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{{Infobox_gene}}
{{PBB_Controls
'''Pyruvate dehydrogenase kinase isoform 2''' (PDK2) also known as '''pyruvate dehydrogenase lipoamide kinase isozyme 2, mitochondrial''' is an [[enzyme]] that in humans is encoded by the ''PDK2'' [[gene]].<ref name="pmid7499431">{{cite journal | vauthors = Gudi R, Bowker-Kinley MM, Kedishvili NY, Zhao Y, Popov KM | title = Diversity of the pyruvate dehydrogenase kinase gene family in humans | journal = The Journal of Biological Chemistry | volume = 270 | issue = 48 | pages = 28989–94 | date = Dec 1995 | pmid = 7499431 | pmc =  | doi = 10.1074/jbc.270.48.28989 }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: PDK2 pyruvate dehydrogenase kinase, isozyme 2| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5164| accessdate = }}</ref> PDK2 is an [[isozyme]] of [[pyruvate dehydrogenase kinase]].
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| update_protein_box = yes
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<!-- The GNF_Protein_box is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
==Structure==
{{GNF_Protein_box
| image = PBB_Protein_PDK2_image.jpg
| image_source = [[Protein_Data_Bank|PDB]] rendering based on 1jm6.
| PDB = {{PDB2|1jm6}}, {{PDB2|2btz}}, {{PDB2|2bu2}}, {{PDB2|2bu5}}, {{PDB2|2bu6}}, {{PDB2|2bu7}}, {{PDB2|2bu8}}
| Name = Pyruvate dehydrogenase kinase, isozyme 2
| HGNCid = 8810
| Symbol = PDK2
| AltSymbols =;
| OMIM = 602525
| ECnumber = 
| Homologene = 68265
| MGIid = 1343087
| GeneAtlas_image1 = PBB_GE_PDK2_202590_s_at_tn.png
| GeneAtlas_image2 = PBB_GE_PDK2_213724_s_at_tn.png
| Function = {{GNF_GO|id=GO:0004673 |text = protein histidine kinase activity}} {{GNF_GO|id=GO:0004740 |text = [pyruvate dehydrogenase (lipoamide)] kinase activity}} {{GNF_GO|id=GO:0005515 |text = protein binding}} {{GNF_GO|id=GO:0005524 |text = ATP binding}}
| Component = {{GNF_GO|id=GO:0005739 |text = mitochondrion}}
| Process = {{GNF_GO|id=GO:0005975 |text = carbohydrate metabolic process}} {{GNF_GO|id=GO:0006006 |text = glucose metabolic process}} {{GNF_GO|id=GO:0016310 |text = phosphorylation}} {{GNF_GO|id=GO:0018106 |text = peptidyl-histidine phosphorylation}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 5164
    | Hs_Ensembl = ENSG00000005882
    | Hs_RefseqProtein = NP_002602
    | Hs_RefseqmRNA = NM_002611
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = 17
    | Hs_GenLoc_start = 45527695
    | Hs_GenLoc_end = 45543419
    | Hs_Uniprot = Q15119
    | Mm_EntrezGene = 18604
    | Mm_Ensembl = ENSMUSG00000038967
    | Mm_RefseqmRNA = XM_975730
    | Mm_RefseqProtein = XP_980824
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 11
    | Mm_GenLoc_start = 94843272
    | Mm_GenLoc_end = 94857346
    | Mm_Uniprot = Q8VC63
  }}
}}
'''Pyruvate dehydrogenase kinase, isozyme 2''', also known as '''PDK2''', is a human [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: PDK2 pyruvate dehydrogenase kinase, isozyme 2| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5164| accessdate = }}</ref> It codes for an [[isozyme]] of [[pyruvate dehydrogenase kinase]].


