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Crystal structure of human cytosolic phosphoenolpyruvate carboxykinase reveals a new GTP-binding site.

Dunten P, Belunis C, Crowther R, Hollfelder K, Kammlott U, Levin W, Michel H, Ramsey GB, Swain A, Weber D, Wertheimer SJ
J Mol Biol 316 257-64 (2002)
Related entries: 1khb, 1khe, 1khf

Cited: 42 times
EuropePMC logo PMID: 11851336

Abstract

We report crystal structures of the human enzyme phosphoenolpyruvate carboxykinase (PEPCK) with and without bound substrates. These structures are the first to be determined for a GTP-dependent PEPCK, and provide the first view of a novel GTP-binding site unique to the GTP-dependent PEPCK family. Three phenylalanine residues form the walls of the guanine-binding pocket on the enzyme's surface and, most surprisingly, one of the phenylalanine side-chains contributes to the enzyme's specificity for GTP. PEPCK catalyzes the rate-limiting step in the metabolic pathway that produces glucose from lactate and other precursors derived from the citric acid cycle. Because the gluconeogenic pathway contributes to the fasting hyperglycemia of type II diabetes, inhibitors of PEPCK may be useful in the treatment of diabetes.

Articles - 1khg mentioned but not cited (4)

  1. c.A2456C-substitution in Pck1 changes the enzyme kinetic and functional properties modifying fat distribution in pigs. Latorre P, Burgos C, Hidalgo J, Varona L, Carrodeguas JA, López-Buesa P. Sci Rep 6 19617 (2016)
  2. Mixed Inhibition of cPEPCK by Genistein, Using an Extended Binding Site Located Adjacent to Its Catalytic Cleft. Katiyar SP, Jain A, Dhanjal JK, Sundar D. PLoS One 10 e0141987 (2015)
  3. Characterization of interaction and ubiquitination of phosphoenolpyruvate carboxykinase by E3 ligase UBR5. Shen Q, Qiu Z, Wu W, Zheng J, Jia Z. Biol Open 7 bio037366 (2018)
  4. Computational evaluation of natural compounds as potential inhibitors of human PEPCK-M: an alternative for lung cancer therapy. Baptista LPR, Sinatti VV, Da Silva JH, Dardenne LE, Guimarães AC. Adv Appl Bioinform Chem 12 15-32 (2019)


Reviews citing this publication (6)

  1. The PEP-pyruvate-oxaloacetate node as the switch point for carbon flux distribution in bacteria. Sauer U, Eikmanns BJ. FEMS Microbiol Rev 29 765-794 (2005)
  2. Regulation and roles of phosphoenolpyruvate carboxykinase in plants. Leegood RC, Walker RP. Arch Biochem Biophys 414 204-210 (2003)
  3. The mitochondrial isoform of phosphoenolpyruvate carboxykinase (PEPCK-M) and glucose homeostasis: has it been overlooked? Stark R, Kibbey RG. Biochim Biophys Acta 1840 1313-1330 (2014)
  4. Structural insights into the mechanism of phosphoenolpyruvate carboxykinase catalysis. Carlson GM, Holyoak T. J Biol Chem 284 27037-27041 (2009)
  5. Emerging chemical tools and techniques for tracking biological manganese. Das S, Khatua K, Rakshit A, Carmona A, Sarkar A, Bakthavatsalam S, Ortega R, Datta A. Dalton Trans 48 7047-7061 (2019)
  6. PCK1 dysregulation in cancer: Metabolic reprogramming, oncogenic activation, and therapeutic opportunities. Xiang J, Wang K, Tang N. Genes Dis 10 101-112 (2023)

Articles citing this publication (32)

