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Protein

[Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 3, mitochondrial

Gene

PDK3

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

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.7 Publications

Catalytic activityi

ATP + [pyruvate dehydrogenase (acetyl-transferring)] = ADP + [pyruvate dehydrogenase (acetyl-transferring)] phosphate.3 Publications

Enzyme regulationi

Activated by interaction with DLAT. Inhibited by AZD7545, dichloroacetate and radicicol.2 Publications

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei287ATP1 Publication1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi247 – 254ATP1 Publication8
Nucleotide bindingi306 – 307ATP1 Publication2
Nucleotide bindingi323 – 328ATP1 Publication6

GO - Molecular functioni

  • ATP binding Source: UniProtKB
  • protein kinase activity Source: UniProtKB
  • protein serine/threonine kinase activity Source: UniProtKB
  • pyruvate dehydrogenase (acetyl-transferring) kinase activity Source: UniProtKB

GO - Biological processi

  • cellular response to fatty acid Source: UniProtKB
  • cellular response to glucose stimulus Source: UniProtKB
  • glucose metabolic process Source: UniProtKB-KW
  • hypoxia-inducible factor-1alpha signaling pathway Source: UniProtKB
  • peptidyl-serine phosphorylation Source: UniProtKB
  • peroxisome proliferator activated receptor signaling pathway Source: UniProtKB
  • regulation of acetyl-CoA biosynthetic process from pyruvate Source: UniProtKB
  • regulation of glucose metabolic process Source: UniProtKB
  • regulation of reactive oxygen species metabolic process Source: UniProtKB
Complete GO annotation...

Keywords - Molecular functioni

Kinase, Transferase

Keywords - Biological processi

Carbohydrate metabolism, Glucose metabolism

Keywords - Ligandi

ATP-binding, Nucleotide-binding

Enzyme and pathway databases

BioCyciZFISH:HS00925-MONOMER.
ReactomeiR-HSA-204174. Regulation of pyruvate dehydrogenase (PDH) complex.
R-HSA-5362517. Signaling by Retinoic Acid.
SIGNORiQ15120.

Names & Taxonomyi

Protein namesi
Recommended name:
[Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 3, mitochondrial (EC:2.7.11.2)
Alternative name(s):
Pyruvate dehydrogenase kinase isoform 3
Gene namesi
Name:PDK3
Synonyms:PDHK3
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome X

Organism-specific databases

HGNCiHGNC:8811. PDK3.

Subcellular locationi

GO - Cellular componenti

  • mitochondrial matrix Source: Reactome
  • mitochondrion Source: ProtInc
Complete GO annotation...

Keywords - Cellular componenti

Mitochondrion

Pathology & Biotechi

Involvement in diseasei

Charcot-Marie-Tooth disease, X-linked dominant, 6 (CMTX6)1 Publication
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA form of Charcot-Marie-Tooth disease, a disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. Charcot-Marie-Tooth disease is classified in two main groups on the basis of electrophysiologic properties and histopathology: primary peripheral demyelinating neuropathies characterized by severely reduced motor nerve conduction velocities (NCVs) (less than 38m/s) and segmental demyelination and remyelination, and primary peripheral axonal neuropathies characterized by normal or mildly reduced NCVs and chronic axonal degeneration and regeneration on nerve biopsy.
See also OMIM:300905
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_070082158R → H in CMTX6; gain of function; results in a 5-fold increase in kinase activity, decreased sensitivity to pyruvate inhibition, reduced affinity for nucleotides and increased affinity for pyruvate dehydrogenase complex component E2 (PDC-E2), leading to PDC hyperphosphorylation and increased inactivation. 1 PublicationCorresponds to variant rs397515323dbSNPEnsembl.1

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi120N → H: No effect on kinase activity; when associated with N-121. 1 Publication1
Mutagenesisi121D → N: No effect on kinase activity; when associated with H-120. 1 Publication1

Keywords - Diseasei

Charcot-Marie-Tooth disease, Disease mutation, Neurodegeneration, Neuropathy

Organism-specific databases

DisGeNETi5165.
MalaCardsiPDK3.
MIMi300905. phenotype.
OpenTargetsiENSG00000067992.
Orphaneti352675. X-linked Charcot-Marie-Tooth disease type 6.
PharmGKBiPA33156.