<!-- The PBB_Summary template is automatically maintained by Protein Box Bot. See Template:PBB_Controls to Stop updates. -->
The protein encoded by the PDK2 gene has two sites, an [[active site]] and an [[Allosteric enzyme|allosteric site]] that allow for the activity and regulation of this enzyme. There are many structural motifs that are important to the regulation of this enzyme. Nov3r and AZ12 inhibitors bind at the [[lipoamide]] binding site that is located at one end of the R domain. Pfz3 binds in an extended site at the other end of the R domain. One inhibitor, [[dicholoroacetate]] (DCA), binds at the center of the R domain.<ref>{{cite journal | vauthors = Knoechel TR, Tucker AD, Robinson CM, Phillips C, Taylor W, Bungay PJ, Kasten SA, Roche TE, Brown DG | title = Regulatory roles of the N-terminal domain based on crystal structures of human pyruvate dehydrogenase kinase 2 containing physiological and synthetic ligands | journal = Biochemistry | volume = 45 | issue = 2 | pages = 402–15 | date = Jan 2006 | pmid = 16401071 | doi = 10.1021/bi051402s }}</ref> Within the active site, there are three amino acid residues, R250, T302, and Y320, that make the kinase resistant to the inhibitor dichloroacetate, which uncouples the active site from the allosteric site. This supports the theory that R250, T302, and Y320 stabilize the "open" and "closed" conformations of the built-in lid that controls the access of a nucleotide into the nucleotide-binding cavity. This strongly suggests that the mobility of ATP lid is central to the allosteric regulation of  PDHK2 activity serving as a conformational switch required for communication between the active site and allosteric sites in the kinase molecule.<ref>{{cite journal | vauthors = Klyuyeva A, Tuganova A, Popov KM | title = Allosteric coupling in pyruvate dehydrogenase kinase 2 | journal = Biochemistry | volume = 47 | issue = 32 | pages = 8358–66 | date = Aug 2008 | pmid = 18627174 | doi = 10.1021/bi800631h | pmc=2568900}}</ref> There is also a DW-motif that is crucial in mediating DCA, nucleotide, and lipoyl domain binding site communication. This network is responsible for rendering PDK2 locked in the closed, or inactive conformation.<ref>{{cite journal | vauthors = Li J, Kato M, Chuang DT | title = Pivotal role of the C-terminal DW-motif in mediating inhibition of pyruvate dehydrogenase kinase 2 by dichloroacetate | journal = The Journal of Biological Chemistry | volume = 284 | issue = 49 | pages = 34458–67 | date = Dec 2009 | pmid = 19833728 | doi = 10.1074/jbc.M109.065557 | pmc=2797213}}</ref>
{{PBB_Summary
 
| section_title =  
== Function ==
| summary_text =  
The Pyruvate Dehydrogenase (PDH) complex must be tightly regulated due to its central role in general metabolism. Within the complex, there are three serine residues on the E1 component that are sites for phosphorylation; this phosphorylation inactivates the complex. In humans, there have been four [[isozymes]] of Pyruvate Dehydrogenase Kinase that have been shown to phosphorylate these three sites: [[PDK1]], PDK2, [[PDK3]], and [[PDK4]].<ref>{{cite journal | vauthors = Kolobova E, Tuganova A, Boulatnikov I, Popov KM | title = Regulation of pyruvate dehydrogenase activity through phosphorylation at multiple sites | journal = The Biochemical Journal | volume = 358 | issue = Pt 1 | pages = 69–77 | date = Aug 2001 | pmid = 11485553 | doi=10.1042/0264-6021:3580069 | pmc=1222033}}</ref> PDK2 has been identified as the most abundant [[Protein isoform|isoform]] in human tissues. Through many studies, it has been made clear that the activity of this enzyme is essential, even at rest, to regulate [[glycolysis]]/[[Carbohydrate metabolism|carbodydrate oxidation]] and producing metabolites for [[oxidative phosphorylation]] and the [[electron transport chain]]. These studies have illustrated that the kinetics of the PDK isoform population, specifically PDK2, is more important in determining PDH activity than measuring PDK activity.<ref>{{cite journal | vauthors = Dunford EC, Herbst EA, Jeoung NH, Gittings W, Inglis JG, Vandenboom R, LeBlanc PJ, Harris RA, Peters SJ | title = PDH activation during in vitro muscle contractions in PDH kinase 2 knockout mice: effect of PDH kinase 1 compensation | journal = American Journal of Physiology. Regulatory, Integrative and Comparative Physiology | volume = 300 | issue = 6 | pages = R1487-93 | date = Jun 2011 | pmid = 21411764 | doi = 10.1152/ajpregu.00498.2010 }}</ref>
}}
 
