AktのKDドメインのThr残基をリン酸化する (Shiojima et. al.,2008)

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/09/02 20:55:18」(JST)

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Pyruvate dehydrogenase lipoamide kinase isozyme 1, mitochondrial is an enzyme that in humans is encoded by the PDK1 gene.^[1]^[2] It codes for an isozyme of pyruvate dehydrogenase kinase (PDK).

Pyruvate dehydrogenase (PDH) is a part of a mitochondrial multienzyme complex that catalyzes the oxidative decarboxylation of pyruvate and is one of the major enzymes responsible for the regulation of homeostasis of carbohydrate fuels in mammals. The enzymatic activity is regulated by a phosphorylation/dephosphorylation cycle. Phosphorylation of PDH by a specific pyruvate dehydrogenase kinase (PDK) results in inactivation.^[2]

Structure

The mature protein encoded by the PDK4 gene contains 407 amino acids in its sequence. To form the active protein, two of the polypeptide chains come together to form an open conformation.^[2] The catalytic domain of PDK1 might exist separately in cells and important for the regulation of the PDK1 substrate. The crystal structural studies suggest that the PIF-pocked is located at the catalytic domain as well.^[3]

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. PDK1 is the only enzyme capable of phosphorylating the 3rd serine site. When the TPP coenzyme is bound, the rates of phosphorylation by all four isozymes are drastically affected; specifically, the incorporation of phosphate groups by PDK1 into sites 2 and 3 is significantly reduced.^[4]

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. PDK activity has been shown to decrease in individuals consuming a diet that is high in n-3 fatty acids; however, PDH activity remained unaffected.^[5] Additionally, PDK1 is inihibited by AZD7545 and dichloroacetic acid; the mechanism was discovered to be the trifluoromethylpropanamide end of AZD7545 projecting into the lipoyl-binding pocket of PDK1. Dichloroacetic acid was found near the helix bundle in the N-terminal domain of PDK1. Bound DCA promotes local conformational changes that are communicated to both nucleotide-binding and lipoyl-binding pockets of PDK1, leading to the inactivation of kinase activity.^[6]

Clinical Significance

PDK1 is relevant in a variety of clinical conditions throughout the body. As PDK1 regulates the PDH complex, it has been proven to be an important regulator in certain cells, including the beta cells within the islets of the pancreas. In order to optimize Glucose-stimulated insulin secretion (GSIS), a primary function of the pancreas, a low PDK1 activity must be maintained to keep PDH in a dephosphorylated and active state.^[7] Maintaining low PDK1 levels has also proven to be beneficial in certain regions of the brain, as it confers a high tolerance to amyloid beta, a metabolite that is directly correlated with the development of Alzheimer’s disease.^[8] PDK1, in conjunction with PDK2, has been identified as a causative agent of autosomal dominant polycystic kidney disease. The disease has an incidence rate of 1:0000, and most patients with the disorder, around 85%, have a mutation in the PDK1 gene.

Cancer

The ubiquitous role of this gene lends itself to being involved in a variety of disease pathologies, including cancer. PDK1 mRNA expression is significantly associated with tumor progression; in fact, the presence of PDK1 can serve as a prognostic marker, indicating the level of success a patient can achieve. Specifically, this may serve as a biomarker in patients with gastric cancer. In coordination, the inhibitor dichloroacetic acid may be used in the future as a treatment option for patients with this type of cancer.^[9] PDK1, as it regulates hypoxia and lactate production, is associated with a poor outcome in patients with head and neck squamous cancer.^[10]^[11] The buildup of glycolytic metabolites may promote Hypoxia-Inducing Factor (HIF) activation, which creates a feed-forward loop for malignancy progression. As such, using HIF-1 as a metabolite to regulate PDK1 is seen as another potential therapy, either on its own or in tandem with other therapies, for this type of cancer.^[12]^[13] In a further developed study, combined PDK1 and CHK1 inhibition was shown to be required to kill glioblastoma stem-like cells in vitro and in vivo.^[14]

