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PEPCK-M

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Synonyms

EC 4.1.1.32; Phosphoenolpyruvate carboxykinase 2 (mitochondrial); PEPCK2; PCK2; Mitochondrial PEPCK

Historical Background

The mitochondrial isoform of phosphoenolpyruvate carboxykinase (PEPCK-M) catalyzes the cataplerotic reaction utilizing mitochondrial GTP (mtGTP) to convert oxaloacetate to phosphoenolpyruvate (PEP), GDP, and CO2 in the mitochondrial matrix. Because of its dependence on mtGTP and since mitochondria lack a GTP transporter, mitochondrial PEP synthesis is enzymatically coupled to the GTP-specific isoform of succinyl-CoA synthetase reaction as a source of GTP. In pancreatic beta-cells, this reaction generates a second messenger coupled to insulin secretion (Stark et al. 2009). In the liver and possibly kidney, the mitochondrial PEP is used for gluconeogenesis and glyceroneogenesis (Stark et al. 2014). This chapter will focus on the mammalian mitochondrial isoform and its relationship to maintaining metabolic homeostasis through the secretion of insulin, the...

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References

  • Agca C, Greenfield RB, Hartwell JR, Donkin SS. Cloning and characterization of bovine cytosolic and mitochondrial PEPCK during transition to lactation. Physiol Genomics. 2002;11(2):53–63.

    Article  CAS  PubMed  Google Scholar 

  • Aich S, Delbaere LT. Phylogenetic study of the evolution of PEP-carboxykinase. Evol Bioinformatics Online. 2007;3:333–40.

    CAS  Google Scholar 

  • Allen A, Kwagh J, Fang J, Stanley CA, Smith TJ. Evolution of glutamate dehydrogenase regulation of insulin homeostasis is an example of molecular exaptation. Biochemistry. 2004;43(45):14431–43.

    Article  CAS  PubMed  Google Scholar 

  • Beale EG, Chrapkiewicz NB, Scoble HA, Metz RJ, Quick DP, Noble RL, et al. Rat hepatic cytosolic phosphoenolpyruvate carboxykinase (GTP). Structures of the protein, messenger RNA, and gene. J Biol Chem. 1985;260(19):10748–60.

    CAS  PubMed  Google Scholar 

  • Beale EG, Harvey BJ, Forest C. PCK1 and PCK2 as candidate diabetes and obesity genes. Cell Biochem Biophys. 2007;48(2–3):89–95.

    Article  CAS  PubMed  Google Scholar 

  • Burgess SC, He T, Yan Z, Lindner J, Sherry AD, Malloy CR, et al. Cytosolic phosphoenolpyruvate carboxykinase does not solely control the rate of hepatic gluconeogenesis in the intact mouse liver. Cell Metab. 2007;5(4):313–20.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Carlson GM, Holyoak T. Structural insights into the mechanism of phosphoenolpyruvate carboxykinase catalysis. J Biol Chem. 2009;284(40):27037–41.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Caro P, Kishan AU, Norberg E, Stanley IA, Chapuy B, Ficarro SB, et al. Metabolic signatures uncover distinct targets in molecular subsets of diffuse large B cell lymphoma. Cancer Cell. 2012;22(4):547–60.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Chen CY, Sato Y, Schramm VL. Isotope trapping and positional isotope exchange with rat and chicken liver phosphoenolpyruvate carboxykinases. Biochemistry. 1991;30(17):4143–51.

    Article  CAS  PubMed  Google Scholar 

  • Chen WW, Freinkman E, Wang T, Birsoy K, Sabatini DM. Absolute quantification of matrix metabolites reveals the dynamics of mitochondrial metabolism. Cell. 2016;166(5):1324–37 .e11

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Dunten P, Belunis C, Crowther R, Hollfelder K, Kammlott U, Levin W, et al. Crystal structure of human cytosolic phosphoenolpyruvate carboxykinase reveals a new GTP-binding site. J Mol Biol. 2002;316(2):257–64.

