
RA Xiang S., Tong L.;
RT "Crystal structures of human and Staphylococcus aureus pyruvate
RT carboxylase and molecular insights into the carboxyltransfer
RT reaction.";
RL Nat. Struct. Mol. Biol. 15:295-302(2008).
RN [10]
RP VARIANTS PC DEFICIENCY THR-610 AND ILE-743.
RX PubMed=9585612; DOI=10.1086/301884;
RA Carbone M.A., MacKay N., Ling M., Cole D.E.C., Douglas C., Rigat B.,
RA Feigenbaum A., Clarke J.T.R., Haworth J.C., Greenberg C.R.,
RA Seargeant L., Robinson B.H.;
RT "Amerindian pyruvate carboxylase deficiency is associated with two
RT distinct missense mutations.";
RL Am. J. Hum. Genet. 62:1312-1319(1998).
RN [11]
RP VARIANTS PC DEFICIENCY ALA-145 AND CYS-451.
RX PubMed=9585002; DOI=10.1203/00006450-199805000-00004;
RA Wexler I.D., Kerr D.S., Du Y., Kaung M.M., Stephenson W., Lusk M.M.,
RA Wappner R.S., Higgins J.J.;
RT "Molecular characterization of pyruvate carboxylase deficiency in two
RT consanguineous families.";
RL Pediatr. Res. 43:579-584(1998).
RN [12]
RP VARIANTS PC DEFICIENCY ALA-145; GLN-156; TRP-270; CYS-304; CYS-451;
RP LEU-583; THR-610; GLN-631; ILE-743 AND 1131-VAL--LYS-1133 DEL.
RX PubMed=19306334; DOI=10.1002/humu.20908;
RA Monnot S., Serre V., Chadefaux-Vekemans B., Aupetit J., Romano S.,
RA De Lonlay P., Rival J.-M., Munnich A., Steffann J., Bonnefont J.-P.;
RT "Structural insights on pathogenic effects of novel mutations causing
RT pyruvate carboxylase deficiency.";
RL Hum. Mutat. 30:734-740(2009).
CC -!- FUNCTION: Pyruvate carboxylase catalyzes a 2-step reaction,
CC involving the ATP-dependent carboxylation of the covalently
CC attached biotin in the first step and the transfer of the carboxyl
CC group to pyruvate in the second. Catalyzes in a tissue specific
CC manner, the initial reactions of glucose (liver, kidney) and lipid
CC (adipose tissue, liver, brain) synthesis from pyruvate.
CC -!- CATALYTIC ACTIVITY: ATP + pyruvate + HCO(3)(-) = ADP + phosphate +
CC oxaloacetate.
CC -!- COFACTOR: Biotin.
CC -!- COFACTOR: Binds 1 manganese ion per subunit.
CC -!- PATHWAY: Carbohydrate biosynthesis; gluconeogenesis.
CC -!- SUBUNIT: Homotetramer.
CC -!- SUBCELLULAR LOCATION: Mitochondrion matrix.
CC -!- DISEASE: Pyruvate carboxylase deficiency (PC deficiency)
CC [MIM:266150]: Leads to lactic acidosis, mental retardation and
CC death. It occurs in three forms: mild or type A, severe neonatal
CC or type B, and a very mild lacticacidemia. Note=The disease is
CC caused by mutations affecting the gene represented in this entry.
CC -!- SIMILARITY: Contains 1 ATP-grasp domain.
CC -!- SIMILARITY: Contains 1 biotin carboxylation domain.
CC -!- SIMILARITY: Contains 1 biotinyl-binding domain.
CC -!- SIMILARITY: Contains 1 carboxyltransferase domain.
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/PC";
CC -!- WEB RESOURCE: Name=Wikipedia; Note=Pyruvate carboxylase entry;
CC URL="http://en.wikipedia.org/wiki/Pyruvate_carboxylase";
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DR EMBL; U04641; AAA99537.1; -; mRNA.
DR EMBL; S72370; AAB31500.1; -; mRNA.
DR EMBL; U30891; AAA82937.1; -; mRNA.
DR EMBL; BC011617; AAH11617.1; -; mRNA.
DR EMBL; M26122; AAA36423.1; -; mRNA.
DR EMBL; K02282; AAA60033.1; -; mRNA.
DR IPI; IPI00299402; -.
DR PIR; G01933; JC2460.
DR RefSeq; NP_000911.2; NM_000920.3.
DR RefSeq; NP_001035806.1; NM_001040716.1.
DR RefSeq; NP_071504.2; NM_022172.2.
DR UniGene; Hs.89890; -.
DR PDB; 3BG3; X-ray; 2.80 A; A/B/C/D=482-1178.
DR PDB; 3BG9; X-ray; 3.00 A; A/B/C/D=482-1178.
