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Q15118 (PDK1_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 131. 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·Interactions·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
[Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 1, mitochondrial

EC=2.7.11.2
Alternative name(s):
Pyruvate dehydrogenase kinase isoform 1
Short name=PDH kinase 1
Gene names
Name:PDK1
Synonyms:PDHK1
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length436 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Serine/threonine kinase that plays a key role in regulation of glucose and fatty acid metabolism and homeostasis via phosphorylation of the pyruvate dehydrogenase subunits PDHA1 and PDHA2. This inhibits pyruvate dehydrogenase activity, and thereby regulates metabolite flux through the tricarboxylic acid cycle, down-regulates aerobic respiration and inhibits the formation of acetyl-coenzyme A from pyruvate. Plays an important role in cellular responses to hypoxia and is important for cell proliferation under hypoxia. Protects cells against apoptosis in response to hypoxia and oxidative stress. Ref.1 Ref.5 Ref.8 Ref.9

Catalytic activity

ATP + [pyruvate dehydrogenase (acetyl-transferring)] = ADP + [pyruvate dehydrogenase (acetyl-transferring)] phosphate. Ref.1 Ref.8 Ref.9

Enzyme regulation

Activity is enhanced by binding to the pyruvate dehydrogenase subunit DLAT. Inhibited by AZD7545; this compound interferes with DLAT binding and thereby inhibits kinase activity. Inhibited by dichloroacetate and radicicol. Ref.9

Subunit structure

Homodimer, and heterodimer with PDK2. Interacts with the pyruvate dehydrogenase complex subunit DLAT, and is part of the multimeric pyruvate dehydrogenase complex that contains multiple copies of pyruvate dehydrogenase (E1), dihydrolipoamide acetyltransferase (DLAT, E2) and lipoamide dehydrogenase (DLD, E3). Ref.9

Subcellular location

Mitochondrion matrix Ref.8.

Tissue specificity

Expressed predominantly in the heart. Detected at lower levels in liver, skeletal muscle and pancreas. Ref.1

Induction

Up-regulated via the HIF1A signaling pathway in response to hypoxia. Ref.6 Ref.9

Post-translational modification

Phosphorylated by constitutively activated ABL1, FGFR1, FLT3 and JAK2 (in vitro), and this may also occur in cancer cells that express constitutively activated ABL1, FGFR1, FLT3 and JAK2. Phosphorylation at Tyr-243 and Tyr-244 strongly increases kinase activity, while phosphorylation at Tyr-136 has a lesser effect. Ref.8

Sequence similarities

Belongs to the PDK/BCKDK protein kinase family.

Contains 1 histidine kinase domain.

Ontologies

Keywords
   Biological processCarbohydrate metabolism
Glucose metabolism
   Cellular componentMitochondrion
   Coding sequence diversityPolymorphism
   DomainTransit peptide
   LigandATP-binding
Nucleotide-binding
   Molecular functionKinase
Serine/threonine-protein kinase
Transferase
   PTMPhosphoprotein
   Technical term3D-structure
Complete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processcell proliferation

Inferred from mutant phenotype Ref.5. Source: UniProtKB

cellular metabolic process

Traceable author statement. Source: Reactome

glucose metabolic process

Traceable author statement Ref.1. Source: ProtInc

hypoxia-inducible factor-1alpha signaling pathway

Inferred from mutant phenotype Ref.6. Source: UniProtKB

intrinsic apoptotic signaling pathway in response to oxidative stress

Inferred from mutant phenotype Ref.5. Source: UniProtKB

protein phosphorylation

Inferred from direct assay Ref.9Ref.1. Source: GOC

pyruvate metabolic process

Traceable author statement. Source: Reactome

regulation of acetyl-CoA biosynthetic process from pyruvate

Traceable author statement. Source: Reactome

regulation of glucose metabolic process

Inferred from mutant phenotype Ref.5. Source: UniProtKB

small molecule metabolic process

Traceable author statement. Source: Reactome

   Cellular_componentmitochondrial matrix

Traceable author statement. Source: Reactome

mitochondrial pyruvate dehydrogenase complex

Inferred from electronic annotation. Source: Ensembl

mitochondrion

Traceable author statement Ref.1. Source: ProtInc

   Molecular_functionATP binding

Inferred from electronic annotation. Source: UniProtKB-KW

protein kinase activity

Inferred from direct assay Ref.9. Source: UniProtKB

protein serine/threonine kinase activity

Inferred from electronic annotation. Source: UniProtKB-KW

pyruvate dehydrogenase (acetyl-transferring) kinase activity

Inferred from direct assay Ref.1. Source: UniProtKB

Complete GO annotation...

