Q15118 (PDK1_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
[Pyruvate dehydrogenase [lipoamide]] 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

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	436 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	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 process	Carbohydrate metabolism Glucose metabolism
Cellular component	Mitochondrion
Coding sequence diversity	Polymorphism
Domain	Transit peptide
Ligand	ATP-binding Nucleotide-binding
Molecular function	Kinase Serine/threonine-protein kinase Transferase
PTM	Phosphoprotein
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	cell proliferation Inferred from mutant phenotype Ref.5. Source: UniProtKB 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 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
Cellular_component	mitochondrial matrix Traceable author statement. Source: Reactome
Molecular_function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW 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...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Transit peptide

1 – 28

28

Mitochondrion Potential

Chain

29 – 436

408

[Pyruvate dehydrogenase [lipoamide]] kinase isozyme 1, mitochondrial

PRO_0000023437

Regions

Domain

163 – 393

231

Histidine kinase

Nucleotide binding

279 – 286

8

ATP By similarity

Nucleotide binding

337 – 338

2

ATP By similarity

Nucleotide binding

354 – 359

6

ATP By similarity

Sites

Binding site

318

1

ATP By similarity

Amino acid modifications

Modified residue

136

1

Phosphotyrosine; by FGFR1 Ref.8

Modified residue

243

1

Phosphotyrosine; by FGFR1, ABL1, FLT3 and JAK2 Ref.8

Modified residue

244

1

Phosphotyrosine; by FGFR1 Ref.8

Natural variations

Natural variant

134

1

A → T.
Corresponds to variant rs35661499 [ dbSNP | Ensembl ].

VAR_050477

Natural variant

412

1

N → T. Ref.10
Corresponds to variant rs34250425 [ dbSNP | Ensembl ].

VAR_042295

Secondary structure

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436

Helix Strand Turn

Details...

Helix

42 – 50

9

Helix

59 – 67

9

Helix

72 – 94

23

Helix

99 – 102

4

Helix

105 – 122

18

Beta strand

125 – 127

3

Helix

132 – 148

17

Turn

149 – 151

3

Helix

152 – 166

15

Helix

171 – 202

32

Beta strand

219 – 224

6

Helix

225 – 244

20

Beta strand

250 – 259

10

Beta strand

265 – 268

4

Helix

270 – 291

22

Turn

293 – 295

3

Beta strand

301 – 307

7

Beta strand

309 – 318

10

Helix

325 – 328

4

Helix

329 – 332

4

Turn

334 – 337

4

Beta strand

352 – 354

3

Helix

358 – 368

11

Beta strand

372 – 378

7

Turn

379 – 381

3

Beta strand

382 – 392

11

Turn

393 – 395

3

Helix

405 – 411

7

Sequences

	Sequence		Length	Mass (Da)
	Q15118 [UniParc]. Last modified November 1, 1996. Version 1. Checksum: D14CD594E0EA45A2	FASTA	436	49,244
	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

References

	« Hide 'large scale' referencesShow '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. , 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. , 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. , 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.

IPI

IPI00014831.

PIR

I55465.

RefSeq

NP_002601.1. NM_002610.3.

UniGene

Hs.470633.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2Q8F	X-ray	2.03	A	30-436	[»]
2Q8G	X-ray	1.90	A	30-436	[»]
2Q8H	X-ray	2.00	A	30-436	[»]

ProteinModelPortal

Q15118.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-29497N.

MINT

MINT-2881420.

STRING

9606.ENSP00000282077.

PTM databases

PhosphoSite

Q15118.

Polymorphism databases

DMDM

3183117.

Proteomic databases

PaxDb

Q15118.

PRIDE

Q15118.

Protocols and materials databases

DNASU

5163.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000282077; ENSP00000282077; ENSG00000152256.
ENST00000410055; ENSP00000386985; ENSG00000152256.

GeneID

5163.

KEGG

hsa:5163.

UCSC

uc002uhs.3. human.

Organism-specific databases

CTD

5163.

GeneCards

GC02P173384.

HGNC

HGNC:8809. PDK1.

HPA

CAB017554.
HPA027376.

MIM

602524. gene.

neXtProt

NX_Q15118.

PharmGKB

PA33154.

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG0642.

HOGENOM

HOG000164315.

HOVERGEN

HBG000511.

KO

K12077.

PhylomeDB

Q15118.

Enzyme and pathway databases

Reactome

REACT_111217. Metabolism.

Gene expression databases

ArrayExpress

Q15118.

Bgee

Q15118.

CleanEx

HS_PDK1.

Genevestigator

Q15118.

Family and domain databases

Gene3D

1.20.140.20. 1 hit.
3.30.565.10. 1 hit.

InterPro

IPR018955. BCDHK/PDK_N.
IPR003594. HATPase_ATP-bd.
IPR005467. Sig_transdc_His_kinase_core.
[Graphical view]

Pfam

PF10436. BCDHK_Adom3. 1 hit.
PF02518. HATPase_c. 1 hit.
[Graphical view]

SMART

SM00387. HATPase_c. 1 hit.
[Graphical view]

SUPFAM

SSF55874. ATP_bd_ATPase. 1 hit.
SSF69012. BCDHK/PDK_N. 1 hit.

PROSITE

PS50109. HIS_KIN. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

BindingDB

Q15118.

ChEMBL

CHEMBL4766.

ChiTaRS

Pdk1. human.

EvolutionaryTrace

Q15118.

GenomeRNAi

5163.

NextBio

19974.

SOURCE

Search...

Entry information

Entry name

PDK1_HUMAN

Accession

Primary (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:	May 1, 2013
This is version 121 of the entry and version 1 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.