  1. Enzymes with lid-gated active sites must operate by an induced fit mechanism instead of conformational selection. Sullivan SM, Holyoak T. Proc Natl Acad Sci U S A 105 13829-13834 (2008)
  2. Metabolic reprogramming by PCK1 promotes TCA cataplerosis, oxidative stress and apoptosis in liver cancer cells and suppresses hepatocellular carcinoma. Liu MX, Jin L, Sun SJ, Liu P, Feng X, Cheng ZL, Liu WR, Guan KL, Shi YH, Yuan HX, Xiong Y. Oncogene 37 1637-1653 (2018)
  3. The GTPase activity and C-terminal cysteine of the Escherichia coli MnmE protein are essential for its tRNA modifying function. Yim L, Martínez-Vicente M, Villarroya M, Aguado C, Knecht E, Armengod ME. J Biol Chem 278 28378-28387 (2003)
  4. First characterization of an archaeal GTP-dependent phosphoenolpyruvate carboxykinase from the hyperthermophilic archaeon Thermococcus kodakaraensis KOD1. Fukuda W, Fukui T, Atomi H, Imanaka T. J Bacteriol 186 4620-4627 (2004)
  5. Nucleotide selectivity of antibiotic kinases. Shakya T, Wright GD. Antimicrob Agents Chemother 54 1909-1913 (2010)
  6. research-article Thematic minireview series: a perspective on the biology of phosphoenolpyruvate carboxykinase 55 years after its discovery. Hanson RW. J Biol Chem 284 27021-27023 (2009)
  7. A putative Alzheimer's disease risk allele in PCK1 influences brain atrophy in multiple sclerosis. Xia Z, Chibnik LB, Glanz BI, Liguori M, Shulman JM, Tran D, Khoury SJ, Chitnis T, Holyoak T, Weiner HL, Guttmann CR, De Jager PL. PLoS One 5 e14169 (2010)
  8. Expression, purification, and characterization of a bacterial GTP-dependent PEP carboxykinase. Aich S, Imabayashi F, Delbaere LT. Protein Expr Purif 31 298-304 (2003)
  9. Evaluation by site-directed mutagenesis of active site amino acid residues of Anaerobiospirillum succiniciproducens phosphoenolpyruvate carboxykinase. Jabalquinto AM, Laivenieks M, González-Nilo FD, Yévenes A, Encinas MV, Zeikus JG, Cardemil E. J Protein Chem 21 393-400 (2002)
  10. Increasing the conformational entropy of the Omega-loop lid domain in phosphoenolpyruvate carboxykinase impairs catalysis and decreases catalytic fidelity . Johnson TA, Holyoak T. Biochemistry 49 5176-5187 (2010)
  11. Tyr235 of human cytosolic phosphoenolpyruvate carboxykinase influences catalysis through an anion-quadrupole interaction with phosphoenolpyruvate carboxylate. Dharmarajan L, Case CL, Dunten P, Mukhopadhyay B. FEBS J 275 5810-5819 (2008)
  12. Phylogenetic study of the evolution of PEP-carboxykinase. Aich S, Delbaere LT. Evol Bioinform Online 3 333-340 (2007)
  13. Phylogenic and phosphorylation regulation difference of phosphoenolpyruvate carboxykinase of C3 and C4 plants. Shen Z, Dong XM, Gao ZF, Chao Q, Wang BC. J Plant Physiol 213 16-22 (2017)
  14. Saccharomyces cerevisiae phosphoenolpyruvate carboxykinase: relevance of arginine 70 for catalysis. Cristina Ravanal M, Flores M, Pérez E, Aroca F, Cardemil E. Biochimie 86 357-362 (2004)
  15. X-ray structures of two xanthine inhibitors bound to PEPCK and N-3 modifications of substituted 1,8-dibenzylxanthines. Foley LH, Wang P, Dunten P, Ramsey G, Gubler ML, Wertheimer SJ. Bioorg Med Chem Lett 13 3871-3874 (2003)