    Article  CAS  PubMed  Google Scholar 

  • Hanson RW, Patel YM. Phosphoenolpyruvate carboxykinase (GTP): the gene and the enzyme. Adv Enzymol Relat Areas Mol Biol. 1994;69:203–81.

    PubMed  CAS  Google Scholar 

  • Hebda CA, Nowak T. The purification, characterization, and activation of phosphoenolpyruvate carboxykinase from chicken liver mitochondria. J Biol Chem. 1982;257(10):5503–14.

    PubMed  CAS  Google Scholar 

  • Hedeskov CJ, Capito K. Pancreatic islet metabolism of pyruvate and other potentiators of insulin release. Effects of starvation. Horm Metab Res Suppl. 1980;Suppl 10:8–13.

    PubMed  CAS  Google Scholar 

  • Hedeskov CJ, Capito K, Thams P. Phosphoenolpyruvate carboxykinase in mouse pancreatic islets. ATP-induced changes in sensitivity to Mn2+ activation. Biochim Biophys Acta. 1984;791(1):37–44.

    Article  CAS  PubMed  Google Scholar 

  • Ishihara N, Kikuchi G. Studies on the functional relationship between the phosphopyruvate synthesis and the substrate level phosphorylation in guinea-pig liver mitochondria. Biochim Biophys Acta. 1968;153(4):733–48.

    Article  CAS  PubMed  Google Scholar 

  • Jamison RA, Stark R, Dong J, Yonemitsu S, Zhang D, Shulman GI, et al. Hyperglucagonemia precedes a decline in insulin secretion and causes hyperglycemia in chronically glucose-infused rats. Am J Physiol Endocrinol Metab. 2011;301(6):E1174–83.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Jiang W, Wang S, Xiao M, Lin Y, Zhou L, Lei Q, et al. Acetylation regulates gluconeogenesis by promoting PEPCK1 degradation via recruiting the UBR5 ubiquitin ligase. Mol Cell. 2011;43(1):33–44.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Jones DH, Raymer DM, Schoelen SL. The activity of phosphoenolpyruvate carboxykinase throughout the lactation cycle of the guinea pig mammary gland. Proc Soc Exp Biol Med. 1989;192(1):16–22.

    Article  CAS  PubMed  Google Scholar 

  • Kibbey RG, Pongratz RL, Romanelli AJ, Wollheim CB, Cline GW, Shulman GI. Mitochondrial GTP regulates glucose-stimulated insulin secretion. Cell Metab. 2007;5(4):253–64.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Leithner K, Wohlkoenig C, Stacher E, Lindenmann J, Hofmann NA, Galle B, et al. Hypoxia increases membrane metallo-endopeptidase expression in a novel lung cancer ex vivo model – role of tumor stroma cells. BMC Cancer. 2014;14:40.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Leonard JV, Hyland K, Furukawa N, Clayton PT. Mitochondrial phosphoenolpyruvate carboxykinase deficiency. Eur J Pediatr. 1991;150(3):198–9.

    Article  CAS  PubMed  Google Scholar 

  • Lin YY, Lu JY, Zhang J, Walter W, Dang W, Wan J, et al. Protein acetylation microarray reveals that NuA4 controls key metabolic target regulating gluconeogenesis. Cell. 2009;136(6):1073–84.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • MacDonald MJ, Chang CM. Do pancreatic islets contain significant amounts of phosphoenolpyruvate carboxykinase or ferroactivator activity? Diabetes. 1985;34(3):246–50.

    Article  CAS  PubMed  Google Scholar 

  • MacDonald MJ, McKenzie DI, Walker TM, Kaysen JH. Lack of glyconeogenesis in pancreatic islets: expression of gluconeogenic enzyme genes in islets. Horm Metab Res. 1992;24(4):158–60.

    Article  CAS  PubMed  Google Scholar 

  • McKee EE, Bentley AT, Smith Jr RM, Ciaccio CE. Origin of guanine nucleotides in isolated heart mitochondria. Biochem Biophys Res Commun. 1999;257(2):466–72.

