PDK1_RAT
ID PDK1_RAT Reviewed; 434 AA.
AC Q63065;
DT 15-JUL-1998, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1996, sequence version 1.
DT 03-AUG-2022, entry version 152.
DE RecName: Full=[Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 1, mitochondrial;
DE EC=2.7.11.2;
DE AltName: Full=PDK p48;
DE AltName: Full=Pyruvate dehydrogenase kinase isoform 1;
DE Short=PDH kinase 1;
DE Flags: Precursor;
GN Name=Pdk1; Synonyms=Pdh;
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], PARTIAL PROTEIN SEQUENCE, FUNCTION, CATALYTIC
RP ACTIVITY, ACTIVITY REGULATION, SUBUNIT, AND TISSUE SPECIFICITY.
RC STRAIN=Sprague-Dawley; TISSUE=Heart;
RX PubMed=8253790; DOI=10.1016/s0021-9258(19)74354-3;
RA Popov K.M., Kedishvili N.Y., Zhao Y., Shimomura Y., Crabb D.W.,
RA Harris R.A.;
RT "Primary structure of pyruvate dehydrogenase kinase establishes a new
RT family of eukaryotic protein kinases.";
RL J. Biol. Chem. 268:26602-26606(1993).
RN [2]
RP CATALYTIC ACTIVITY, ACTIVITY REGULATION, AND TISSUE SPECIFICITY.
RX PubMed=9405293; DOI=10.1042/bj3290191;
RA Bowker-Kinley M.M., Davis W.I., Wu P., Harris R.A., Popov K.M.;
RT "Evidence for existence of tissue-specific regulation of the mammalian
RT pyruvate dehydrogenase complex.";
RL Biochem. J. 329:191-196(1998).
RN [3]
RP INDUCTION, AND TISSUE SPECIFICITY.
RX PubMed=11723055; DOI=10.2337/diabetes.50.12.2729;
RA Sugden M.C., Bulmer K., Augustine D., Holness M.J.;
RT "Selective modification of pyruvate dehydrogenase kinase isoform expression
RT in rat pancreatic islets elicited by starvation and activation of
RT peroxisome proliferator-activated receptor-alpha: implications for glucose-
RT stimulated insulin secretion.";
RL Diabetes 50:2729-2736(2001).
RN [4]
RP CATALYTIC ACTIVITY, AND FUNCTION.
RX PubMed=11486000; DOI=10.1074/jbc.m103069200;
RA Korotchkina L.G., Patel M.S.;
RT "Site specificity of four pyruvate dehydrogenase kinase isoenzymes toward
RT the three phosphorylation sites of human pyruvate dehydrogenase.";
RL J. Biol. Chem. 276:37223-37229(2001).
RN [5]
RP INTERACTION WITH DLAT, ACTIVITY REGULATION, AND CATALYTIC ACTIVITY.
RX PubMed=11978179; DOI=10.1042/bj20020301;
RA Tuganova A., Boulatnikov I., Popov K.M.;
RT "Interaction between the individual isoenzymes of pyruvate dehydrogenase
RT kinase and the inner lipoyl-bearing domain of transacetylase component of
RT pyruvate dehydrogenase complex.";
RL Biochem. J. 366:129-136(2002).
RN [6]
RP CATALYTIC ACTIVITY, FUNCTION, INTERACTION WITH PDK2, AND SUBUNIT.
RX PubMed=12573248; DOI=10.1016/s1570-9639(02)00542-3;
RA Boulatnikov I., Popov K.M.;
RT "Formation of functional heterodimers by isozymes 1 and 2 of pyruvate
RT dehydrogenase kinase.";
RL Biochim. Biophys. Acta 1645:183-192(2003).
RN [7]
RP FUNCTION.
RX PubMed=21541279; DOI=10.1371/journal.pone.0019191;
RA Newington J.T., Pitts A., Chien A., Arseneault R., Schubert D.,
RA Cumming R.C.;
RT "Amyloid beta resistance in nerve cell lines is mediated by the Warburg
RT effect.";
RL PLoS ONE 6:E19191-E19191(2011).
RN [8]
RP FUNCTION.
RX PubMed=22948140; DOI=10.1074/jbc.m112.366195;
RA Newington J.T., Rappon T., Albers S., Wong D.Y., Rylett R.J., Cumming R.C.;
RT "Overexpression of pyruvate dehydrogenase kinase 1 and lactate
RT dehydrogenase A in nerve cells confers resistance to amyloid beta and other
RT toxins by decreasing mitochondrial respiration and reactive oxygen species
RT production.";
RL J. Biol. Chem. 287:37245-37258(2012).
RN [9]
RP INDUCTION BY HYPOXIA, AND FUNCTION.
RX PubMed=22575885; DOI=10.1016/j.surg.2012.03.003;
RA Abe Y., Uchinami H., Kudoh K., Nakagawa Y., Ise N., Watanabe G., Sato T.,
RA Seki E., Yamamoto Y.;
RT "Liver epithelial cells proliferate under hypoxia and protect the liver
RT from ischemic injury via expression of HIF-1 alpha target genes.";
RL Surgery 152:869-878(2012).