DR PDBsum; 3BG3; -.
DR PDBsum; 3BG9; -.
DR ProteinModelPortal; P11498; -.
DR DIP; DIP-46372N; -.
DR IntAct; P11498; 2.
DR STRING; 9606.ENSP00000377527; -.
DR PhosphoSite; P11498; -.
DR DMDM; 1709947; -.
DR PaxDb; P11498; -.
DR PeptideAtlas; P11498; -.
DR PRIDE; P11498; -.
DR Ensembl; ENST00000393955; ENSP00000377527; ENSG00000173599.
DR Ensembl; ENST00000393958; ENSP00000377530; ENSG00000173599.
DR Ensembl; ENST00000393960; ENSP00000377532; ENSG00000173599.
DR GeneID; 5091; -.
DR KEGG; hsa:5091; -.
DR UCSC; uc001ojn.1; human.
DR CTD; 5091; -.
DR GeneCards; GC11M066615; -.
DR HGNC; HGNC:8636; PC.
DR HPA; CAB033742; -.
DR MIM; 266150; phenotype.
DR MIM; 608786; gene.
DR neXtProt; NX_P11498; -.
DR Orphanet; 3008; Pyruvate carboxylase deficiency.
DR PharmGKB; PA32975; -.
DR eggNOG; COG1038; -.
DR HOGENOM; HOG000282801; -.
DR HOVERGEN; HBG008340; -.
DR InParanoid; P11498; -.
DR KO; K01958; -.
DR OrthoDB; EOG4ZCT3P; -.
DR PhylomeDB; P11498; -.
DR BRENDA; 6.4.1.1; 2681.
DR Reactome; REACT_111217; Metabolism.
DR SABIO-RK; P11498; -.
DR UniPathway; UPA00138; -.
DR ChiTaRS; PC; human.
DR DrugBank; DB00121; Biotin.
DR DrugBank; DB00119; Pyruvic acid.
DR EvolutionaryTrace; P11498; -.
DR GenomeRNAi; 5091; -.
DR NextBio; 19632; -.
DR ArrayExpress; P11498; -.
DR Bgee; P11498; -.
DR CleanEx; HS_PC; -.
DR Genevestigator; P11498; -.
DR GermOnline; ENSG00000173599; Homo sapiens.
DR GO; GO:0005743; C:mitochondrial inner membrane; IEA:Compara.
DR GO; GO:0005759; C:mitochondrial matrix; TAS:Reactome.
DR GO; GO:0005524; F:ATP binding; TAS:ProtInc.
DR GO; GO:0009374; F:biotin binding; TAS:ProtInc.
DR GO; GO:0004075; F:biotin carboxylase activity; IEA:InterPro.
DR GO; GO:0003677; F:DNA binding; IEA:InterPro.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0004736; F:pyruvate carboxylase activity; TAS:Reactome.
DR GO; GO:0006094; P:gluconeogenesis; TAS:Reactome.
DR GO; GO:0006629; P:lipid metabolic process; IEA:UniProtKB-KW.
DR GO; GO:0006107; P:oxaloacetate metabolic process; IEA:Compara.
DR GO; GO:0006090; P:pyruvate metabolic process; IEA:Compara.
DR GO; GO:0044281; P:small molecule metabolic process; TAS:Reactome.
DR Gene3D; 1.10.10.60; -; 1.
DR Gene3D; 3.20.20.70; -; 1.
DR Gene3D; 3.30.1490.20; -; 1.
DR Gene3D; 3.30.470.20; -; 1.
DR Gene3D; 3.40.50.20; -; 1.
DR InterPro; IPR013785; Aldolase_TIM.
DR InterPro; IPR011761; ATP-grasp.
DR InterPro; IPR013815; ATP_grasp_subdomain_1.
DR InterPro; IPR013816; ATP_grasp_subdomain_2.
DR InterPro; IPR001882; Biotin_BS.
DR InterPro; IPR011764; Biotin_carboxylation_dom.
DR InterPro; IPR005482; Biotin_COase_C.
DR InterPro; IPR000089; Biotin_lipoyl.
DR InterPro; IPR005481; CarbamoylP_synth_lsu_N.
DR InterPro; IPR003379; Carboxylase_cons_dom.
DR InterPro; IPR005479; CbamoylP_synth_lsu-like_ATP-bd.
DR InterPro; IPR009057; Homeodomain-like.
DR InterPro; IPR016185; PreATP-grasp_dom.
DR InterPro; IPR000891; PYR_CT.
DR InterPro; IPR005930; Pyruv_COase.
DR InterPro; IPR011054; Rudment_hybrid_motif.
DR InterPro; IPR011053; Single_hybrid_motif.
DR PANTHER; PTHR18866:SF10; PTHR18866:SF10; 1.