    Article  CAS  PubMed  Google Scholar 

  • McKee EE, Bentley AT, Smith Jr RM, Kraas JR, Ciaccio CE. Guanine nucleotide transport by atractyloside-sensitive and -insensitive carriers in isolated heart mitochondria. Am J Physiol Cell Physiol. 2000;279(6):C1870–9.

    Article  CAS  PubMed  Google Scholar 

  • Mendez-Lucas A, Hyrossova P, Novellasdemunt L, Vinals F, Perales JC. Mitochondrial phosphoenolpyruvate carboxykinase (PEPCK-M) is a pro-survival, endoplasmic reticulum (ER) stress response gene involved in tumor cell adaptation to nutrient availability. J Biol Chem. 2014;289(32):22090–102.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Modaressi S, Brechtel K, Christ B, Jungermann K. Human mitochondrial phosphoenolpyruvate carboxykinase 2 gene. Structure, chromosomal localization and tissue-specific expression. Biochem J. 1998;333(Pt 2):359–66.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Samuel VT, Beddow SA, Iwasaki T, Zhang XM, Chu X, Still CD, et al. Fasting hyperglycemia is not associated with increased expression of PEPCK or G6Pc in patients with Type 2 Diabetes. Proc Natl Acad Sci U S A. 2009;106(29):12121–6.

    Article  PubMed  PubMed Central  Google Scholar 

  • Siess EA, Brocks DG, Lattke HK, Wieland OH. Effect of glucagon on metabolite compartmentation in isolated rat liver cells during gluconeogenesis from lactate. Biochem J. 1977;166(2):225–35.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Stark R, Kibbey RG. The mitochondrial isoform of phosphoenolpyruvate carboxykinase (PEPCK-M) and glucose homeostasis: has it been overlooked? Biochim Biophys Acta. 2014;1840:1313–30.

    Article  CAS  PubMed  Google Scholar 

  • Stark R, Pasquel F, Turcu A, Pongratz RL, Roden M, Cline GW, et al. Phosphoenolpyruvate cycling via mitochondrial phosphoenolpyruvate carboxykinase links anaplerosis and mitochondrial GTP with insulin secretion. J Biol Chem. 2009;284(39):26578–90.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Stark R, Guebre-Egziabher F, Zhao X, Feriod C, Dong J, Alves TC, et al. A role for mitochondrial phosphoenolpyruvate carboxykinase (PEPCK-M) in the regulation of hepatic gluconeogenesis. J Biol Chem. 2014;289(11):7257–63.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Suzuki M, Yamasaki T, Shinohata R, Hata M, Nakajima H, Kono N. Cloning and reporter analysis of human mitochondrial phosphoenolpyruvate carboxykinase gene promoter. Gene. 2004;338(2):157–62.

    Article  CAS  PubMed  Google Scholar 

  • Utter MF, Kurahashi K. Purification of oxalacetic carboxylase from chicken liver. J Biol Chem. 1954;207(2):787–802.

    PubMed  CAS  Google Scholar 

  • Vozza A, Blanco E, Palmieri L, Palmieri F. Identification of the mitochondrial GTP/GDP transporter in Saccharomyces cerevisiae. J Biol Chem. 2004;279(20):20850–7.

    Article  CAS  PubMed  Google Scholar 

  • Watt WB, Hudson RR, Wang B, Wang E. A genetic polymorphism evolving in parallel in two cell compartments and in two clades. BMC Evol Biol. 2013;13:9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Wood HG, Werkman CH. The utilization of CO(2) by the propionic acid bacteria. Biochem J. 1938;32(7):1262–71.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Xiong Y, Lei QY, Zhao S, Guan KL. Regulation of glycolysis and gluconeogenesis by acetylation of PKM and PEPCK. Cold Spring Harb Symp Quant Biol. 2011;76:285–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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Correspondence to Richard G. Kibbey .

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Kibbey, R.G. (2018). PEPCK-M. In: Choi, S. (eds) Encyclopedia of Signaling Molecules. Springer, Cham. https://doi.org/10.1007/978-3-319-67199-4_101756

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