PDK2_RAT
ID PDK2_RAT Reviewed; 407 AA.
AC Q64536;
DT 15-JUL-1998, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1996, sequence version 1.
DT 03-AUG-2022, entry version 158.
DE RecName: Full=[Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 2, mitochondrial;
DE EC=2.7.11.2;
DE AltName: Full=PDK P45;
DE AltName: Full=Pyruvate dehydrogenase kinase isoform 2;
DE Short=PDH kinase 2;
DE Flags: Precursor;
GN Name=Pdk2;
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], CATALYTIC ACTIVITY, FUNCTION, AND TISSUE
RP SPECIFICITY.
RC TISSUE=Heart;
RX PubMed=7961963; DOI=10.1016/s0021-9258(18)43940-3;
RA Popov K.M., Kedishvili N.Y., Zhao Y., Gudi R., Harris R.A.;
RT "Molecular cloning of the p45 subunit of pyruvate dehydrogenase kinase.";
RL J. Biol. Chem. 269:29720-29724(1994).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Prostate;
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 project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [3]
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 [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.
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 FUNCTION.
RX PubMed=14641018; DOI=10.1042/bst0311165;
RA Mayers R.M., Butlin R.J., Kilgour E., Leighton B., Martin D., Myatt J.,
RA Orme J.P., Holloway B.R.;
RT "AZD7545, a novel inhibitor of pyruvate dehydrogenase kinase 2 (PDHK2),
RT activates pyruvate dehydrogenase in vivo and improves blood glucose control
RT in obese (fa/fa) Zucker rats.";
RL Biochem. Soc. Trans. 31:1165-1167(2003).
RN [7]
RP CATALYTIC ACTIVITY, FUNCTION, INTERACTION WITH PDK1, 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 [8]
RP FUNCTION, CATALYTIC ACTIVITY, SUBCELLULAR LOCATION, ACTIVITY REGULATION,
RP AND TISSUE SPECIFICITY.
RX PubMed=22910903; DOI=10.1074/jbc.m112.400002;
RA Hurd T.R., Collins Y., Abakumova I., Chouchani E.T., Baranowski B.,
RA Fearnley I.M., Prime T.A., Murphy M.P., James A.M.;
RT "Inactivation of pyruvate dehydrogenase kinase 2 by mitochondrial reactive
RT oxygen species.";
RL J. Biol. Chem. 287:35153-35160(2012).
RN [9]
RP X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) IN COMPLEX WITH ADP.
RX PubMed=11483605; DOI=10.1074/jbc.m104285200;
RA Steussy C.N., Popov K.M., Bowker-Kinley M.M., Sloan R.B. Jr., Harris R.A.,
RA Hamilton J.A.;
RT "Structure of pyruvate dehydrogenase kinase. Novel folding pattern for a
RT serine protein kinase.";
RL J. Biol. Chem. 276:37443-37450(2001).
RN [10]
RP X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) IN COMPLEX WITH ATP ANALOG AND DLAT,
RP CATALYTIC ACTIVITY, AND SUBUNIT.
RX PubMed=18387944; DOI=10.1074/jbc.m800311200;
RA Green T., Grigorian A., Klyuyeva A., Tuganova A., Luo M., Popov K.M.;
RT "Structural and functional insights into the molecular mechanisms
RT responsible for the regulation of pyruvate dehydrogenase kinase 2.";
RL J. Biol. Chem. 283:15789-15798(2008).
CC -!- FUNCTION: Kinase that plays a key role in the 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. Inhibition
CC of pyruvate dehydrogenase decreases glucose utilization and increases
CC fat metabolism. Mediates cellular responses to insulin. Plays an
CC important role in maintaining normal blood glucose levels and in
CC metabolic adaptation to nutrient availability. Via its regulation of
CC pyruvate dehydrogenase activity, plays an important role in maintaining
CC normal blood pH and in preventing the accumulation of ketone bodies
CC under starvation. Plays a role in the regulation of cell proliferation
CC and in resistance to apoptosis under oxidative stress. Plays a role in
CC p53/TP53-mediated apoptosis. {ECO:0000269|PubMed:11486000,
CC ECO:0000269|PubMed:12573248, ECO:0000269|PubMed:14641018,
CC ECO:0000269|PubMed:22910903, ECO:0000269|PubMed:7961963}.
