[Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 4, mitochondrial

Details

Name

[Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 4, mitochondrial

Synonyms

• 2.7.11.2
• PDHK4
• Pyruvate dehydrogenase kinase isoform 4

Gene Name

PDK4

Organism

Humans

Amino acid sequence

>lcl|BSEQ0017394|[Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 4, mitochondrial
MKAARFVLRSAGSLNGAGLVPREVEHFSRYSPSPLSMKQLLDFGSENACERTSFAFLRQE
LPVRLANILKEIDILPTQLVNTSSVQLVKSWYIQSLMDLVEFHEKSPDDQKALSDFVDTL
IKVRNRHHNVVPTMAQGIIEYKDACTVDPVTNQNLQYFLDRFYMNRISTRMLMNQHILIF
SDSQTGNPSHIGSIDPNCDVVAVVQDAFECSRMLCDQYYLSSPELKLTQVNGKFPDQPIH
IVYVPSHLHHMLFELFKNAMRATVEHQENQPSLTPIEVIVVLGKEDLTIKISDRGGGVPL
RIIDRLFSYTYSTAPTPVMDNSRNAPLAGFGYGLPISRLYAKYFQGDLNLYSLSGYGTDA
IIYLKALSSESIEKLPVFNKSAFKHYQMSSEADDWCIPSREPKNLAKEVAM

Number of residues

411

Molecular Weight

46468.79

Theoretical pI

6.65

GO Classification

Functions

ATP binding / protein kinase activity / pyruvate dehydrogenase (acetyl-transferring) kinase activity

Processes

cellular metabolic process / cellular response to fatty acid / cellular response to starvation / glucose homeostasis / glucose metabolic process / insulin receptor signaling pathway / negative regulation of anoikis / positive regulation of defense response to virus by host / protein phosphorylation / pyruvate metabolic process / reactive oxygen species metabolic process / regulation of acetyl-CoA biosynthetic process from pyruvate / regulation of bone resorption / regulation of cellular ketone metabolic process / regulation of fatty acid biosynthetic process / regulation of fatty acid oxidation / regulation of glucose metabolic process / regulation of pH / response to starvation / small molecule metabolic process / xenophagy

Components

mitochondrial inner membrane / mitochondrial matrix / mitochondrion

General Function

Pyruvate dehydrogenase (acetyl-transferring) kinase activity

Specific Function

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. Inhibition of pyruvate dehydrogenase decreases glucose utilization and increases fat metabolism in response to prolonged fasting and starvation. Plays an important role in maintaining normal blood glucose levels under starvation, and is involved in the insulin signaling cascade. Via its regulation of pyruvate dehydrogenase activity, plays an important role in maintaining normal blood pH and in preventing the accumulation of ketone bodies under starvation. In the fed state, mediates cellular responses to glucose levels and to a high-fat diet. Regulates both fatty acid oxidation and de novo fatty acid biosynthesis. Plays a role in the generation of reactive oxygen species. Protects detached epithelial cells against anoikis. Plays a role in cell proliferation via its role in regulating carbohydrate and fatty acid metabolism.

Pfam Domain Function

• HATPase_c (PF02518)
• BCDHK_Adom3 (PF10436)

Transmembrane Regions

Not Available

Cellular Location

Mitochondrion matrix

Gene sequence

>lcl|BSEQ0017395|[Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 4, mitochondrial (PDK4)
ATGAAGGCGGCCCGCTTCGTGCTGCGCAGCGCTGGCTCGCTCAACGGCGCCGGCCTGGTG
CCCCGAGAGGTGGAGCATTTCTCGCGCTACAGCCCGTCCCCGCTGTCCATGAAGCAGCTA
CTGGACTTTGGTTCAGAAAATGCATGTGAAAGAACTTCTTTTGCATTTTTGCGACAAGAA
TTGCCTGTGAGACTCGCCAACATTCTGAAGGAAATTGATATCCTCCCGACCCAATTAGTA
AATACCTCTTCAGTGCAATTGGTTAAAAGCTGGTATATACAGAGCCTGATGGATTTGGTG
GAATTCCATGAGAAAAGCCCAGATGACCAGAAAGCATTATCAGACTTTGTAGATACACTC
ATCAAAGTTCGAAATAGACACCATAATGTAGTCCCTACAATGGCACAAGGAATCATAGAG
TATAAAGATGCCTGTACAGTTGACCCAGTCACCAATCAAAATCTTCAATATTTCTTGGAT
CGATTTTACATGAACCGTATTTCTACTCGGATGCTGATGAACCAGCACATTCTTATATTT
AGTGACTCACAGACAGGAAACCCAAGCCACATTGGAAGCATTGATCCTAACTGTGATGTG
GTAGCAGTGGTCCAAGATGCCTTTGAGTGTTCAAGGATGCTCTGTGATCAGTATTATTTA
TCATCTCCAGAATTAAAGCTTACACAAGTGAATGGAAAATTTCCAGACCAACCAATTCAC
ATCGTGTATGTTCCTTCTCACCTCCATCATATGCTCTTTGAACTATTTAAGAATGCAATG
CGGGCAACAGTTGAACACCAGGAAAATCAGCCTTCCCTTACACCAATAGAGGTTATTGTT
GTCTTGGGAAAAGAAGACCTTACCATTAAGATTTCAGACAGAGGAGGTGGTGTTCCCCTG
AGAATTATTGACCGCCTCTTTAGTTATACATACTCCACTGCACCAACGCCTGTGATGGAT
AATTCCCGGAATGCTCCTTTGGCTGGTTTTGGTTACGGCTTGCCAATTTCTCGTCTGTAT
GCAAAGTACTTTCAAGGAGATCTGAATCTCTACTCTTTATCAGGATATGGAACAGATGCT
ATCATCTACTTAAAGGCTTTGTCTTCTGAGTCTATAGAAAAACTTCCAGTTTTTAACAAG
TCAGCCTTCAAACATTATCAGATGAGCTCTGAGGCTGATGACTGGTGTATCCCAAGCAGG
GAACCAAAGAACCTGGCAAAAGAAGTGGCCATGTGA