===Regulation===
As the primary regulators of a crucial step in the central metabolic pathway, the pyruvate dehydrogenase family is tightly regulated itself by a myriad of factors. PDK2 activity is modulated by low levels of hydrogen peroxide; this happens because the compound temporarily oxidizes the cysteine residues 45 and 392 on the enzyme, resulting in an inactive PDK2 and greater PDH activity. These conditions also inactivate the [[TCA cycle]], the next step in [[aerobic respiration]]. This alludes to the fact that when there is a high level of O<sub>2</sub> production in the [[mitochondria]], which may occur because of nutrient excess, the increase in the products serve as a [[negative feedback]] that control mitochondria metabolism.<ref>{{cite journal|last1=Hurd|first1=TR|last2=Collins|first2=Y|last3=Abakumova|first3=I|last4=Chouchani|first4=ET|last5=Baranowski|first5=B|last6=Fearnley|first6=IM|last7=Prime|first7=TA|last8=Murphy|first8=MP|last9=James|first9=AM|title=Inactivation of pyruvate dehydrogenase kinase 2 by mitochondrial reactive oxygen species.|journal=The Journal of Biological Chemistry|date=12 October 2012|volume=287|issue=42|pages=35153–60|pmid=22910903|doi=10.1074/jbc.m112.400002|pmc=3471752}}</ref>
PDK2, in conjunction with PDK3 and PDK4, are primary targets of [[Peroxisome proliferator-activated receptor delta]] or beta, with PDK2 having two elements that respond to these receptors.<ref>{{cite journal|last1=Degenhardt|first1=T|last2=Saramäki|first2=A|last3=Malinen|first3=M|last4=Rieck|first4=M|last5=Väisänen|first5=S|last6=Huotari|first6=A|last7=Herzig|first7=KH|last8=Müller|first8=R|last9=Carlberg|first9=C|title=Three members of the human pyruvate dehydrogenase kinase gene family are direct targets of the peroxisome proliferator-activated receptor beta/delta.|journal=Journal of Molecular Biology|date=14 September 2007|volume=372|issue=2|pages=341–55|pmid=17669420|doi=10.1016/j.jmb.2007.06.091}}</ref>
 
==Clinical significance==
All of the pyruvate dehydrogenase isozymes have been associated with various metabolic disorders, including [[diabetes]]. This is due to a mechanism by which consistently elevated [[free fatty acid]] levels stimulate the PDK enzymes, particularly, PDK2 and PDK4 in the liver. In stimulating this activity, there is less PDH activity, and therefore less glucose uptake.<ref>{{cite journal|last1=Bajotto|first1=G|last2=Murakami|first2=T|last3=Nagasaki|first3=M|last4=Qin|first4=B|last5=Matsuo|first5=Y|last6=Maeda|first6=K|last7=Ohashi|first7=M|last8=Oshida|first8=Y|last9=Sato|first9=Y|last10=Shimomura|first10=Y|title=Increased expression of hepatic pyruvate dehydrogenase kinases 2 and 4 in young and middle-aged Otsuka Long-Evans Tokushima Fatty rats: induction by elevated levels of free fatty acids.|journal=Metabolism: clinical and experimental|date=March 2006|volume=55|issue=3|pages=317–23|pmid=16483874|doi=10.1016/j.metabol.2005.09.014}}</ref>
 
===Cancer===
As the PDK enzymes are associated with central metabolism and growth, they are often associated with various mechanisms of cancer progression. Enhanced PDK2 activity leads to increased [[glycolysis]] and [[lactic acid fermentation|lactic acid production]], known as the [[Warburg effect (oncology)|Warburg effect]]. In some studies, the wild-type form of tumor protein [[p53]] prevents manifestation of [[tumorigenesis]] by regulating PDK2 activity.<ref>{{cite journal|last1=Contractor|first1=T|last2=Harris|first2=CR|title=p53 negatively regulates transcription of the pyruvate dehydrogenase kinase Pdk2.|journal=Cancer Research|date=15 January 2012|volume=72|issue=2|pages=560–7|pmid=22123926|doi=10.1158/0008-5472.can-11-1215}}</ref>
Additionally, inhibition of PDK2 subsequently inhibits [[HIF1A]] in cancer cells by both a prolyl-hydroxylase (PHD)-dependent mechanism and a PHD-independent mechanism. Therefore, mitochondria-targeting metabolic modulators increase [[pyruvate dehydrogenase]] activity, and suppress [[angiogenesis]] as well, normalizing the pseudo-hypoxic signals that lead to normoxic HIF1A activation in [[solid tumors]].<ref>{{cite journal|last1=Sutendra|first1=G|last2=Dromparis|first2=P|last3=Kinnaird|first3=A|last4=Stenson|first4=TH|last5=Haromy|first5=A|last6=Parker|first6=JM|last7=McMurtry|first7=MS|last8=Michelakis|first8=ED|title=Mitochondrial activation by inhibition of PDKII suppresses HIF1a signaling and angiogenesis in cancer.|journal=Oncogene|date=28 March 2013|volume=32|issue=13|pages=1638–50|pmid=22614004|doi=10.1038/onc.2012.198}}</ref>