CC -!- FUNCTION: Kinase that plays a key role in regulation of glucose and
CC fatty acid metabolism and homeostasis via phosphorylation of the
CC pyruvate dehydrogenase subunits PDHA1 and PDHA2. This inhibits pyruvate
CC dehydrogenase activity, and thereby regulates metabolite flux through
CC the tricarboxylic acid cycle, down-regulates aerobic respiration and
CC inhibits the formation of acetyl-coenzyme A from pyruvate. Plays an
CC important role in cellular responses to hypoxia and is important for
CC cell proliferation under hypoxia. Protects cells against apoptosis in
CC response to hypoxia and oxidative stress. {ECO:0000269|PubMed:11486000,
CC ECO:0000269|PubMed:12573248, ECO:0000269|PubMed:21541279,
CC ECO:0000269|PubMed:22575885, ECO:0000269|PubMed:22948140,
CC ECO:0000269|PubMed:8253790}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-seryl-[pyruvate dehydrogenase E1 alpha subunit] = ADP
CC + H(+) + O-phospho-L-seryl-[pyruvate dehydrogenase E1 alpha subunit];
CC Xref=Rhea:RHEA:23052, Rhea:RHEA-COMP:13689, Rhea:RHEA-COMP:13690,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616,
CC ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.2;
CC Evidence={ECO:0000269|PubMed:11486000, ECO:0000269|PubMed:11978179,
CC ECO:0000269|PubMed:12573248, ECO:0000269|PubMed:8253790,
CC ECO:0000269|PubMed:9405293};
CC -!- ACTIVITY REGULATION: Activated by binding to the pyruvate dehydrogenase
CC complex subunit DLAT. Strongly activated by NADH plus acetyl-coenzyme
CC A. Inhibited by dichloroacetate. {ECO:0000269|PubMed:11978179,
CC ECO:0000269|PubMed:8253790, ECO:0000269|PubMed:9405293}.
CC -!- SUBUNIT: Homodimer, and heterodimer with PDK2. Interacts with the
CC pyruvate dehydrogenase complex subunit DLAT, and is part of the
CC multimeric pyruvate dehydrogenase complex that contains multiple copies
CC of pyruvate dehydrogenase (E1), dihydrolipoamide acetyltransferase
CC (DLAT, E2) and lipoamide dehydrogenase (DLD, E3).
CC {ECO:0000269|PubMed:11978179, ECO:0000269|PubMed:12573248,
CC ECO:0000269|PubMed:8253790}.
CC -!- SUBCELLULAR LOCATION: Mitochondrion matrix.
CC -!- TISSUE SPECIFICITY: Detected in pancreas islets (at protein level).
CC Expressed predominantly in the heart. {ECO:0000269|PubMed:11723055,
CC ECO:0000269|PubMed:8253790, ECO:0000269|PubMed:9405293}.
CC -!- INDUCTION: Up-regulated via the HIF1A signaling pathway in response to
CC hypoxia. Down-regulated in response to prolonged fasting.
CC {ECO:0000269|PubMed:11723055, ECO:0000269|PubMed:22575885}.
CC -!- PTM: Phosphorylated by constitutively activated ABL1, FGFR1, FLT3 and
CC JAK2 (in vitro), and this may also occur in cancer cells that express
CC constitutively activated ABL1, FGFR1, FLT3 and JAK2. Phosphorylation at
CC Tyr-241 and Tyr-242 strongly increases kinase activity, while
CC phosphorylation at Tyr-136 has a lesser effect (By similarity).
CC {ECO:0000250}.
CC -!- SIMILARITY: Belongs to the PDK/BCKDK protein kinase family.
CC {ECO:0000305}.
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DR EMBL; L22294; AAA62851.1; -; mRNA.
DR PIR; A49686; A49686.
DR AlphaFoldDB; Q63065; -.
DR SMR; Q63065; -.
DR IntAct; Q63065; 2.
DR MINT; Q63065; -.
DR STRING; 10116.ENSRNOP00000002072; -.
DR BindingDB; Q63065; -.
DR ChEMBL; CHEMBL2096663; -.
DR iPTMnet; Q63065; -.
DR PhosphoSitePlus; Q63065; -.
DR jPOST; Q63065; -.
DR PaxDb; Q63065; -.
DR PRIDE; Q63065; -.
DR UCSC; RGD:69427; rat.
DR RGD; 69427; Pdk1.
DR eggNOG; KOG0787; Eukaryota.
DR InParanoid; Q63065; -.
DR PhylomeDB; Q63065; -.
DR BRENDA; 2.7.11.2; 5301.
DR Reactome; R-RNO-204174; Regulation of pyruvate dehydrogenase (PDH) complex.
DR Reactome; R-RNO-5362517; Signaling by Retinoic Acid.
DR PRO; PR:Q63065; -.
DR Proteomes; UP000002494; Unplaced.
DR GO; GO:0005967; C:mitochondrial pyruvate dehydrogenase complex; ISO:RGD.