Chromosome Location

7

Locus

7q21.3

External Identifiers

Resource	Link
UniProtKB ID	Q16654
UniProtKB Entry Name	PDK4_HUMAN
GenBank Protein ID	1399197
GenBank Gene ID	U54617
HGNC ID	HGNC:8812

General References

1. Rowles J, Scherer SW, Xi T, Majer M, Nickle DC, Rommens JM, Popov KM, Harris RA, Riebow NL, Xia J, Tsui LC, Bogardus C, Prochazka M: Cloning and characterization of PDK4 on 7q21.3 encoding a fourth pyruvate dehydrogenase kinase isoenzyme in human. J Biol Chem. 1996 Sep 13;271(37):22376-82. [Article]
2. Hillier LW, Fulton RS, Fulton LA, Graves TA, Pepin KH, Wagner-McPherson C, Layman D, Maas J, Jaeger S, Walker R, Wylie K, Sekhon M, Becker MC, O'Laughlin MD, Schaller ME, Fewell GA, Delehaunty KD, Miner TL, Nash WE, Cordes M, Du H, Sun H, Edwards J, Bradshaw-Cordum H, Ali J, Andrews S, Isak A, Vanbrunt A, Nguyen C, Du F, Lamar B, Courtney L, Kalicki J, Ozersky P, Bielicki L, Scott K, Holmes A, Harkins R, Harris A, Strong CM, Hou S, Tomlinson C, Dauphin-Kohlberg S, Kozlowicz-Reilly A, Leonard S, Rohlfing T, Rock SM, Tin-Wollam AM, Abbott A, Minx P, Maupin R, Strowmatt C, Latreille P, Miller N, Johnson D, Murray J, Woessner JP, Wendl MC, Yang SP, Schultz BR, Wallis JW, Spieth J, Bieri TA, Nelson JO, Berkowicz N, Wohldmann PE, Cook LL, Hickenbotham MT, Eldred J, Williams D, Bedell JA, Mardis ER, Clifton SW, Chissoe SL, Marra MA, Raymond C, Haugen E, Gillett W, Zhou Y, James R, Phelps K, Iadanoto S, Bubb K, Simms E, Levy R, Clendenning J, Kaul R, Kent WJ, Furey TS, Baertsch RA, Brent MR, Keibler E, Flicek P, Bork P, Suyama M, Bailey JA, Portnoy ME, Torrents D, Chinwalla AT, Gish WR, Eddy SR, McPherson JD, Olson MV, Eichler EE, Green ED, Waterston RH, Wilson RK: The DNA sequence of human chromosome 7. Nature. 2003 Jul 10;424(6945):157-64. [Article]
3. Gerhard DS, Wagner L, Feingold EA, Shenmen CM, Grouse LH, Schuler G, Klein SL, Old S, Rasooly R, Good P, Guyer M, Peck AM, Derge JG, Lipman D, Collins FS, Jang W, Sherry S, Feolo M, Misquitta L, Lee E, Rotmistrovsky K, Greenhut SF, Schaefer CF, Buetow K, Bonner TI, Haussler D, Kent J, Kiekhaus M, Furey T, Brent M, Prange C, Schreiber K, Shapiro N, Bhat NK, Hopkins RF, Hsie F, Driscoll T, Soares MB, Casavant TL, Scheetz TE, Brown-stein MJ, Usdin TB, Toshiyuki S, Carninci P, Piao Y, Dudekula DB, Ko MS, Kawakami K, Suzuki Y, Sugano S, Gruber CE, Smith MR, Simmons B, Moore T, Waterman R, Johnson SL, Ruan Y, Wei CL, Mathavan S, Gunaratne PH, Wu J, Garcia AM, Hulyk SW, Fuh E, Yuan Y, Sneed A, Kowis C, Hodgson A, Muzny DM, McPherson J, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madari A, Young AC, Wetherby KD, Granite SJ, Kwong PN, Brinkley CP, Pearson RL, Bouffard GG, Blakesly RW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Griffith M, Griffith OL, Krzywinski MI, Liao N, Morin R, Palmquist D, Petrescu AS, Skalska U, Smailus DE, Stott JM, Schnerch A, Schein JE, Jones SJ, Holt RA, Baross A, Marra MA, Clifton S, Makowski KA, Bosak S, Malek J: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome Res. 2004 Oct;14(10B):2121-7. [Article]