==References==
==References==
{{reflist|2}}
{{reflist}}
==Further reading==
 
== Further reading ==
{{refbegin | 2}}
{{refbegin | 2}}
{{PBB_Further_reading
* {{cite journal | vauthors = Sugden MC, Holness MJ | title = Recent advances in mechanisms regulating glucose oxidation at the level of the pyruvate dehydrogenase complex by PDKs | journal = American Journal of Physiology. Endocrinology and Metabolism | volume = 284 | issue = 5 | pages = E855–62 | date = May 2003 | pmid = 12676647 | doi = 10.1152/ajpendo.00526.2002 }}
| citations =
* {{cite journal | vauthors = Kobayashi T, Cohen P | title = Activation of serum- and glucocorticoid-regulated protein kinase by agonists that activate phosphatidylinositide 3-kinase is mediated by 3-phosphoinositide-dependent protein kinase-1 (PDK1) and PDK2 | journal = The Biochemical Journal | volume = 339 | issue = 2 | pages = 319–28 | date = Apr 1999 | pmid = 10191262 | pmc = 1220160 | doi = 10.1042/0264-6021:3390319 }}
*{{cite journal | author=Sugden MC, Holness MJ |title=Recent advances in mechanisms regulating glucose oxidation at the level of the pyruvate dehydrogenase complex by PDKs. |journal=Am. J. Physiol. Endocrinol. Metab. |volume=284 |issue= 5 |pages= E855-62 |year= 2003 |pmid= 12676647 |doi= 10.1152/ajpendo.00526.2002 }}
* {{cite journal | vauthors = Gold MR, Scheid MP, Santos L, Dang-Lawson M, Roth RA, Matsuuchi L, Duronio V, Krebs DL | title = The B cell antigen receptor activates the Akt (protein kinase B)/glycogen synthase kinase-3 signaling pathway via phosphatidylinositol 3-kinase | journal = Journal of Immunology | volume = 163 | issue = 4 | pages = 1894–905 | date = Aug 1999 | pmid = 10438924 | doi =  }}
*{{cite journal | author=Gudi R, Bowker-Kinley MM, Kedishvili NY, ''et al.'' |title=Diversity of the pyruvate dehydrogenase kinase gene family in humans. |journal=J. Biol. Chem. |volume=270 |issue= 48 |pages= 28989-94 |year= 1996 |pmid= 7499431 |doi=  }}
* {{cite journal | vauthors = Baker JC, Yan X, Peng T, Kasten S, Roche TE | title = Marked differences between two isoforms of human pyruvate dehydrogenase kinase | journal = The Journal of Biological Chemistry | volume = 275 | issue = 21 | pages = 15773–81 | date = May 2000 | pmid = 10748134 | doi = 10.1074/jbc.M909488199 }}
*{{cite journal  | author=Kobayashi T, Cohen P |title=Activation of serum- and glucocorticoid-regulated protein kinase by agonists that activate phosphatidylinositide 3-kinase is mediated by 3-phosphoinositide-dependent protein kinase-1 (PDK1) and PDK2. |journal=Biochem. J. |volume=339 ( Pt 2) |issue= |pages= 319-28 |year= 1999 |pmid= 10191262 |doi= }}
* {{cite journal | vauthors = Steussy CN, Popov KM, Bowker-Kinley MM, Sloan RB, Harris RA, Hamilton JA | title = Structure of pyruvate dehydrogenase kinase. Novel folding pattern for a serine protein kinase | journal = The Journal of Biological Chemistry | volume = 276 | issue = 40 | pages = 37443–50 | date = Oct 2001 | pmid = 11483605 | pmc = 2147663 | doi = 10.1074/jbc.M104285200 }}
*{{cite journal | author=Gold MR, Scheid MP, Santos L, ''et al.'' |title=The B cell antigen receptor activates the Akt (protein kinase B)/glycogen synthase kinase-3 signaling pathway via phosphatidylinositol 3-kinase. |journal=J. Immunol. |volume=163 |issue= 4 |pages= 1894-905 |year= 1999 |pmid= 10438924 |doi=  }}
* {{cite journal | vauthors = Kolobova E, Tuganova A, Boulatnikov I, Popov KM | title = Regulation of pyruvate dehydrogenase activity through phosphorylation at multiple sites | journal = The Biochemical Journal | volume = 358 | issue = Pt 1 | pages = 69–77 | date = Aug 2001 | pmid = 11485553 | pmc = 1222033 | doi = 10.1042/0264-6021:3580069 }}