Chemistry databases

ChEMBLiCHEMBL3893.

Polymorphism and mutation databases

BioMutaiPDK3.
DMDMi3183119.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_0000023443? – 406[Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 3, mitochondrial
Transit peptidei1 – ?MitochondrionSequence analysis

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei211PhosphotyrosineBy similarity1
Modified residuei212PhosphotyrosineBy similarity1
Modified residuei278N6-succinyllysineBy similarity1
Modified residuei374N6-succinyllysineBy similarity1

Keywords - PTMi

Phosphoprotein

Proteomic databases

EPDiQ15120.
MaxQBiQ15120.
PaxDbiQ15120.
PeptideAtlasiQ15120.
PRIDEiQ15120.

PTM databases

iPTMnetiQ15120.
PhosphoSitePlusiQ15120.

Expressioni

Tissue specificityi

Expressed in heart, skeletal muscle, spinal cord, as well as fetal and adult brain.1 Publication

Inductioni

Up-regulated in response to hypoxia. Up-regulated in response to fatty acids. Up-regulated by PPARD.3 Publications

Gene expression databases

BgeeiENSG00000067992.
CleanExiHS_PDK3.
GenevisibleiQ15120. HS.

Organism-specific databases

HPAiHPA046583.

Interactioni

Subunit structurei

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).5 Publications

Protein-protein interaction databases

BioGridi111191. 35 interactors.
DIPiDIP-29498N.
IntActiQ15120. 19 interactors.
STRINGi9606.ENSP00000387536.

Chemistry databases

BindingDBiQ15120.

Structurei

Secondary structure

1406
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Helixi14 – 21Combined sources8
Helixi29 – 38Combined sources10
Helixi42 – 64Combined sources23
Helixi69 – 72Combined sources4
Helixi75 – 92Combined sources18
Helixi93 – 96Combined sources4
Beta strandi99 – 101Combined sources3
Helixi102 – 118Combined sources17
Helixi119 – 121Combined sources3
Helixi122 – 137Combined sources16
Helixi141 – 172Combined sources32
Beta strandi179 – 184Combined sources6
Beta strandi187 – 192Combined sources6
Helixi193 – 212Combined sources20
Beta strandi218 – 224Combined sources7
Beta strandi233 – 236Combined sources4
Helixi238 – 260Combined sources23
Beta strandi262 – 265Combined sources4
Beta strandi270 – 276Combined sources7
Beta strandi278 – 287Combined sources10
Helixi294 – 297Combined sources4
Helixi298 – 301Combined sources4
Turni303 – 305Combined sources3
Beta strandi323 – 325Combined sources3
Helixi327 – 337Combined sources11
Beta strandi341 – 347Combined sources7
Turni348 – 350Combined sources3
Beta strandi351 – 360Combined sources10
Helixi362 – 364Combined sources3
Helixi374 – 380Combined sources7

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1Y8NX-ray2.60A9-406[»]
1Y8OX-ray2.48A9-406[»]
1Y8PX-ray2.63A9-406[»]
2PNRX-ray2.50A/B/E/F9-406[»]
2Q8IX-ray2.60A9-406[»]
ProteinModelPortaliQ15120.
SMRiQ15120.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiQ15120.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini131 – 362Histidine kinasePROSITE-ProRule annotationAdd BLAST232

Sequence similaritiesi

Belongs to the PDK/BCKDK protein kinase family.Curated
Contains 1 histidine kinase domain.PROSITE-ProRule annotation

Keywords - Domaini

Transit peptide

Phylogenomic databases

eggNOGiKOG0787. Eukaryota.
COG0642. LUCA.
GeneTreeiENSGT00550000074574.
HOGENOMiHOG000164315.
HOVERGENiHBG000511.
InParanoidiQ15120.
KOiK00898.
OMAiDPHVLDD.
OrthoDBiEOG091G07DJ.
PhylomeDBiQ15120.
TreeFamiTF314918.

