Pyruvate dehydrogenase phosphatase explained

Pyruvate dehydrogenase phosphatase catalytic subunit 1 (PDPC 1), also known as protein phosphatase 2C, is an enzyme that in humans is encoded by the PDP1 gene.^{[1] [2]} PDPC 1 is an enzyme which serves to reverse the effects of pyruvate dehydrogenase kinase upon pyruvate dehydrogenase, activating pyruvate dehydrogenase.

Function

Pyruvate dehydrogenase (E1) is one of the three components (E1, E2, and E3) of the large pyruvate dehydrogenase complex. Pyruvate dehydrogenase kinases catalyze phosphorylation of serine residues of E1 to inactivate the E1 component and inhibit the complex. Pyruvate dehydrogenase phosphatases catalyze the dephosphorylation and activation of the E1 component to reverse the effects of pyruvate dehydrogenase kinases.

Pyruvate dehydrogenase phosphatase is a heterodimer consisting of catalytic and regulatory subunits. Two catalytic subunits have been reported; one is predominantly expressed in skeletal muscle, and another one is much more abundant in the liver. The catalytic subunit, encoded by this gene, is the former, and belongs to the protein phosphatase 2C (PP2C) superfamily. Along with the pyruvate dehydrogenase complex and pyruvate dehydrogenase kinases, this enzyme is located in the mitochondrial matrix.

Regulation

Pyruvate dehydrogenase phosphatase is stimulated by insulin, PEP, and AMP, but competitively inhibited by ATP, NADH, and Acetyl-CoA.

Clinical significance

Mutation in the PDP1 gene causes pyruvate dehydrogenase phosphatase deficiency.^[1]