References

^ Gudi R, Bowker-Kinley MM, Kedishvili NY, Zhao Y, Popov KM (Jan 1996). "Diversity of the pyruvate dehydrogenase kinase gene family in humans". J Biol Chem 270 (48): 28989–94. doi:10.1074/jbc.270.48.28989. PMID 7499431.
^ ^a ^b ^c "Entrez Gene: PDK1 pyruvate dehydrogenase kinase, isozyme 1".
^ Park J, Li Y, Kim SH, Kong G, Shrestha R, Tran Q, Hong J, Hur GM, Hemmings BA, Koo BS, Park J (Nov 2013). "Characterization of fragmented 3-phosphoinsitide-dependent protein kinase-1 (PDK1) by phosphosite-specific antibodies". Life Sciences 93 (18-19): 700–6. doi:10.1016/j.lfs.2013.09.007. PMID 24044887.
^ 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. PMID 11485553.
^ Turvey EA, Heigenhauser GJ, Parolin M, Peters SJ (Jan 2005). "Elevated n-3 fatty acids in a high-fat diet attenuate the increase in PDH kinase activity but not PDH activity in human skeletal muscle". Journal of Applied Physiology 98 (1): 350–5. doi:10.1152/japplphysiol.00604.2005. PMID 15591305.
^ Kato M, Li J, Chuang JL, Chuang DT (Aug 2007). "Distinct structural mechanisms for inhibition of pyruvate dehydrogenase kinase isoforms by AZD7545, dichloroacetate, and radicicol". Structure 15 (8): 992–1004. doi:10.1016/j.str.2007.07.001. PMID 17683942.
^ Krus U, Kotova O, Spégel P, Hallgard E, Sharoyko VV, Vedin A, Moritz T, Sugden MC, Koeck T, Mulder H (Jul 2010). "Pyruvate dehydrogenase kinase 1 controls mitochondrial metabolism and insulin secretion in INS-1 832/13 clonal beta-cells". The Biochemical Journal 429 (1): 205–13. doi:10.1042/BJ20100142. PMID 20415663.
^ Newington JT, Rappon T, Albers S, Wong DY, Rylett RJ, Cumming RC (Oct 2012). "Overexpression of pyruvate dehydrogenase kinase 1 and lactate dehydrogenase A in nerve cells confers resistance to amyloid β and other toxins by decreasing mitochondrial respiration and reactive oxygen species production". The Journal of Biological Chemistry 287 (44): 37245–58. doi:10.1074/jbc.M112.366195. PMID 22948140.
^ Hur H, Xuan Y, Kim YB, Lee G, Shim W, Yun J, Ham IH, Han SU (Jan 2013). "Expression of pyruvate dehydrogenase kinase-1 in gastric cancer as a potential therapeutic target". International Journal of Oncology 42 (1): 44–54. doi:10.3892/ijo.2012.1687. PMID 23135628.
^ Wigfield SM, Winter SC, Giatromanolaki A, Taylor J, Koukourakis ML, Harris AL (Jun 2008). "PDK-1 regulates lactate production in hypoxia and is associated with poor prognosis in head and neck squamous cancer". British Journal of Cancer 98 (12): 1975–84. doi:10.1038/sj.bjc.6604356. PMID 18542064.
^ Hitosugi T, Fan J, Chung TW, Lythgoe K, Wang X, Xie J, Ge Q, Gu TL, Polakiewicz RD, Roesel JL, Chen GZ, Boggon TJ, Lonial S, Fu H, Khuri FR, Kang S, Chen J (Dec 2011). "Tyrosine phosphorylation of mitochondrial pyruvate dehydrogenase kinase 1 is important for cancer metabolism". Molecular Cell 44 (6): 864–77. doi:10.1016/j.molcel.2011.10.015. PMID 22195962.
^ Kim JW, Tchernyshyov I, Semenza GL, Dang CV (Mar 2006). "HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia". Cell Metabolism 3 (3): 177–85. doi:10.1016/j.cmet.2006.02.002. PMID 16517405.
^ McFate T, Mohyeldin A, Lu H, Thakar J, Henriques J, Halim ND, Wu H, Schell MJ, Tsang TM, Teahan O, Zhou S, Califano JA, Jeoung NH, Harris RA, Verma A (Aug 2008). "Pyruvate dehydrogenase complex activity controls metabolic and malignant phenotype in cancer cells". The Journal of Biological Chemistry 283 (33): 22700–8. doi:10.1074/jbc.M801765200. PMID 18541534.
^ Signore M, Pelacchi F, di Martino S, Runci D, Biffoni M, Giannetti S, Morgante L, De Majo M, Petricoin EF, Stancato L, Larocca LM, De Maria R, Pallini R, Ricci-Vitiani L (8 May 2014). "Combined PDK1 and CHK1 inhibition is required to kill glioblastoma stem-like cells in vitro and in vivo". Cell Death & Disease 5: e1223. doi:10.1038/cddis.2014.188. PMID 24810059.

UpToDate Contents

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1. T細胞受容体シグナル伝達 t cell receptor signaling

English Journal

Inhibition of constitutive Akt (PKB) phosphorylation by docosahexaenoic acid in the human breast cancer cell line MDA-MB-453.

Sato SB, Park J, Kawamoto J, Sato S, Kurihara T.SourceResearch Center for Low Temperature and Materials Sciences, Kyoto University, Kyoto, 606-8501, Japan. Electronic address: sbsato@ltm.kyoto-u.ac.jp.
Biochimica et biophysica acta.Biochim Biophys Acta.2013 Feb;1831(2):306-13. doi: 10.1016/j.bbalip.2012.10.004. Epub 2012 Oct 23.
Many breast cancer cells express aberrantly activated receptor tyrosine kinases and are associated with deregulated phosphorylation of Akt (PKB). They are also often associated with a high level of free monounsaturated (MUFA) and saturated (SFA) fatty acids. We studied the effect of DHA and other po
PMID 23085420

1-42 β-Amyloid peptide requires PDK1/nPKC/Rac 1 pathway to induce neuronal death.

