Q15120 (PDK3_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
[Pyruvate dehydrogenase [lipoamide]] kinase isozyme 3, mitochondrial
EC=2.7.11.2

Alternative name(s):
Pyruvate dehydrogenase kinase isoform 3

Gene names

Name:	PDK3
Synonyms:	PDHK3

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	406 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	Inhibits pyruvate dehydrogenase activity by phosphorylation of the E1 subunit PDHA1, and thereby regulates glucose metabolism and aerobic respiration. Can also phosphorylate PDHA2. Decreases glucose utilization and increases fat metabolism in response to prolonged fasting, and as adaptation to a high-fat diet. Plays a role in glucose homeostasis and in maintaining normal blood glucose levels in function of nutrient levels and under starvation. Plays a role in the generation of reactive oxygen species. Ref.5 Ref.6 Ref.8 Ref.9 Ref.12 Ref.13 Ref.15
Catalytic activity	ATP + [pyruvate dehydrogenase (acetyl-transferring)] = ADP + [pyruvate dehydrogenase (acetyl-transferring)] phosphate. Ref.5 Ref.6 Ref.8
Enzyme regulation	Activated by interaction with DLAT. Inhibited by AZD7545, dichloroacetate and radicicol. Ref.5 Ref.15
Subunit structure	Homodimer. 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.5 Ref.7 Ref.13 Ref.14 Ref.15
Subcellular location	Mitochondrion matrix.
Tissue specificity	Found almost exclusively in heart and skeletal muscle.
Induction	Up-regulated in response to hypoxia. Up-regulated in response to fatty acids. Ref.5 Ref.9 Ref.10 Ref.15
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	Alternative splicing Polymorphism
Domain	Transit peptide
Ligand	ATP-binding Nucleotide-binding
Molecular function	Kinase Serine/threonine-protein kinase Transferase
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	cellular response to fatty acid Inferred from mutant phenotype Ref.10. Source: UniProtKB cellular response to glucose stimulus Inferred from sequence or structural similarity. Source: UniProtKB glucose metabolic process Inferred from electronic annotation. Source: UniProtKB-KW hypoxia-inducible factor-1alpha signaling pathway Inferred from mutant phenotype Ref.9. Source: UniProtKB peptidyl-serine phosphorylation Inferred from direct assay Ref.6. Source: UniProtKB peroxisome proliferator activated receptor signaling pathway Inferred from mutant phenotype PubMed 17669420. Source: UniProtKB pyruvate metabolic process Traceable author statement. Source: Reactome regulation of acetyl-CoA biosynthetic process from pyruvate Inferred from mutant phenotype Ref.12. Source: UniProtKB regulation of glucose metabolic process Inferred from mutant phenotype Ref.12. Source: UniProtKB regulation of reactive oxygen species metabolic process Inferred from mutant phenotype Ref.12. Source: UniProtKB
Cellular_component	mitochondrial matrix Traceable author statement. Source: Reactome
Molecular_function	ATP binding Inferred from direct assay Ref.13. Source: UniProtKB protein serine/threonine kinase activity Inferred from direct assay Ref.6. Source: UniProtKB pyruvate dehydrogenase (acetyl-transferring) kinase activity Inferred from direct assay Ref.6. Source: UniProtKB
Complete GO annotation...

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: Q15120-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform 2 (identifier: Q15120-2)

The sequence of this isoform differs from the canonical sequence as follows:
     406-406: Q → QDKIKTNRTF

Note: No experimental confirmation available.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Transit peptide

1 – ?

Mitochondrion Potential

Chain

? – 406

[Pyruvate dehydrogenase [lipoamide]] kinase isozyme 3, mitochondrial

PRO_0000023443

Regions

Domain

131 – 362

232

Histidine kinase

Nucleotide binding

247 – 254

8

ATP

Nucleotide binding

306 – 307

2

ATP

Nucleotide binding

323 – 328

6

ATP

Sites

Binding site

287

1

ATP

Natural variations

Alternative sequence

406

1

Q → QDKIKTNRTF in isoform 2.

VSP_043365

Natural variant

219

1

E → A in a head & Neck squamous cell carcinoma sample; somatic mutation. Ref.16

VAR_042297

Secondary structure

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406

Helix Strand Turn

Details...