*{{cite journal | author=Baker JC, Yan X, Peng T, ''et al.'' |title=Marked differences between two isoforms of human pyruvate dehydrogenase kinase. |journal=J. Biol. Chem. |volume=275 |issue= 21 |pages= 15773-81 |year= 2000 |pmid= 10748134 |doi= 10.1074/jbc.M909488199 }}
* {{cite journal | vauthors = Korotchkina LG, Patel MS | title = Site specificity of four pyruvate dehydrogenase kinase isoenzymes toward the three phosphorylation sites of human pyruvate dehydrogenase | journal = The Journal of Biological Chemistry | volume = 276 | issue = 40 | pages = 37223–9 | date = Oct 2001 | pmid = 11486000 | doi = 10.1074/jbc.M103069200 }}
*{{cite journal | author=Steussy CN, Popov KM, Bowker-Kinley MM, ''et al.'' |title=Structure of pyruvate dehydrogenase kinase. Novel folding pattern for a serine protein kinase. |journal=J. Biol. Chem. |volume=276 |issue= 40 |pages= 37443-50 |year= 2001 |pmid= 11483605 |doi= 10.1074/jbc.M104285200 }}
* {{cite journal | vauthors = Peters SJ, Harris RA, Wu P, Pehleman TL, Heigenhauser GJ, Spriet LL | title = Human skeletal muscle PDH kinase activity and isoform expression during a 3-day high-fat/low-carbohydrate diet | journal = American Journal of Physiology. Endocrinology and Metabolism | volume = 281 | issue = 6 | pages = E1151–8 | date = Dec 2001 | pmid = 11701428 | doi = 10.1152/ajpendo.2001.281.6.e1151 }}
*{{cite journal | author=Kolobova E, Tuganova A, Boulatnikov I, Popov KM |title=Regulation of pyruvate dehydrogenase activity through phosphorylation at multiple sites. |journal=Biochem. J. |volume=358 |issue= Pt 1 |pages= 69-77 |year= 2001 |pmid= 11485553 |doi= }}
* {{cite journal | vauthors = Tuganova A, Boulatnikov I, Popov KM | title = Interaction between the individual isoenzymes of pyruvate dehydrogenase kinase and the inner lipoyl-bearing domain of transacetylase component of pyruvate dehydrogenase complex | journal = The Biochemical Journal | volume = 366 | issue = Pt 1 | pages = 129–36 | date = Aug 2002 | pmid = 11978179 | pmc = 1222743 | doi = 10.1042/BJ20020301 }}
*{{cite journal | author=Korotchkina LG, Patel MS |title=Site specificity of four pyruvate dehydrogenase kinase isoenzymes toward the three phosphorylation sites of human pyruvate dehydrogenase. |journal=J. Biol. Chem. |volume=276 |issue= 40 |pages= 37223-9 |year= 2001 |pmid= 11486000 |doi= 10.1074/jbc.M103069200 }}
* {{cite journal | vauthors = Boulatnikov I, Popov KM | title = Formation of functional heterodimers by isozymes 1 and 2 of pyruvate dehydrogenase kinase | journal = Biochimica et Biophysica Acta | volume = 1645 | issue = 2 | pages = 183–92 | date = Feb 2003 | pmid = 12573248 | doi = 10.1016/S1570-9639(02)00542-3 }}
*{{cite journal | author=Peters SJ, Harris RA, Wu P, ''et al.'' |title=Human skeletal muscle PDH kinase activity and isoform expression during a 3-day high-fat/low-carbohydrate diet. |journal=Am. J. Physiol. Endocrinol. Metab. |volume=281 |issue= 6 |pages= E1151-8 |year= 2002 |pmid= 11701428 |doi= }}
* {{cite journal | vauthors = Hiromasa Y, Roche TE | title = Facilitated interaction between the pyruvate dehydrogenase kinase isoform 2 and the dihydrolipoyl acetyltransferase | journal = The Journal of Biological Chemistry | volume = 278 | issue = 36 | pages = 33681–93 | date = Sep 2003 | pmid = 12816949 | doi = 10.1074/jbc.M212733200 }}
*{{cite journal | author=Tuganova A, Boulatnikov I, Popov KM |title=Interaction between the individual isoenzymes of pyruvate dehydrogenase kinase and the inner lipoyl-bearing domain of transacetylase component of pyruvate dehydrogenase complex. |journal=Biochem. J. |volume=366 |issue= Pt 1 |pages= 129-36 |year= 2002 |pmid= 11978179 |doi= 10.1042/BJ20020301 }}