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:12573248,
CC ECO:0000269|PubMed:18387944, ECO:0000269|PubMed:22910903,
CC ECO:0000269|PubMed:7961963, ECO:0000269|PubMed:9405293};
CC -!- ACTIVITY REGULATION: Activity increases in response to increased
CC acetyl-CoA and NADH levels and upon binding to the pyruvate
CC dehydrogenase subunit DLAT. Inhibited by ADP and pyruvate; these
CC compounds interfere with DLAT binding and thereby inhibit kinase
CC activity. Inhibited by dichloroacetate. Inhibited by AZD7545; this
CC compound interferes with DLAT binding and thereby inhibits kinase
CC activity. Reactive oxygen species cause the formation of disulfide
CC bonds, and thereby inhibit the enzyme. {ECO:0000269|PubMed:22910903,
CC ECO:0000269|PubMed:9405293}.
CC -!- SUBUNIT: Homodimer, and heterodimer with PDK1. 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:11483605, ECO:0000269|PubMed:11978179,
CC ECO:0000269|PubMed:12573248, ECO:0000269|PubMed:18387944}.
CC -!- SUBCELLULAR LOCATION: Mitochondrion matrix
CC {ECO:0000269|PubMed:22910903}.
CC -!- TISSUE SPECIFICITY: Detected in heart (at protein level). Highest level
CC of expression in heart and skeletal muscle and the lowest in spleen and
CC lung. Liver, kidney, brain and testis levels are intermediate.
CC {ECO:0000269|PubMed:22910903, ECO:0000269|PubMed:7961963,
CC ECO:0000269|PubMed:9405293}.
CC -!- SIMILARITY: Belongs to the PDK/BCKDK protein kinase family.
CC {ECO:0000305}.
CC ---------------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC ---------------------------------------------------------------------------
DR EMBL; U10357; AAB54084.1; -; mRNA.
DR EMBL; BC061823; AAH61823.1; -; mRNA.
DR PIR; A55305; A55305.
DR RefSeq; NP_110499.1; NM_030872.1.
DR PDB; 1JM6; X-ray; 2.50 A; A/B=1-407.
DR PDB; 3CRK; X-ray; 2.30 A; A/B=1-407.
DR PDB; 3CRL; X-ray; 2.61 A; A/B=1-407.
DR PDBsum; 1JM6; -.
DR PDBsum; 3CRK; -.
DR PDBsum; 3CRL; -.
DR AlphaFoldDB; Q64536; -.
DR SMR; Q64536; -.
DR BioGRID; 249527; 1.
DR IntAct; Q64536; 1.
DR STRING; 10116.ENSRNOP00000005641; -.
DR BindingDB; Q64536; -.
DR ChEMBL; CHEMBL2096663; -.
DR iPTMnet; Q64536; -.
DR PhosphoSitePlus; Q64536; -.
DR jPOST; Q64536; -.
DR PRIDE; Q64536; -.
DR GeneID; 81530; -.
DR KEGG; rno:81530; -.
DR UCSC; RGD:69428; rat.
DR CTD; 5164; -.
DR RGD; 69428; Pdk2.
DR eggNOG; KOG0787; Eukaryota.
DR InParanoid; Q64536; -.
DR OrthoDB; 1242599at2759; -.
DR PhylomeDB; Q64536; -.
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 EvolutionaryTrace; Q64536; -.
DR PRO; PR:Q64536; -.
DR Proteomes; UP000002494; Unplaced.
DR GO; GO:0005967; C:mitochondrial pyruvate dehydrogenase complex; ISS:UniProtKB.
DR GO; GO:0005739; C:mitochondrion; IDA:RGD.
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:0042803; F:protein homodimerization 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:0031670; P:cellular response to nutrient; ISS:UniProtKB.
DR GO; GO:0034614; P:cellular response to reactive oxygen species; ISO:RGD.
DR GO; GO:0042593; P:glucose homeostasis; ISS:UniProtKB.
DR GO; GO:0006006; P:glucose metabolic process; IEA:UniProtKB-KW.
DR GO; GO:0008286; P:insulin receptor signaling pathway; ISS:UniProtKB.
DR GO; GO:0072332; P:intrinsic apoptotic signaling pathway by p53 class mediator; ISO:RGD.
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; ISS:UniProtKB.
DR GO; GO:0050848; P:regulation of calcium-mediated signaling; ISO:RGD.
DR GO; GO:0010565; P:regulation of cellular ketone metabolic process; ISS:UniProtKB.
DR GO; GO:0006111; P:regulation of gluconeogenesis; ISS:UniProtKB.
DR GO; GO:0010906; P:regulation of glucose metabolic process; ISS:UniProtKB.
DR GO; GO:0006885; P:regulation of pH; 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 3D-structure; ATP-binding; Carbohydrate metabolism; Glucose metabolism;
KW Kinase; Mitochondrion; Nucleotide-binding; Phosphoprotein;
KW Reference proteome; Transferase; Transit peptide.