Manterola L, Hernando-Rodríguez M, Ruiz A, Apraiz A, Arrizabalaga O, Vellón L, Alberdi E, Cavaliere F, Lacerda HM, Jimenez S, Parada LA, Matute C, Zugaza JL.SourceBiodonostia Institute, Hospital Donostia, P Doctor Begiristain, Donostia, Spain.
Translational psychiatry.Transl Psychiatry.2013 Jan 22;3:e219. doi: 10.1038/tp.2012.147.
1-42 β-Amyloid (Aβ(1-42)) peptide is a key molecule involved in the development of Alzheimer's disease. Some of its effects are manifested at the neuronal morphological level. These morphological changes involve loss of neurites due to cytoskeleton alterations. However, the mechanism of Aβ(1-42)
PMID 23340502

Japanese Journal

Cardioprotective Effects of 3-Phosphoinositide-Dependent Protein Kinase-1 on Hypoxic Injury in Cultured Neonatal Rat Cardiomyocytes and Myocardium in a Rat Myocardial Infarct Model

SHIM Tae-Jin,BAE Jang-Whan,KIM Yeon-Jung [他],KIM Dae Joong,HWANG Kyung-Kuk,KIM Dong-Woon,CHO Myeong-Chan
Bioscience, biotechnology, and biochemistry 76(1), 101-107, 2012-01-23
… 3-Phosphoinositide-dependent protein kinase-1 (PDK1) is involved in numerous cellular responses. … In this study, we investigated the protective effects of PDK1 gene expression against hypoxic conditions in cultured rat CMCs (rCMCs) and in a rat myocardial infarction (MI) model using the lentiviral vector (LeV) system. …
NAID 10030398626

Akt kinase-interacting protein1, a novel therapeutic target for lung cancer with EGFR-activating and gatekeeper mutations

Yamada Tadaaki,Takeuchi Shinji,Fujita Naoya,Nakamura Akito,Wang Wei,Li Qi,Oda Makoto,Mitsudomi Tetsuya,Yatabe Yasushi,Sekido Yoshitaka,Yoshida Junji,Higashiyama Masahiko,Noguchi Masayuki,Uehara Hisanori,Nishioka Yasuhiko,Sone Saburo,Yano Seiji
Oncogene xx(xx), xxxx-xxxx, 2012-00-00
… Here, we focused on Akt kinase-interacting protein1 (Aki1), a scaffold protein of PI3K (phosphoinositide 3-kinase)/PDK1 (3-phosphoinositide-dependent protein kinase)/Akt that determines receptor signal selectivity for non-mutated EGFR, and assessed its role in EGFR mutant lung cancer with or without gatekeeper T790M mutation. …
NAID 120004997024

Clionosterol and Ethyl Cholestan-22-enol Isolated from the Rhizome of Polygala tenuifolia Inhibit Phosphatidylinositol 3-Kinase/Akt Pathway

Le Thi Kim Van,Jeong Jin Ju,Kim Dong-Hyun
Biological and Pharmaceutical Bulletin 35(8), 1379-1383, 2012
… These constituents (1) and (2) inhibited the activation of 3-phosphoinositide-dependent kinase 1 (PDK1) and its downstream molecules, Akt/glycogen synthase kinase (GSK)3β, in PI3K/Akt cell survival signaling pathway, but did not suppress the activation of PI3K. … Based on these finding, (1) and (2) may abolish the cytoprotective phenotype of Tat-transduced CHME5 cells by inhibiting PDK1 phosphorylation in PI3K/Akt pathway. …
NAID 130001872156

Related Pictures

★リンクテーブル★

リンク元	「受容体チロシンキナーゼ」「Akt」
関連記事	「PD」「PDK」

「受容体チロシンキナーゼ」

Pyruvate dehydrogenase kinase, isozyme 1
	Rendering based on PDB 2Q8F.
Available structures
PDB	Ortholog search: PDBe, RCSB
List of PDB id codes
	2Q8F, 2Q8G, 2Q8H
Identifiers
Symbol	PDK1
External IDs	OMIM: 602524 MGI: 1926119 HomoloGene: 134437 ChEMBL: 4766 GeneCards: PDK1 Gene
EC number	2.7.11.2
Gene ontology
Molecular function	• protein kinase activity; • pyruvate dehydrogenase (acetyl-transferring) kinase activity; • protein binding; • ATP binding;
Cellular component	• mitochondrion; • mitochondrial matrix; • mitochondrial pyruvate dehydrogenase complex;
Biological process	• glucose metabolic process; • pyruvate metabolic process; • protein phosphorylation; • cell proliferation; • intrinsic apoptotic signaling pathway in response to oxidative stress; • regulation of acetyl-CoA biosynthetic process from pyruvate; • regulation of glucose metabolic process; • cellular metabolic process; • small molecule metabolic process; • hypoxia-inducible factor-1alpha signaling pathway; • activation of mitophagy in response to mitochondrial depolarization;
	Sources: Amigo / QuickGO
RNA expression pattern
	More reference expression data
Orthologs
	v; t; e;