* {{cite journal | vauthors = Watt MJ, Heigenhauser GJ, LeBlanc PJ, Inglis JG, Spriet LL, Peters SJ | title = Rapid upregulation of pyruvate dehydrogenase kinase activity in human skeletal muscle during prolonged exercise | journal = Journal of Applied Physiology | volume = 97 | issue = 4 | pages = 1261–7 | date = Oct 2004 | pmid = 15169745 | doi = 10.1152/japplphysiol.00132.2004 }}
*{{cite journal | author=Strausberg RL, Feingold EA, Grouse LH, ''et al.'' |title=Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 26 |pages= 16899-903 |year= 2003 |pmid= 12477932 |doi= 10.1073/pnas.242603899 }}
* {{cite journal | vauthors = Bao H, Kasten SA, Yan X, Roche TE | title = Pyruvate dehydrogenase kinase isoform 2 activity limited and further inhibited by slowing down the rate of dissociation of ADP | journal = Biochemistry | volume = 43 | issue = 42 | pages = 13432–41 | date = Oct 2004 | pmid = 15491150 | doi = 10.1021/bi049488x }}
*{{cite journal  | author=Boulatnikov I, Popov KM |title=Formation of functional heterodimers by isozymes 1 and 2 of pyruvate dehydrogenase kinase. |journal=Biochim. Biophys. Acta |volume=1645 |issue= 2 |pages= 183-92 |year= 2003 |pmid= 12573248 |doi= }}
* {{cite journal | vauthors = Bao H, Kasten SA, Yan X, Hiromasa Y, Roche TE | title = Pyruvate dehydrogenase kinase isoform 2 activity stimulated by speeding up the rate of dissociation of ADP | journal = Biochemistry | volume = 43 | issue = 42 | pages = 13442–51 | date = Oct 2004 | pmid = 15491151 | doi = 10.1021/bi0494875 }}
*{{cite journal | author=Hiromasa Y, Roche TE |title=Facilitated interaction between the pyruvate dehydrogenase kinase isoform 2 and the dihydrolipoyl acetyltransferase. |journal=J. Biol. Chem. |volume=278 |issue= 36 |pages= 33681-93 |year= 2003 |pmid= 12816949 |doi= 10.1074/jbc.M212733200 }}
* {{cite journal | vauthors = Abbot EL, McCormack JG, Reynet C, Hassall DG, Buchan KW, Yeaman SJ | title = Diverging regulation of pyruvate dehydrogenase kinase isoform gene expression in cultured human muscle cells | journal = The FEBS Journal | volume = 272 | issue = 12 | pages = 3004–14 | date = Jun 2005 | pmid = 15955060 | doi = 10.1111/j.1742-4658.2005.04713.x }}
*{{cite journal | author=Ota T, Suzuki Y, Nishikawa T, ''et al.'' |title=Complete sequencing and characterization of 21,243 full-length human cDNAs. |journal=Nat. Genet. |volume=36 |issue= 1 |pages= 40-5 |year= 2004 |pmid= 14702039 |doi= 10.1038/ng1285 }}
*{{cite journal  | author=Watt MJ, Heigenhauser GJ, LeBlanc PJ, ''et al.'' |title=Rapid upregulation of pyruvate dehydrogenase kinase activity in human skeletal muscle during prolonged exercise. |journal=J. Appl. Physiol. |volume=97 |issue= 4 |pages= 1261-7 |year= 2005 |pmid= 15169745 |doi= 10.1152/japplphysiol.00132.2004 }}
*{{cite journal | author=Gerhard DS, Wagner L, Feingold EA, ''et al.'' |title=The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). |journal=Genome Res. |volume=14 |issue= 10B |pages= 2121-7 |year= 2004 |pmid= 15489334 |doi= 10.1101/gr.2596504 }}
*{{cite journal  | author=Bao H, Kasten SA, Yan X, Roche TE |title=Pyruvate dehydrogenase kinase isoform 2 activity limited and further inhibited by slowing down the rate of dissociation of ADP. |journal=Biochemistry |volume=43 |issue= 42 |pages= 13432-41 |year= 2004 |pmid= 15491150 |doi= 10.1021/bi049488x }}
*{{cite journal | author=Bao H, Kasten SA, Yan X, ''et al.'' |title=Pyruvate dehydrogenase kinase isoform 2 activity stimulated by speeding up the rate of dissociation of ADP. |journal=Biochemistry |volume=43 |issue= 42 |pages= 13442-51 |year= 2004 |pmid= 15491151 |doi= 10.1021/bi0494875 }}
*{{cite journal | author=Abbot EL, McCormack JG, Reynet C, ''et al.'' |title=Diverging regulation of pyruvate dehydrogenase kinase isoform gene expression in cultured human muscle cells. |journal=FEBS J. |volume=272 |issue= 12 |pages= 3004-14 |year= 2005 |pmid= 15955060 |doi= 10.1111/j.1742-4658.2005.04713.x }}
}}
{{refend}}
{{refend}}