Binary interactions

With

Entry

#Exp.

IntAct

Notes

PKN2Q165136EBI-7016221,EBI-2511350

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Transit peptide1 – 2828Mitochondrion Potential
Chain29 – 436408[Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 1, mitochondrial
PRO_0000023437

Regions

Domain163 – 393231Histidine kinase
Nucleotide binding279 – 2868ATP By similarity
Nucleotide binding337 – 3382ATP By similarity
Nucleotide binding354 – 3596ATP By similarity

Sites

Binding site3181ATP By similarity

Amino acid modifications

Modified residue1361Phosphotyrosine; by FGFR1 Ref.8
Modified residue2431Phosphotyrosine; by FGFR1, ABL1, FLT3 and JAK2 Ref.8
Modified residue2441Phosphotyrosine; by FGFR1 Ref.8
Modified residue4051N6-succinyllysine By similarity

Natural variations

Natural variant1341A → T.
Corresponds to variant rs35661499 [ dbSNP | Ensembl ].
VAR_050477
Natural variant4121N → T. Ref.10
Corresponds to variant rs34250425 [ dbSNP | Ensembl ].
VAR_042295

Secondary structure

.................................................. 436
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
Q15118 [UniParc].

Last modified November 1, 1996. Version 1.
Checksum: D14CD594E0EA45A2

FASTA43649,244
        10         20         30         40         50         60 
MRLARLLRGA ALAGPGPGLR AAGFSRSFSS DSGSSPASER GVPGQVDFYA RFSPSPLSMK 

        70         80         90        100        110        120 
QFLDFGSVNA CEKTSFMFLR QELPVRLANI MKEISLLPDN LLRTPSVQLV QSWYIQSLQE 

       130        140        150        160        170        180 
LLDFKDKSAE DAKAIYDFTD TVIRIRNRHN DVIPTMAQGV IEYKESFGVD PVTSQNVQYF 

       190        200        210        220        230        240 
LDRFYMSRIS IRMLLNQHSL LFGGKGKGSP SHRKHIGSIN PNCNVLEVIK DGYENARRLC 

       250        260        270        280        290        300 
DLYYINSPEL ELEELNAKSP GQPIQVVYVP SHLYHMVFEL FKNAMRATME HHANRGVYPP 

       310        320        330        340        350        360 
IQVHVTLGNE DLTVKMSDRG GGVPLRKIDR LFNYMYSTAP RPRVETSRAV PLAGFGYGLP 

       370        380        390        400        410        420 
ISRLYAQYFQ GDLKLYSLEG YGTDAVIYIK ALSTDSIERL PVYNKAAWKH YNTNHEADDW 

       430 
CVPSREPKDM TTFRSA 

« Hide

References

« Hide 'large scale' references
[1]"Diversity of the pyruvate dehydrogenase kinase gene family in humans."
Gudi R., Bowker-Kinley M.M., Kedishvili N.Y., Zhao Y., Popov K.M.
J. Biol. Chem. 270:28989-28994(1995) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, CATALYTIC ACTIVITY, TISSUE SPECIFICITY.
Tissue: Liver.
[2]"Complete sequencing and characterization of 21,243 full-length human cDNAs."
Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. expand/collapse author list , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.
Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
[3]Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. expand/collapse author list , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C.
Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[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: Skin.
[5]"Pyruvate dehydrogenase complex activity controls metabolic and malignant phenotype in cancer cells."
McFate T., Mohyeldin A., Lu H., Thakar J., Henriques J., Halim N.D., Wu H., Schell M.J., Tsang T.M., Teahan O., Zhou S., Califano J.A., Jeoung N.H., Harris R.A., Verma A.
J. Biol. Chem. 283:22700-22708(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[6]"Overexpression of pyruvate dehydrogenase kinase 3 increases drug resistance and early recurrence in colon cancer."
Lu C.W., Lin S.C., Chien C.W., Lin S.C., Lee C.T., Lin B.W., Lee J.C., Tsai S.J.
Am. J. Pathol. 179:1405-1414(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: INDUCTION BY HYPOXIA.
[7]"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].
[8]"Tyrosine phosphorylation of mitochondrial pyruvate dehydrogenase kinase 1 is important for cancer metabolism."
Hitosugi T., Fan J., Chung T.W., Lythgoe K., Wang X., Xie J., Ge Q., Gu T.L., Polakiewicz R.D., Roesel J.L., Chen G.Z., Boggon T.J., Lonial S., Fu H., Khuri F.R., Kang S., Chen J.
Mol. Cell 44:864-877(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: CATALYTIC ACTIVITY, FUNCTION, SUBCELLULAR LOCATION, PHOSPHORYLATION AT TYR-136; TYR-243 AND TYR-244.
[9]"Distinct structural mechanisms for inhibition of pyruvate dehydrogenase kinase isoforms by AZD7545, dichloroacetate, and radicicol."
Kato M., Li J., Chuang J.L., Chuang D.T.
Structure 15:992-1004(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS) OF 30-436 IN COMPLEX WITH THE INHIBITORS AZD7545 AND DICHLOROACETATE, FUNCTION, SUBUNIT, CATALYTIC ACTIVITY, ENZYME REGULATION.
[10]"Patterns of somatic mutation in human cancer genomes."
Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G. expand/collapse author list , Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R.
Nature 446:153-158(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT [LARGE SCALE ANALYSIS] THR-412.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
L42450 mRNA. Translation: AAC42009.1.
AK312700 mRNA. Translation: BAG35578.1.
CH471058 Genomic DNA. Translation: EAX11173.1.
CH471058 Genomic DNA. Translation: EAX11174.1.
BC039158 mRNA. Translation: AAH39158.1.
PIRI55465.
RefSeqNP_002601.1. NM_002610.4.
UniGeneHs.470633.
Hs.733780.