FT TRANSIT 1..?
FT /note="Mitochondrion"
FT /evidence="ECO:0000255"
FT CHAIN ?..407
FT /note="[Pyruvate dehydrogenase (acetyl-transferring)]
FT kinase isozyme 2, mitochondrial"
FT /id="PRO_0000023442"
FT DOMAIN 135..364
FT /note="Histidine kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00107"
FT BINDING 251..258
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT BINDING 290
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT BINDING 309..310
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT BINDING 325..330
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT MOD_RES 215
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:Q15118"
FT MOD_RES 216
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:Q15118"
FT MOD_RES 376
FT /note="N6-succinyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q8BFP9"
FT HELIX 13..15
FT /evidence="ECO:0007829|PDB:3CRL"
FT HELIX 16..24
FT /evidence="ECO:0007829|PDB:3CRK"
FT HELIX 33..39
FT /evidence="ECO:0007829|PDB:3CRK"
FT STRAND 41..43
FT /evidence="ECO:0007829|PDB:3CRL"
FT HELIX 46..68
FT /evidence="ECO:0007829|PDB:3CRK"
FT HELIX 73..76
FT /evidence="ECO:0007829|PDB:3CRK"
FT HELIX 79..96
FT /evidence="ECO:0007829|PDB:3CRK"
FT TURN 97..100
FT /evidence="ECO:0007829|PDB:3CRK"
FT HELIX 106..122
FT /evidence="ECO:0007829|PDB:3CRK"
FT TURN 123..125
FT /evidence="ECO:0007829|PDB:3CRK"
FT HELIX 126..141
FT /evidence="ECO:0007829|PDB:3CRK"
FT HELIX 145..176
FT /evidence="ECO:0007829|PDB:3CRK"
FT STRAND 185..188
FT /evidence="ECO:0007829|PDB:3CRL"
FT STRAND 191..196
FT /evidence="ECO:0007829|PDB:3CRK"
FT HELIX 197..215
FT /evidence="ECO:0007829|PDB:3CRK"
FT STRAND 222..231
FT /evidence="ECO:0007829|PDB:3CRK"
FT STRAND 237..240
FT /evidence="ECO:0007829|PDB:3CRK"
FT HELIX 242..262
FT /evidence="ECO:0007829|PDB:3CRK"
FT STRAND 267..269
FT /evidence="ECO:0007829|PDB:3CRK"
FT STRAND 273..279
FT /evidence="ECO:0007829|PDB:3CRK"
FT STRAND 281..290
FT /evidence="ECO:0007829|PDB:3CRK"
FT HELIX 297..300
FT /evidence="ECO:0007829|PDB:3CRK"
FT HELIX 301..304
FT /evidence="ECO:0007829|PDB:3CRK"
FT TURN 306..309
FT /evidence="ECO:0007829|PDB:3CRK"
FT HELIX 329..339
FT /evidence="ECO:0007829|PDB:3CRK"
FT STRAND 343..349
FT /evidence="ECO:0007829|PDB:3CRK"
FT TURN 350..352
FT /evidence="ECO:0007829|PDB:3CRK"
FT STRAND 353..363
FT /evidence="ECO:0007829|PDB:3CRK"
FT TURN 364..366
FT /evidence="ECO:0007829|PDB:3CRK"
FT HELIX 376..380
FT /evidence="ECO:0007829|PDB:3CRK"
SQ SEQUENCE 407 AA; 46106 MW; A01C377290A69EF4 CRC64;
MRWFRALLKN ASLAGAPKYI EHFSKFSPSP LSMKQFLDFG SSNACEKTSF TFLRQELPVR
LANIMKEINL LPDRVLSTPS VQLVQSWYVQ SLLDIMEFLD KDPEDHRTLS QFTDALVTIR
NRHNDVVPTM AQGVLEYKDT YGDDPVSNQN IQYFLDRFYL SRISIRMLIN QHTLIFDGST
NPAHPKHIGS IDPNCSVSDV VKDAYDMAKL LCDKYYMASP DLEIQEVNAT NATQPIHMVY
VPSHLYHMLF ELFKNAMRAT VESHESSLTL PPIKIMVALG EEDLSIKMSD RGGGVPLRKI
ERLFSYMYST APTPQPGTGG TPLAGFGYGL PISRLYAKYF QGDLQLFSME GFGTDAVIYL
KALSTDSVER LPVYNKSAWR HYQTIQEAGD WCVPSTEPKN TSTYRVS