Helix

14 – 21

8

Helix

29 – 38

10

Helix

42 – 64

23

Helix

69 – 72

4

Helix

75 – 92

18

Helix

93 – 96

4

Beta strand

99 – 101

3

Helix

102 – 118

17

Helix

119 – 121

3

Helix

122 – 137

16

Helix

141 – 172

32

Beta strand

179 – 184

6

Beta strand

187 – 192

6

Helix

193 – 212

20

Beta strand

218 – 224

7

Beta strand

233 – 236

4

Helix

238 – 260

23

Beta strand

262 – 265

4

Beta strand

270 – 276

7

Beta strand

278 – 287

10

Helix

294 – 297

4

Helix

298 – 301

4

Turn

303 – 305

3

Beta strand

323 – 325

3

Helix

327 – 337

11

Beta strand

341 – 347

7

Turn

348 – 350

3

Beta strand

351 – 360

10

Helix

362 – 364

3

Helix

374 – 380

7

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified November 1, 1996. Version 1. Checksum: EF2415D3F9D8D61E	FASTA	406	46,939
	10 20 30 40 50 60 MRLFRWLLKQ PVPKQIERYS RFSPSPLSIK QFLDFGRDNA CEKTSYMFLR KELPVRLANT 70 80 90 100 110 120 MREVNLLPDN LLNRPSVGLV QSWYMQSFLE LLEYENKSPE DPQVLDNFLQ VLIKVRNRHN 130 140 150 160 170 180 DVVPTMAQGV IEYKEKFGFD PFISTNIQYF LDRFYTNRIS FRMLINQHTL LFGGDTNPVH 190 200 210 220 230 240 PKHIGSIDPT CNVADVVKDA YETAKMLCEQ YYLVAPELEV EEFNAKAPDK PIQVVYVPSH 250 260 270 280 290 300 LFHMLFELFK NSMRATVELY EDRKEGYPAV KTLVTLGKED LSIKISDLGG GVPLRKIDRL 310 320 330 340 350 360 FNYMYSTAPR PSLEPTRAAP LAGFGYGLPI SRLYARYFQG DLKLYSMEGV GTDAVIYLKA 370 380 390 400 LSSESFERLP VFNKSAWRHY KTTPEADDWS NPSSEPRDAS KYKAKQ
	Isoform 2 [UniParc]. Checksum: BDE814D88CE6A279	FASTA	415	48,043
	10 20 30 40 50 60 MRLFRWLLKQ PVPKQIERYS RFSPSPLSIK QFLDFGRDNA CEKTSYMFLR KELPVRLANT 70 80 90 100 110 120 MREVNLLPDN LLNRPSVGLV QSWYMQSFLE LLEYENKSPE DPQVLDNFLQ VLIKVRNRHN 130 140 150 160 170 180 DVVPTMAQGV IEYKEKFGFD PFISTNIQYF LDRFYTNRIS FRMLINQHTL LFGGDTNPVH 190 200 210 220 230 240 PKHIGSIDPT CNVADVVKDA YETAKMLCEQ YYLVAPELEV EEFNAKAPDK PIQVVYVPSH 250 260 270 280 290 300 LFHMLFELFK NSMRATVELY EDRKEGYPAV KTLVTLGKED LSIKISDLGG GVPLRKIDRL 310 320 330 340 350 360 FNYMYSTAPR PSLEPTRAAP LAGFGYGLPI SRLYARYFQG DLKLYSMEGV GTDAVIYLKA 370 380 390 400 410 LSSESFERLP VFNKSAWRHY KTTPEADDWS NPSSEPRDAS KYKAKQDKIK TNRTF