DR Pfam; PF02785; Biotin_carb_C; 1.
DR Pfam; PF00364; Biotin_lipoyl; 1.
DR Pfam; PF00289; CPSase_L_chain; 1.
DR Pfam; PF02786; CPSase_L_D2; 1.
DR Pfam; PF00682; HMGL-like; 1.
DR Pfam; PF02436; PYC_OADA; 1.
DR PIRSF; PIRSF001594; Pyruv_carbox; 1.
DR SMART; SM00878; Biotin_carb_C; 1.
DR SUPFAM; SSF51230; Hybrid_motif; 1.
DR SUPFAM; SSF52440; PreATP-grasp-like; 1.
DR SUPFAM; SSF51246; Rudmnt_hyb_motif; 1.
DR TIGRFAMs; TIGR01235; pyruv_carbox; 1.
DR PROSITE; PS50975; ATP_GRASP; 1.
DR PROSITE; PS50979; BC; 1.
DR PROSITE; PS00188; BIOTIN; 1.
DR PROSITE; PS50968; BIOTINYL_LIPOYL; 1.
DR PROSITE; PS50989; COA_CT_CTER; FALSE_NEG.
DR PROSITE; PS50980; COA_CT_NTER; FALSE_NEG.
DR PROSITE; PS50991; PYR_CT; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; ATP-binding; Biotin; Complete proteome;
KW Disease mutation; Gluconeogenesis; Ligase; Lipid biosynthesis;
KW Lipid metabolism; Manganese; Metal-binding; Mitochondrion;
KW Multifunctional enzyme; Nucleotide-binding; Polymorphism; Pyruvate;
KW Reference proteome; Transit peptide.
FT TRANSIT 1 20 Mitochondrion (Potential).
FT CHAIN 21 1178 Pyruvate carboxylase, mitochondrial.
FT /FTId=PRO_0000002840.
FT DOMAIN 36 486 Biotin carboxylation.
FT DOMAIN 156 353 ATP-grasp.
FT DOMAIN 563 832 Carboxyltransferase.
FT DOMAIN 1110 1177 Biotinyl-binding.
FT REGION 571 575 Substrate binding.
FT ACT_SITE 328 328 By similarity.
FT METAL 572 572 Manganese.
FT METAL 741 741 Manganese; via carbamate group.
FT METAL 771 771 Manganese.
FT METAL 773 773 Manganese.
FT BINDING 152 152 ATP (By similarity).
FT BINDING 236 236 ATP (By similarity).
FT BINDING 271 271 ATP (By similarity).
FT BINDING 644 644 Substrate.
FT BINDING 908 908 Substrate.
FT MOD_RES 741 741 N6-carboxylysine.
FT MOD_RES 1090 1090 N6-acetyllysine.
FT MOD_RES 1144 1144 N6-biotinyllysine.
FT VARIANT 76 76 H -> L (in dbSNP:rs7104156).
FT /FTId=VAR_048416.
FT VARIANT 145 145 V -> A (in PC deficiency; mild;
FT dbSNP:rs28940591).
FT /FTId=VAR_015199.
FT VARIANT 156 156 R -> Q (in PC deficiency).
FT /FTId=VAR_058957.
FT VARIANT 270 270 R -> W (in PC deficiency).
FT /FTId=VAR_058958.
FT VARIANT 304 304 Y -> C (in PC deficiency).
FT /FTId=VAR_058959.
FT VARIANT 451 451 R -> C (in PC deficiency; mild).
FT /FTId=VAR_015200.
FT VARIANT 583 583 R -> L (in PC deficiency).
FT /FTId=VAR_058960.
FT VARIANT 610 610 A -> T (in PC deficiency; mild;
FT dbSNP:rs28940589).
FT /FTId=VAR_008095.
FT VARIANT 631 631 R -> Q (in PC deficiency).
FT /FTId=VAR_058961.
FT VARIANT 743 743 M -> I (in PC deficiency; mild;
FT dbSNP:rs28940590).
FT /FTId=VAR_008096.
FT VARIANT 1131 1133 Missing (in PC deficiency).
FT /FTId=VAR_058962.
FT MUTAGEN 1077 1077 F->A,E: Loss of tetramerization and
FT enzyme activity, resulting in an inactive
FT homodimer.
FT CONFLICT 225 226 LA -> WP (in Ref. 2; AAB31500).
FT CONFLICT 352 352 A -> S (in Ref. 3; AAA82937).
FT CONFLICT 385 386 RS -> PT (in Ref. 2; AAB31500).
FT CONFLICT 486 487 EL -> DV (in Ref. 2; AAB31500).
FT CONFLICT 638 638 P -> R (in Ref. 2; AAB31500).
FT CONFLICT 729 729 E -> A (in Ref. 2; AAB31500).