Family and domain databases

Gene3Di1.20.140.20. 1 hit.
3.30.565.10. 1 hit.
InterProiIPR018955. BCDHK/PDK_N.
IPR003594. HATPase_C.
IPR005467. His_kinase_dom.
[Graphical view]
PfamiPF10436. BCDHK_Adom3. 1 hit.
PF02518. HATPase_c. 1 hit.
[Graphical view]
SMARTiSM00387. HATPase_c. 1 hit.
[Graphical view]
SUPFAMiSSF55874. SSF55874. 1 hit.
SSF69012. SSF69012. 1 hit.
PROSITEiPS50109. HIS_KIN. 1 hit.
[Graphical view]

Sequences (2)i

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: Q15120-1) [UniParc]FASTAAdd to basket

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.

« Hide

        10         20         30         40         50
MRLFRWLLKQ PVPKQIERYS RFSPSPLSIK QFLDFGRDNA CEKTSYMFLR
60 70 80 90 100
KELPVRLANT MREVNLLPDN LLNRPSVGLV QSWYMQSFLE LLEYENKSPE
110 120 130 140 150
DPQVLDNFLQ VLIKVRNRHN DVVPTMAQGV IEYKEKFGFD PFISTNIQYF
160 170 180 190 200
LDRFYTNRIS FRMLINQHTL LFGGDTNPVH PKHIGSIDPT CNVADVVKDA
210 220 230 240 250
YETAKMLCEQ YYLVAPELEV EEFNAKAPDK PIQVVYVPSH LFHMLFELFK
260 270 280 290 300
NSMRATVELY EDRKEGYPAV KTLVTLGKED LSIKISDLGG GVPLRKIDRL
310 320 330 340 350
FNYMYSTAPR PSLEPTRAAP LAGFGYGLPI SRLYARYFQG DLKLYSMEGV
360 370 380 390 400
GTDAVIYLKA LSSESFERLP VFNKSAWRHY KTTPEADDWS NPSSEPRDAS

KYKAKQ
Length:406
Mass (Da):46,939
Last modified:November 1, 1996 - v1
Checksum:iEF2415D3F9D8D61E
GO
Isoform 2 (identifier: Q15120-2) [UniParc]FASTAAdd to basket

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

Note: No experimental confirmation available.
Show »
Length:415
Mass (Da):48,043
Checksum:iBDE814D88CE6A279
GO

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_070081114K → T.1 PublicationCorresponds to variant rs146331370dbSNPEnsembl.1
Natural variantiVAR_070082158R → H in CMTX6; gain of function; results in a 5-fold increase in kinase activity, decreased sensitivity to pyruvate inhibition, reduced affinity for nucleotides and increased affinity for pyruvate dehydrogenase complex component E2 (PDC-E2), leading to PDC hyperphosphorylation and increased inactivation. 1 PublicationCorresponds to variant rs397515323dbSNPEnsembl.1
Natural variantiVAR_042297219E → A in a head & neck squamous cell carcinoma sample; somatic mutation. 1 Publication1
Natural variantiVAR_070083334Y → S.1 Publication1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_043365406Q → QDKIKTNRTF in isoform 2. 1 Publication1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
L42452 mRNA. Translation: AAC42011.1.
AK301965 mRNA. Translation: BAG63378.1.
CH471074 Genomic DNA. Translation: EAW99019.1.
BC015948 mRNA. Translation: AAH15948.1.
CCDSiCCDS14212.1. [Q15120-1]
CCDS48088.1. [Q15120-2]
PIRiI70160.
RefSeqiNP_001135858.1. NM_001142386.2. [Q15120-2]
NP_005382.1. NM_005391.4. [Q15120-1]
UniGeneiHs.296031.