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] (ISOFORM 1). 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] (ISOFORM 2). Tissue: Testis.
[3]	Mural R.J., Istrail S., Sutton 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 (JUL-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] (ISOFORM 1). Tissue: Skin.
[5]	"Marked differences between two isoforms of human pyruvate dehydrogenase kinase." Baker J.C., Yan X., Peng T., Kasten S., Roche T.E. J. Biol. Chem. 275:15773-15781(2000) [PubMed] [Europe PMC] [Abstract] Cited for: CATALYTIC ACTIVITY, FUNCTION, INTERACTION WITH DLAT, ENZYME REGULATION.
[6]	"Site specificity of four pyruvate dehydrogenase kinase isoenzymes toward the three phosphorylation sites of human pyruvate dehydrogenase." Korotchkina L.G., Patel M.S. J. Biol. Chem. 276:37223-37229(2001) [PubMed] [Europe PMC] [Abstract] Cited for: CATALYTIC ACTIVITY, FUNCTION.
[7]	"Interaction between the individual isoenzymes of pyruvate dehydrogenase kinase and the inner lipoyl-bearing domain of transacetylase component of pyruvate dehydrogenase complex." Tuganova A., Boulatnikov I., Popov K.M. Biochem. J. 366:129-136(2002) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH DLAT.
[8]	"Characterization of testis-specific isoenzyme of human pyruvate dehydrogenase." Korotchkina L.G., Sidhu S., Patel M.S. J. Biol. Chem. 281:9688-9696(2006) [PubMed] [Europe PMC] [Abstract] Cited for: CATALYTIC ACTIVITY, FUNCTION.
[9]	"Induction of pyruvate dehydrogenase kinase-3 by hypoxia-inducible factor-1 promotes metabolic switch and drug resistance." Lu C.W., Lin S.C., Chen K.F., Lai Y.Y., Tsai S.J. J. Biol. Chem. 283:28106-28114(2008) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, INDUCTION.
[10]	"Butyrate elicits a metabolic switch in human colon cancer cells by targeting the pyruvate dehydrogenase complex." Blouin J.M., Penot G., Collinet M., Nacfer M., Forest C., Laurent-Puig P., Coumoul X., Barouki R., Benelli C., Bortoli S. Int. J. Cancer 128:2591-2601(2011) [PubMed] [Europe PMC] [Abstract] Cited for: INDUCTION.
[11]	"System-wide temporal characterization of the proteome and phosphoproteome of human embryonic stem cell differentiation." Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B. Sci. Signal. 4:RS3-RS3(2011) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[12]	"Inactivation of the HIF-1alpha/PDK3 signaling axis drives melanoma toward mitochondrial oxidative metabolism and potentiates the therapeutic activity of pro-oxidants." Kluza J., Corazao-Rozas P., Touil Y., Jendoubi M., Maire C., Guerreschi P., Jonneaux A., Ballot C., Balayssac S., Valable S., Corroyer-Dulmont A., Bernaudin M., Malet-Martino M., de Lassalle E.M., Maboudou P., Formstecher P., Polakowska R., Mortier L., Marchetti P. Cancer Res. 72:5035-5047(2012) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[13]	"Crystal structure of pyruvate dehydrogenase kinase 3 bound to lipoyl domain 2 of human pyruvate dehydrogenase complex." Kato M., Chuang J.L., Tso S.C., Wynn R.M., Chuang D.T. EMBO J. 24:1763-1774(2005) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.48 ANGSTROMS) OF 9-406 IN COMPLEX WITH ATP, FUNCTION, INTERACTION WITH DLAT.
[14]	"Crystal structure of an asymmetric complex of pyruvate dehydrogenase kinase 3 with lipoyl domain 2 and its biological implications." Devedjiev Y., Steussy C.N., Vassylyev D.G. J. Mol. Biol. 370:407-416(2007) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 9-406, INTERACTION WITH DLAT.
[15]	"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 (2.6 ANGSTROMS) OF 9-406 IN COMPLEX WITH THE INHIBITOR RADICICOL, FUNCTION, ENZYME REGULATION, INTERACTION WITH DLAT.
[16]	"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] ALA-219.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

L42452 mRNA. Translation: AAC42011.1.
AK301965 mRNA. Translation: BAG63378.1.
CH471074 Genomic DNA. Translation: EAW99019.1.
BC015948 mRNA. Translation: AAH15948.1.

IPI

IPI00014849.
IPI00915357.

PIR

I70160.

RefSeq

NP_001135858.1. NM_001142386.2.
NP_005382.1. NM_005391.4.

UniGene

Hs.296031.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1Y8N	X-ray	2.60	A	9-406	[»]
1Y8O	X-ray	2.48	A	9-406	[»]
1Y8P	X-ray	2.63	A	9-406	[»]
2PNR	X-ray	2.50	A/B/E/F	9-406	[»]
2Q8I	X-ray	2.60	A	9-406	[»]

ProteinModelPortal

Q15120.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-29498N.

IntAct

Q15120. 1 interaction.

STRING

9606.ENSP00000387536.

PTM databases

PhosphoSite

Q15120.

Polymorphism databases

DMDM

3183119.

Proteomic databases

PaxDb

Q15120.

PRIDE

Q15120.

Protocols and materials databases

DNASU

5165.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000379162; ENSP00000368460; ENSG00000067992.
ENST00000441463; ENSP00000387536; ENSG00000067992.

GeneID

5165.

KEGG

hsa:5165.

UCSC

uc004dbg.3. human.

Organism-specific databases

CTD

5165.

GeneCards

GC0XP024393.

HGNC

HGNC:8811. PDK3.

HPA

HPA046583.

MIM

602526. gene.

neXtProt

NX_Q15120.

PharmGKB

PA33156.

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG0642.

HOGENOM

HOG000164315.

HOVERGEN

HBG000511.

InParanoid

Q15120.

KO

K00898.

OMA

APNKPIQ.

OrthoDB

EOG4P5K96.

PhylomeDB

Q15120.

Enzyme and pathway databases

Reactome

REACT_111217. Metabolism.

Gene expression databases

Bgee

Q15120.

CleanEx

HS_PDK3.

Genevestigator

Q15120.

GermOnline

ENSG00000067992. Homo sapiens.

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

Q15120.

ChEMBL

CHEMBL3893.

EvolutionaryTrace

Q15120.

GenomeRNAi

5165.

NextBio

19982.

SOURCE

Search...

Entry information

Entry name

PDK3_HUMAN

Accession

Primary (citable) accession number: Q15120
Secondary accession number(s): B4DXG6

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 15, 1998
Last sequence update:	November 1, 1996
Last modified:	May 1, 2013
This is version 133 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.