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[[Category:EC 2.7.11]]

Latest revision as of 14:23, 28 September 2018

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External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
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UniProt

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Pyruvate dehydrogenase kinase isoform 2 (PDK2) also known as pyruvate dehydrogenase lipoamide kinase isozyme 2, mitochondrial is an enzyme that in humans is encoded by the PDK2 gene.[1][2] PDK2 is an isozyme of pyruvate dehydrogenase kinase.

Structure

The protein encoded by the PDK2 gene has two sites, an active site and an allosteric site that allow for the activity and regulation of this enzyme. There are many structural motifs that are important to the regulation of this enzyme. Nov3r and AZ12 inhibitors bind at the lipoamide binding site that is located at one end of the R domain. Pfz3 binds in an extended site at the other end of the R domain. One inhibitor, dicholoroacetate (DCA), binds at the center of the R domain.[3] Within the active site, there are three amino acid residues, R250, T302, and Y320, that make the kinase resistant to the inhibitor dichloroacetate, which uncouples the active site from the allosteric site. This supports the theory that R250, T302, and Y320 stabilize the "open" and "closed" conformations of the built-in lid that controls the access of a nucleotide into the nucleotide-binding cavity. This strongly suggests that the mobility of ATP lid is central to the allosteric regulation of PDHK2 activity serving as a conformational switch required for communication between the active site and allosteric sites in the kinase molecule.[4] There is also a DW-motif that is crucial in mediating DCA, nucleotide, and lipoyl domain binding site communication. This network is responsible for rendering PDK2 locked in the closed, or inactive conformation.[5]

Function

The Pyruvate Dehydrogenase (PDH) complex must be tightly regulated due to its central role in general metabolism. Within the complex, there are three serine residues on the E1 component that are sites for phosphorylation; this phosphorylation inactivates the complex. In humans, there have been four isozymes of Pyruvate Dehydrogenase Kinase that have been shown to phosphorylate these three sites: PDK1, PDK2, PDK3, and PDK4.[6] PDK2 has been identified as the most abundant isoform in human tissues. Through many studies, it has been made clear that the activity of this enzyme is essential, even at rest, to regulate glycolysis/carbodydrate oxidation and producing metabolites for oxidative phosphorylation and the electron transport chain. These studies have illustrated that the kinetics of the PDK isoform population, specifically PDK2, is more important in determining PDH activity than measuring PDK activity.[7]

Regulation

As the primary regulators of a crucial step in the central metabolic pathway, the pyruvate dehydrogenase family is tightly regulated itself by a myriad of factors. PDK2 activity is modulated by low levels of hydrogen peroxide; this happens because the compound temporarily oxidizes the cysteine residues 45 and 392 on the enzyme, resulting in an inactive PDK2 and greater PDH activity. These conditions also inactivate the TCA cycle, the next step in aerobic respiration. This alludes to the fact that when there is a high level of O2 production in the mitochondria, which may occur because of nutrient excess, the increase in the products serve as a negative feedback that control mitochondria metabolism.[8] PDK2, in conjunction with PDK3 and PDK4, are primary targets of Peroxisome proliferator-activated receptor delta or beta, with PDK2 having two elements that respond to these receptors.[9]

Clinical significance

All of the pyruvate dehydrogenase isozymes have been associated with various metabolic disorders, including diabetes. This is due to a mechanism by which consistently elevated free fatty acid levels stimulate the PDK enzymes, particularly, PDK2 and PDK4 in the liver. In stimulating this activity, there is less PDH activity, and therefore less glucose uptake.[10]

Cancer

As the PDK enzymes are associated with central metabolism and growth, they are often associated with various mechanisms of cancer progression. Enhanced PDK2 activity leads to increased glycolysis and lactic acid production, known as the Warburg effect. In some studies, the wild-type form of tumor protein p53 prevents manifestation of tumorigenesis by regulating PDK2 activity.[11] Additionally, inhibition of PDK2 subsequently inhibits HIF1A in cancer cells by both a prolyl-hydroxylase (PHD)-dependent mechanism and a PHD-independent mechanism. Therefore, mitochondria-targeting metabolic modulators increase pyruvate dehydrogenase activity, and suppress angiogenesis as well, normalizing the pseudo-hypoxic signals that lead to normoxic HIF1A activation in solid tumors.[12]