Further reading

• Piccinini M, Mostert M, Alberto G, Ramondetti C, Novi RF, Dalmasso P, Rinaudo MT . Down-regulation of pyruvate dehydrogenase phosphatase in obese subjects is a defect that signals insulin resistance . Obesity Research . 13 . 4 . 678–86 . Apr 2005 . 15897476 . 10.1038/oby.2005.76 . free .
• Kimura K, Wakamatsu A, Suzuki Y, Ota T, Nishikawa T, Yamashita R, Yamamoto J, Sekine M, Tsuritani K, Wakaguri H, Ishii S, Sugiyama T, Saito K, Isono Y, Irie R, Kushida N, Yoneyama T, Otsuka R, Kanda K, Yokoi T, Kondo H, Wagatsuma M, Murakawa K, Ishida S, Ishibashi T, Takahashi-Fujii A, Tanase T, Nagai K, Kikuchi H, Nakai K, Isogai T, Sugano S . Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes . Genome Research . 16 . 1 . 55–65 . Jan 2006 . 16344560 . 1356129 . 10.1101/gr.4039406 .
• Hu RM, Han ZG, Song HD, Peng YD, Huang QH, Ren SX, Gu YJ, Huang CH, Li YB, Jiang CL, Fu G, Zhang QH, Gu BW, Dai M, Mao YF, Gao GF, Rong R, Ye M, Zhou J, Xu SH, Gu J, Shi JX, Jin WR, Zhang CK, Wu TM, Huang GY, Chen Z, Chen MD, Chen JL . Gene expression profiling in the human hypothalamus-pituitary-adrenal axis and full-length cDNA cloning . Proceedings of the National Academy of Sciences of the United States of America . 97 . 17 . 9543–8 . Aug 2000 . 10931946 . 16901 . 10.1073/pnas.160270997 . 2000PNAS...97.9543H . free .
• Auffray C, Behar G, Bois F, Bouchier C, Da Silva C, Devignes MD, Duprat S, Houlgatte R, Jumeau MN, Lamy B . [IMAGE: molecular integration of the analysis of the human genome and its expression] . Comptes Rendus de l'Académie des Sciences, Série III . 318 . 2 . 263–72 . Feb 1995 . 7757816 .
• Lejeune F, Li X, Maquat LE . Nonsense-mediated mRNA decay in mammalian cells involves decapping, deadenylating, and exonucleolytic activities . Molecular Cell . 12 . 3 . 675–87 . Sep 2003 . 14527413 . 10.1016/S1097-2765(03)00349-6 . free .
• Cameron JM, Maj M, Levandovskiy V, Barnett CP, Blaser S, Mackay N, Raiman J, Feigenbaum A, Schulze A, Robinson BH . Pyruvate dehydrogenase phosphatase 1 (PDP1) null mutation produces a lethal infantile phenotype . Human Genetics . 125 . 3 . 319–26 . Apr 2009 . 19184109 . 10.1007/s00439-009-0629-6 . 20251714 .
• Maj MC, MacKay N, Levandovskiy V, Addis J, Baumgartner ER, Baumgartner MR, Robinson BH, Cameron JM . Pyruvate dehydrogenase phosphatase deficiency: identification of the first mutation in two brothers and restoration of activity by protein complementation . The Journal of Clinical Endocrinology and Metabolism . 90 . 7 . 4101–7 . Jul 2005 . 15855260 . 10.1210/jc.2005-0123 . free .
• Sugden MC, Holness MJ . Recent advances in mechanisms regulating glucose oxidation at the level of the pyruvate dehydrogenase complex by PDKs . American Journal of Physiology. Endocrinology and Metabolism . 284 . 5 . E855-62 . May 2003 . 12676647 . 10.1152/ajpendo.00526.2002 .
• Kato J, Kato M . Crystallization and preliminary crystallographic studies of the catalytic subunits of human pyruvate dehydrogenase phosphatase isoforms 1 and 2 . Acta Crystallographica Section F . 66 . Pt 3 . 342–5 . Mar 2010 . 20208177 . 2833053 . 10.1107/S1744309110003131 .
• Korotchkina LG, Patel MS . Mutagenesis studies of the phosphorylation sites of recombinant human pyruvate dehydrogenase. Site-specific regulation . The Journal of Biological Chemistry . 270 . 24 . 14297–304 . Jun 1995 . 7782287 . 10.1074/jbc.270.24.14297 . free .
• Stellingwerff T, Spriet LL, Watt MJ, Kimber NE, Hargreaves M, Hawley JA, Burke LM . Decreased PDH activation and glycogenolysis during exercise following fat adaptation with carbohydrate restoration . American Journal of Physiology. Endocrinology and Metabolism . 290 . 2 . E380-8 . Feb 2006 . 16188909 . 10.1152/ajpendo.00268.2005 .
• Ito M, Kobashi H, Naito E, Saijo T, Takeda E, Huq AH, Kuroda Y . Decrease of pyruvate dehydrogenase phosphatase activity in patients with congenital lactic acidemia . Clinica Chimica Acta; International Journal of Clinical Chemistry . 209 . 1–2 . 1–7 . Jul 1992 . 1327585 . 10.1016/0009-8981(92)90327-M .
• Adams MD, Kerlavage AR, Fleischmann RD, Fuldner RA, Bult CJ, Lee NH, Kirkness EF, Weinstock KG, Gocayne JD, White O . Initial assessment of human gene diversity and expression patterns based upon 83 million nucleotides of cDNA sequence . Nature . 377 . 6547 Suppl . 3–174 . Sep 1995 . 7566098 .
• Caruso M, Maitan MA, Bifulco G, Miele C, Vigliotta G, Oriente F, Formisano P, Beguinot F . Activation and mitochondrial translocation of protein kinase Cdelta are necessary for insulin stimulation of pyruvate dehydrogenase complex activity in muscle and liver cells . The Journal of Biological Chemistry . 276 . 48 . 45088–97 . Nov 2001 . 11577086 . 10.1074/jbc.M105451200 . free .
• Bonaldo MF, Lennon G, Soares MB . Normalization and subtraction: two approaches to facilitate gene discovery . Genome Research . 6 . 9 . 791–806 . Sep 1996 . 8889548 . 10.1101/gr.6.9.791 . free .
• Huang B, Gudi R, Wu P, Harris RA, Hamilton J, Popov KM . Isoenzymes of pyruvate dehydrogenase phosphatase. DNA-derived amino acid sequences, expression, and regulation . The Journal of Biological Chemistry . 273 . 28 . 17680–8 . Jul 1998 . 9651365 . 10.1074/jbc.273.28.17680 . free .

Notes and References

1. Web site: Entrez Gene: pyruvate dehydrogenase phosphatase catalytic subunit 1.
2. Lawson JE, Niu XD, Browning KS, Trong HL, Yan J, Reed LJ . Molecular cloning and expression of the catalytic subunit of bovine pyruvate dehydrogenase phosphatase and sequence similarity with protein phosphatase 2C . Biochemistry . 32 . 35 . 8987–93 . Sep 1993 . 8396421 . 10.1021/bi00086a002 .