4. Spriet LL, Tunstall RJ, Watt MJ, Mehan KA, Hargreaves M, Cameron-Smith D: Pyruvate dehydrogenase activation and kinase expression in human skeletal muscle during fasting. J Appl Physiol (1985). 2004 Jun;96(6):2082-7. Epub 2004 Feb 13. [Article]
5. Abbot EL, McCormack JG, Reynet C, Hassall DG, Buchan KW, Yeaman SJ: Diverging regulation of pyruvate dehydrogenase kinase isoform gene expression in cultured human muscle cells. FEBS J. 2005 Jun;272(12):3004-14. [Article]
6. Degenhardt T, Saramaki A, Malinen M, Rieck M, Vaisanen S, Huotari A, Herzig KH, Muller R, Carlberg C: Three members of the human pyruvate dehydrogenase kinase gene family are direct targets of the peroxisome proliferator-activated receptor beta/delta. J Mol Biol. 2007 Sep 14;372(2):341-55. Epub 2007 Jul 19. [Article]
7. Grassian AR, Metallo CM, Coloff JL, Stephanopoulos G, Brugge JS: Erk regulation of pyruvate dehydrogenase flux through PDK4 modulates cell proliferation. Genes Dev. 2011 Aug 15;25(16):1716-33. doi: 10.1101/gad.16771811. [Article]
8. Blouin JM, Penot G, Collinet M, Nacfer M, Forest C, Laurent-Puig P, Coumoul X, Barouki R, Benelli C, Bortoli S: Butyrate elicits a metabolic switch in human colon cancer cells by targeting the pyruvate dehydrogenase complex. Int J Cancer. 2011 Jun 1;128(11):2591-601. doi: 10.1002/ijc.25599. Epub 2010 Oct 8. [Article]
9. Kulkarni SS, Salehzadeh F, Fritz T, Zierath JR, Krook A, Osler ME: Mitochondrial regulators of fatty acid metabolism reflect metabolic dysfunction in type 2 diabetes mellitus. Metabolism. 2012 Feb;61(2):175-85. doi: 10.1016/j.metabol.2011.06.014. Epub 2011 Aug 3. [Article]
10. Wynn RM, Kato M, Chuang JL, Tso SC, Li J, Chuang DT: Pyruvate dehydrogenase kinase-4 structures reveal a metastable open conformation fostering robust core-free basal activity. J Biol Chem. 2008 Sep 12;283(37):25305-15. doi: 10.1074/jbc.M802249200. Epub 2008 Jul 24. [Article]
11. Kukimoto-Niino M, Tokmakov A, Terada T, Ohbayashi N, Fujimoto T, Gomi S, Shiromizu I, Kawamoto M, Matsusue T, Shirouzu M, Yokoyama S: Inhibitor-bound structures of human pyruvate dehydrogenase kinase 4. Acta Crystallogr D Biol Crystallogr. 2011 Sep;67(Pt 9):763-73. doi: 10.1107/S090744491102405X. Epub 2011 Aug 9. [Article]
12. Greenman C, Stephens P, Smith R, Dalgliesh GL, Hunter C, Bignell G, Davies H, Teague J, Butler A, Stevens C, Edkins S, O'Meara S, Vastrik I, Schmidt EE, 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 DP, Louis DN, Goldstraw P, Nicholson AG, Brasseur F, Looijenga L, Weber BL, Chiew YE, DeFazio A, Greaves MF, Green AR, Campbell P, Birney E, Easton DF, Chenevix-Trench G, Tan MH, Khoo SK, Teh BT, Yuen ST, Leung SY, Wooster R, Futreal PA, Stratton MR: Patterns of somatic mutation in human cancer genomes. Nature. 2007 Mar 8;446(7132):153-8. [Article]

Drug Relations

Drug Relations

DrugBank ID	Name	Drug group	Pharmacological action?	Actions	Details
DB08356	4-[4-(4-methoxyphenyl)-5-methyl-1H-pyrazol-3-yl]benzene-1,3-diol	experimental	unknown		Details
DB00755	Tretinoin	approved, investigational, nutraceutical	unknown	upregulator	Details