References

  1. ↑ Gudi R, Bowker-Kinley MM, Kedishvili NY, Zhao Y, Popov KM (Dec 1995). "Diversity of the pyruvate dehydrogenase kinase gene family in humans". The Journal of Biological Chemistry. 270 (48): 28989–94. doi:10.1074/jbc.270.48.28989. PMID 7499431.
  2. ↑ "Entrez Gene: PDK2 pyruvate dehydrogenase kinase, isozyme 2".
  3. ↑ Knoechel TR, Tucker AD, Robinson CM, Phillips C, Taylor W, Bungay PJ, Kasten SA, Roche TE, Brown DG (Jan 2006). "Regulatory roles of the N-terminal domain based on crystal structures of human pyruvate dehydrogenase kinase 2 containing physiological and synthetic ligands". Biochemistry. 45 (2): 402–15. doi:10.1021/bi051402s. PMID 16401071.
  4. ↑ Klyuyeva A, Tuganova A, Popov KM (Aug 2008). "Allosteric coupling in pyruvate dehydrogenase kinase 2". Biochemistry. 47 (32): 8358–66. doi:10.1021/bi800631h. PMC 2568900. PMID 18627174.
  5. ↑ Li J, Kato M, Chuang DT (Dec 2009). "Pivotal role of the C-terminal DW-motif in mediating inhibition of pyruvate dehydrogenase kinase 2 by dichloroacetate". The Journal of Biological Chemistry. 284 (49): 34458–67. doi:10.1074/jbc.M109.065557. PMC 2797213. PMID 19833728.
  6. ↑ Kolobova E, Tuganova A, Boulatnikov I, Popov KM (Aug 2001). "Regulation of pyruvate dehydrogenase activity through phosphorylation at multiple sites". The Biochemical Journal. 358 (Pt 1): 69–77. doi:10.1042/0264-6021:3580069. PMC 1222033. PMID 11485553.
  7. ↑ Dunford EC, Herbst EA, Jeoung NH, Gittings W, Inglis JG, Vandenboom R, LeBlanc PJ, Harris RA, Peters SJ (Jun 2011). "PDH activation during in vitro muscle contractions in PDH kinase 2 knockout mice: effect of PDH kinase 1 compensation". American Journal of Physiology. Regulatory, Integrative and Comparative Physiology. 300 (6): R1487–93. doi:10.1152/ajpregu.00498.2010. PMID 21411764.
  8. ↑ Hurd, TR; Collins, Y; Abakumova, I; Chouchani, ET; Baranowski, B; Fearnley, IM; Prime, TA; Murphy, MP; James, AM (12 October 2012). "Inactivation of pyruvate dehydrogenase kinase 2 by mitochondrial reactive oxygen species". The Journal of Biological Chemistry. 287 (42): 35153–60. doi:10.1074/jbc.m112.400002. PMC 3471752. PMID 22910903.
  9. ↑ Degenhardt, T; Saramäki, A; Malinen, M; Rieck, M; Väisänen, S; Huotari, A; Herzig, KH; Müller, R; Carlberg, C (14 September 2007). "Three members of the human pyruvate dehydrogenase kinase gene family are direct targets of the peroxisome proliferator-activated receptor beta/delta". Journal of Molecular Biology. 372 (2): 341–55. doi:10.1016/j.jmb.2007.06.091. PMID 17669420.
  10. ↑ Bajotto, G; Murakami, T; Nagasaki, M; Qin, B; Matsuo, Y; Maeda, K; Ohashi, M; Oshida, Y; Sato, Y; Shimomura, Y (March 2006). "Increased expression of hepatic pyruvate dehydrogenase kinases 2 and 4 in young and middle-aged Otsuka Long-Evans Tokushima Fatty rats: induction by elevated levels of free fatty acids". Metabolism: clinical and experimental. 55 (3): 317–23. doi:10.1016/j.metabol.2005.09.014. PMID 16483874.
  11. ↑ Contractor, T; Harris, CR (15 January 2012). "p53 negatively regulates transcription of the pyruvate dehydrogenase kinase Pdk2". Cancer Research. 72 (2): 560–7. doi:10.1158/0008-5472.can-11-1215. PMID 22123926.
  12. ↑ Sutendra, G; Dromparis, P; Kinnaird, A; Stenson, TH; Haromy, A; Parker, JM; McMurtry, MS; Michelakis, ED (28 March 2013). "Mitochondrial activation by inhibition of PDKII suppresses HIF1a signaling and angiogenesis in cancer". Oncogene. 32 (13): 1638–50. doi:10.1038/onc.2012.198. PMID 22614004.

Further reading

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