3D structure databases

PDBe
RCSB PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
2Q8FX-ray2.03A30-436[»]
2Q8GX-ray1.90A30-436[»]
2Q8HX-ray2.00A30-436[»]
ProteinModelPortalQ15118.
SMRQ15118. Positions 41-423.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid111189. 16 interactions.
DIPDIP-29497N.
IntActQ15118. 6 interactions.
MINTMINT-2881420.
STRING9606.ENSP00000282077.

Chemistry

BindingDBQ15118.
ChEMBLCHEMBL4766.

PTM databases

PhosphoSiteQ15118.

Polymorphism databases

DMDM3183117.

Proteomic databases

PaxDbQ15118.
PRIDEQ15118.

Protocols and materials databases

DNASU5163.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000282077; ENSP00000282077; ENSG00000152256.
ENST00000410055; ENSP00000386985; ENSG00000152256.
GeneID5163.
KEGGhsa:5163.
UCSCuc002uhs.3. human.

Organism-specific databases

CTD5163.
GeneCardsGC02P173384.
HGNCHGNC:8809. PDK1.
HPACAB017554.
HPA027376.
MIM602524. gene.
neXtProtNX_Q15118.
PharmGKBPA33154.
GenAtlasSearch...

Phylogenomic databases

eggNOGCOG0642.
HOGENOMHOG000164315.
HOVERGENHBG000511.
KOK12077.
OrthoDBEOG71VSSV.
PhylomeDBQ15118.
TreeFamTF314918.

Enzyme and pathway databases

ReactomeREACT_111217. Metabolism.
SignaLinkQ15118.

Gene expression databases

ArrayExpressQ15118.
BgeeQ15118.
CleanExHS_PDK1.
GenevestigatorQ15118.

Family and domain databases

Gene3D1.20.140.20. 1 hit.
3.30.565.10. 1 hit.
InterProIPR018955. BCDHK/PDK_N.
IPR003594. HATPase_ATP-bd.
IPR005467. Sig_transdc_His_kinase_core.
[Graphical view]
PfamPF10436. BCDHK_Adom3. 1 hit.
PF02518. HATPase_c. 1 hit.
[Graphical view]
SMARTSM00387. HATPase_c. 1 hit.
[Graphical view]
SUPFAMSSF55874. SSF55874. 1 hit.
SSF69012. SSF69012. 1 hit.
PROSITEPS50109. HIS_KIN. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

ChiTaRSPdk1. human.
EvolutionaryTraceQ15118.
GeneWikiPyruvate_dehydrogenase_lipoamide_kinase_isozyme_1.
GenomeRNAi5163.
NextBio19974.
PROQ15118.
SOURCESearch...

Entry information

Entry namePDK1_HUMAN
AccessionPrimary (citable) accession number: Q15118
Secondary accession number(s): B2R6T1, D3DPD8
Entry history
Integrated into UniProtKB/Swiss-Prot: July 15, 1998
Last sequence update: November 1, 1996
Last modified: April 16, 2014
This is version 131 of the entry and version 1 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

Human and mouse protein kinases

Human and mouse protein kinases: classification and index

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

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 2

Human chromosome 2: entries, gene names and cross-references to MIM