DR GO; GO:0005739; C:mitochondrion; IBA:GO_Central.
DR GO; GO:0045254; C:pyruvate dehydrogenase complex; IDA:RGD.
DR GO; GO:0005524; F:ATP binding; IDA:RGD.
DR GO; GO:0042802; F:identical protein binding; IPI:RGD.
DR GO; GO:0004672; F:protein kinase activity; ISO:RGD.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; IDA:UniProtKB.
DR GO; GO:0044877; F:protein-containing complex binding; IDA:RGD.
DR GO; GO:0004740; F:pyruvate dehydrogenase (acetyl-transferring) kinase activity; IDA:UniProtKB.
DR GO; GO:0008283; P:cell population proliferation; ISS:UniProtKB.
DR GO; GO:0007166; P:cell surface receptor signaling pathway; IMP:RGD.
DR GO; GO:0006006; P:glucose metabolic process; IEA:UniProtKB-KW.
DR GO; GO:0097411; P:hypoxia-inducible factor-1alpha signaling pathway; ISS:UniProtKB.
DR GO; GO:0008631; P:intrinsic apoptotic signaling pathway in response to oxidative stress; ISS:UniProtKB.
DR GO; GO:0018105; P:peptidyl-serine phosphorylation; IDA:UniProtKB.
DR GO; GO:0006468; P:protein phosphorylation; IDA:RGD.
DR GO; GO:0010510; P:regulation of acetyl-CoA biosynthetic process from pyruvate; ISO:RGD.
DR GO; GO:0010906; P:regulation of glucose metabolic process; ISS:UniProtKB.
DR Gene3D; 1.20.140.20; -; 1.
DR Gene3D; 3.30.565.10; -; 1.
DR InterPro; IPR036784; AK/P_DHK_N_sf.
DR InterPro; IPR018955; BCDHK/PDK_N.
DR InterPro; IPR039028; BCKD/PDK.
DR InterPro; IPR003594; HATPase_C.
DR InterPro; IPR036890; HATPase_C_sf.
DR InterPro; IPR005467; His_kinase_dom.
DR PANTHER; PTHR11947; PTHR11947; 1.
DR Pfam; PF10436; BCDHK_Adom3; 1.
DR Pfam; PF02518; HATPase_c; 1.
DR SMART; SM00387; HATPase_c; 1.
DR SUPFAM; SSF55874; SSF55874; 1.
DR SUPFAM; SSF69012; SSF69012; 1.
DR PROSITE; PS50109; HIS_KIN; 1.
PE 1: Evidence at protein level;
KW ATP-binding; Carbohydrate metabolism; Direct protein sequencing;
KW Glucose metabolism; Kinase; Mitochondrion; Nucleotide-binding;
KW Phosphoprotein; Reference proteome; Transferase; Transit peptide.
FT TRANSIT 1..26
FT /note="Mitochondrion"
FT /evidence="ECO:0000255"
FT CHAIN 27..434
FT /note="[Pyruvate dehydrogenase (acetyl-transferring)]
FT kinase isozyme 1, mitochondrial"
FT /id="PRO_0000023439"
FT DOMAIN 161..391
FT /note="Histidine kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00107"
FT BINDING 277..284
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250"
FT BINDING 316
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250"
FT BINDING 335..336
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250"
FT BINDING 352..357
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250"
FT MOD_RES 136
FT /note="Phosphotyrosine; by FGFR1"
FT /evidence="ECO:0000250|UniProtKB:Q15118"
FT MOD_RES 241
FT /note="Phosphotyrosine; by FGFR1, ABL1, FLT3 and JAK2"
FT /evidence="ECO:0000250|UniProtKB:Q15118"
FT MOD_RES 242
FT /note="Phosphotyrosine; by FGFR1"
FT /evidence="ECO:0000250|UniProtKB:Q15118"
FT MOD_RES 403
FT /note="N6-succinyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q8BFP9"
SQ SEQUENCE 434 AA; 49081 MW; A8C304507D64ED61 CRC64;
MRLARLLRGG TSVRPLCAVP CASRSLASDS ASGSGPASES GVPGQVDFYA RFSPSPLSMK
QFLDFGSVNA CEKTSFMFLR QELPVRLANI MKEISLLPDN LLRTPSVQLV QSWYIQSLQE
LLDFKDKSAE DAKTIYEFTD TVIRIRNRHN DVIPTMAQGV TEYKESFGVD PVTSQNVQYF
LDRFYMSRIS IRMLLNQHSL LFGGKGSPSH RKHIGSINPN CDVVEVIKDG YENARRLCDL
YYVNSPELEL EELNAKSPGQ PIQVVYVPSH LYHMVFELFK NAMRATMEHH ADKGVYPPIQ
VHVTLGEEDL TVKMSDRGGG VPLRKIDRLF NYMYSTAPRP RVETSRAVPL AGFGYGLPIS
RLYAQYFQGD LKLYSLEGYG TDAVIYIKAL STESIERLPV YNKAAWKHYR TNHEADDWCV
PSREPKDMTT FRSS