Genome annotation databases

EnsembliENST00000379162; ENSP00000368460; ENSG00000067992. [Q15120-1]
ENST00000441463; ENSP00000387536; ENSG00000067992. [Q15120-2]
GeneIDi5165.
KEGGihsa:5165.
UCSCiuc004dbg.4. human. [Q15120-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
L42452 mRNA. Translation: AAC42011.1.
AK301965 mRNA. Translation: BAG63378.1.
CH471074 Genomic DNA. Translation: EAW99019.1.
BC015948 mRNA. Translation: AAH15948.1.
CCDSiCCDS14212.1. [Q15120-1]
CCDS48088.1. [Q15120-2]
PIRiI70160.
RefSeqiNP_001135858.1. NM_001142386.2. [Q15120-2]
NP_005382.1. NM_005391.4. [Q15120-1]
UniGeneiHs.296031.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1Y8NX-ray2.60A9-406[»]
1Y8OX-ray2.48A9-406[»]
1Y8PX-ray2.63A9-406[»]
2PNRX-ray2.50A/B/E/F9-406[»]
2Q8IX-ray2.60A9-406[»]
ProteinModelPortaliQ15120.
SMRiQ15120.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi111191. 35 interactors.
DIPiDIP-29498N.
IntActiQ15120. 19 interactors.
STRINGi9606.ENSP00000387536.

Chemistry databases

BindingDBiQ15120.
ChEMBLiCHEMBL3893.

PTM databases

iPTMnetiQ15120.
PhosphoSitePlusiQ15120.

Polymorphism and mutation databases

BioMutaiPDK3.
DMDMi3183119.

Proteomic databases

EPDiQ15120.
MaxQBiQ15120.
PaxDbiQ15120.
PeptideAtlasiQ15120.
PRIDEiQ15120.

Protocols and materials databases

DNASUi5165.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000379162; ENSP00000368460; ENSG00000067992. [Q15120-1]
ENST00000441463; ENSP00000387536; ENSG00000067992. [Q15120-2]
GeneIDi5165.
KEGGihsa:5165.
UCSCiuc004dbg.4. human. [Q15120-1]

Organism-specific databases

CTDi5165.
DisGeNETi5165.
GeneCardsiPDK3.
HGNCiHGNC:8811. PDK3.
HPAiHPA046583.
MalaCardsiPDK3.
MIMi300905. phenotype.
300906. gene.
neXtProtiNX_Q15120.
OpenTargetsiENSG00000067992.
Orphaneti352675. X-linked Charcot-Marie-Tooth disease type 6.
PharmGKBiPA33156.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG0787. Eukaryota.
COG0642. LUCA.
GeneTreeiENSGT00550000074574.
HOGENOMiHOG000164315.
HOVERGENiHBG000511.
InParanoidiQ15120.
KOiK00898.
OMAiDPHVLDD.
OrthoDBiEOG091G07DJ.
PhylomeDBiQ15120.
TreeFamiTF314918.

Enzyme and pathway databases

BioCyciZFISH:HS00925-MONOMER.
ReactomeiR-HSA-204174. Regulation of pyruvate dehydrogenase (PDH) complex.
R-HSA-5362517. Signaling by Retinoic Acid.
SIGNORiQ15120.

Miscellaneous databases

ChiTaRSiPDK3. human.
EvolutionaryTraceiQ15120.
GeneWikiiPDK3.
GenomeRNAii5165.
PROiQ15120.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000067992.
CleanExiHS_PDK3.
GenevisibleiQ15120. HS.

Family and domain databases

Gene3Di1.20.140.20. 1 hit.
3.30.565.10. 1 hit.
InterProiIPR018955. BCDHK/PDK_N.
IPR003594. HATPase_C.
IPR005467. His_kinase_dom.
[Graphical view]
PfamiPF10436. BCDHK_Adom3. 1 hit.
PF02518. HATPase_c. 1 hit.
[Graphical view]
SMARTiSM00387. HATPase_c. 1 hit.
[Graphical view]
SUPFAMiSSF55874. SSF55874. 1 hit.
SSF69012. SSF69012. 1 hit.
PROSITEiPS50109. HIS_KIN. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiPDK3_HUMAN
AccessioniPrimary (citable) accession number: Q15120
Secondary accession number(s): B4DXG6
Entry historyi
Integrated into UniProtKB/Swiss-Prot: July 15, 1998
Last sequence update: November 1, 1996
Last modified: November 2, 2016
This is version 169 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (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.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. Human chromosome X
    Human chromosome X: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  6. Human and mouse protein kinases
    Human and mouse protein kinases: classification and index
  7. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.