FT CONFLICT 774 775 DT -> AP (in Ref. 2; AAB31500).
FT HELIX 495 510
FT HELIX 541 559
FT STRAND 564 567
FT TURN 569 571
FT HELIX 572 577
FT HELIX 584 597
FT STRAND 602 608
FT HELIX 611 617
FT HELIX 623 633
FT STRAND 635 637
FT STRAND 639 643
FT HELIX 645 647
FT STRAND 650 652
FT HELIX 656 669
FT STRAND 673 677
FT HELIX 683 694
FT TURN 695 697
FT STRAND 698 705
FT HELIX 720 733
FT STRAND 736 741
FT HELIX 749 762
FT STRAND 768 771
FT HELIX 779 788
FT STRAND 792 797
FT HELIX 799 801
FT HELIX 810 817
FT HELIX 828 844
FT HELIX 845 848
FT HELIX 850 852
FT HELIX 861 864
FT HELIX 868 875
FT HELIX 876 878
FT TURN 879 881
FT HELIX 886 900
FT HELIX 910 923
FT HELIX 928 934
FT TURN 935 937
FT HELIX 942 947
FT TURN 948 950
FT HELIX 961 968
FT STRAND 969 971
FT HELIX 978 981
FT HELIX 989 997
FT HELIX 1004 1012
FT HELIX 1014 1026
FT HELIX 1035 1040
FT STRAND 1047 1051
FT TURN 1053 1055
FT STRAND 1057 1068
FT STRAND 1072 1090
FT HELIX 1092 1094
FT STRAND 1108 1110
FT STRAND 1118 1123
FT STRAND 1138 1144
FT STRAND 1146 1149
FT STRAND 1164 1168
FT STRAND 1173 1175
SQ SEQUENCE 1178 AA; 129634 MW; 381F527553A20095 CRC64;
MLKFRTVHGG LRLLGIRRTS TAPAASPNVR RLEYKPIKKV MVANRGEIAI RVFRACTELG
IRTVAIYSEQ DTGQMHRQKA DEAYLIGRGL APVQAYLHIP DIIKVAKENN VDAVHPGYGF
LSERADFAQA CQDAGVRFIG PSPEVVRKMG DKVEARAIAI AAGVPVVPGT DAPITSLHEA
HEFSNTYGFP IIFKAAYGGG GRGMRVVHSY EELEENYTRA YSEALAAFGN GALFVEKFIE
KPRHIEVQIL GDQYGNILHL YERDCSIQRR HQKVVEIAPA AHLDPQLRTR LTSDSVKLAK
QVGYENAGTV EFLVDRHGKH YFIEVNSRLQ VEHTVTEEIT DVDLVHAQIH VAEGRSLPDL
GLRQENIRIN GCAIQCRVTT EDPARSFQPD TGRIEVFRSG EGMGIRLDNA SAFQGAVISP
HYDSLLVKVI AHGKDHPTAA TKMSRALAEF RVRGVKTNIA FLQNVLNNQQ FLAGTVDTQF
IDENPELFQL RPAQNRAQKL LHYLGHVMVN GPTTPIPVKA SPSPTDPVVP AVPIGPPPAG
FRDILLREGP EGFARAVRNH PGLLLMDTTF RDAHQSLLAT RVRTHDLKKI APYVAHNFSK
LFSMENWGGA TFDVAMRFLY ECPWRRLQEL RELIPNIPFQ MLLRGANAVG YTNYPDNVVF
KFCEVAKENG MDVFRVFDSL NYLPNMLLGM EAAGSAGGVV EAAISYTGDV ADPSRTKYSL
QYYMGLAEEL VRAGTHILCI KDMAGLLKPT ACTMLVSSLR DRFPDLPLHI HTHDTSGAGV
AAMLACAQAG ADVVDVAADS MSGMTSQPSM GALVACTRGT PLDTEVPMER VFDYSEYWEG
ARGLYAAFDC TATMKSGNSD VYENEIPGGQ YTNLHFQAHS MGLGSKFKEV KKAYVEANQM
LGDLIKVTPS SKIVGDLAQF MVQNGLSRAE AEAQAEELSF PRSVVEFLQG YIGVPHGGFP
EPFRSKVLKD LPRVEGRPGA SLPPLDLQAL EKELVDRHGE EVTPEDVLSA AMYPDVFAHF
KDFTATFGPL DSLNTRLFLQ GPKIAEEFEV ELERGKTLHI KALAVSDLNR AGQRQVFFEL
NGQLRSILVK DTQAMKEMHF HPKALKDVKG QIGAPMPGKV IDIKVVAGAK VAKGQPLCVL
SAMKMETVVT SPMEGTVRKV HVTKDMTLEG DDLILEIE
//