  16. Electrostatic interactions play a significant role in the affinity of Saccharomyces cerevisiae phosphoenolpyruvate carboxykinase for Mn2+. Sepúlveda C, Poch A, Espinoza R, Cardemil E. Biochimie 92 814-819 (2010)
  17. Ligand interactions and protein conformational changes of phosphopyridoxyl-labeled Escherichia coli phosphoenolpyruvate carboxykinase determined by fluorescence spectroscopy. Encinas MV, González-Nilo FD, Goldie H, Cardemil E. Eur J Biochem 269 4960-4968 (2002)
  18. Role of cysteine 306 in the catalytic mechanism of Ascaris suum phosphoenolpyruvate carboxykinase. Ríos SE, Nowak T. Arch Biochem Biophys 404 25-37 (2002)
  19. Site-directed mutagenesis study of the microenvironment characteristics of Lys213 of Saccharomyces cerevisiae phosphoenolpyruvate carboxykinase. Yévenes A, Espinoza R, Rivas-Pardo JA, Villarreal JM, González-Nilo FD, Cardemil E. Biochimie 88 663-672 (2006)
  20. Substrate binding to fluorescent labeled wild type, Lys213Arg, and HIS233Gln Saccharomyces cerevisiae phosphoenolpyruvate carboxykinases. Bueno C, González-Nilo FD, Victoria Encinas M, Cardemil E. Int J Biochem Cell Biol 36 861-869 (2004)
  21. Phosphoenolpyruvate carboxykinase 1 gene (Pck1) displays parallel evolution between Old World and New World fruit bats. Zhu L, Yin Q, Irwin DM, Zhang S. PLoS One 10 e0118666 (2015)
  22. Structural and functional studies of phosphoenolpyruvate carboxykinase from Mycobacterium tuberculosis. Machová I, Snášel J, Dostál J, Brynda J, Fanfrlík J, Singh M, Tarábek J, Vaněk O, Bednárová L, Pichová I. PLoS One 10 e0120682 (2015)
  23. Structural comparisons of phosphoenolpyruvate carboxykinases reveal the evolutionary trajectories of these phosphodiester energy conversion enzymes. Chiba Y, Miyakawa T, Shimane Y, Takai K, Tanokura M, Nozaki T. J Biol Chem 294 19269-19278 (2019)
  24. C-8 Modifications of 3-alkyl-1,8-dibenzylxanthines as inhibitors of human cytosolic phosphoenolpyruvate carboxykinase. Pietranico SL, Foley LH, Huby N, Yun W, Dunten P, Vermeulen J, Wang P, Toth K, Ramsey G, Gubler ML, Wertheimer SJ. Bioorg Med Chem Lett 17 3835-3839 (2007)
  25. Dynamic behavior of rat phosphoenolpyruvate carboxykinase inhibitors: new mechanism for enzyme inhibition. Dayer MR, Dayer MS, Ghayour O. Protein J 32 253-258 (2013)
  26. Relevance of Arg457 for the nucleotide affinity of Saccharomyces cerevisiae phosphoenolpyruvate carboxykinase. Tobar I, González-Nilo FD, Jabalquinto AM, Cardemil E. Int J Biochem Cell Biol 40 1883-1889 (2008)
  27. Relevance of phenylalanine 216 in the affinity of Saccharomyces cerevisiae phosphoenolpyruvate carboxykinase for Mn(II). Yévenes A, González-Nilo FD, Cardemil E. Protein J 26 135-141 (2007)
  28. Thermal stability of phosphoenolpyruvate carboxykinases from Escherichia coli, Trypanosoma brucei, and Saccharomyces cerevisiae. Ravanal MC, Goldie H, Cardemil E. J Protein Chem 22 311-315 (2003)
  29. Anaerobiospirillum succiniciproducens phosphoenolpyruvate carboxykinase. Mutagenesis at metal site 1. Jabalquinto AM, González-Nilo FD, Laivenieks M, Cabezas M, Zeikus JG, Cardemil E. Biochimie 86 47-51 (2004)
  30. Anaerobiospirillum succiniciproducens phosphoenolpyruvate carboxykinase: mutagenesis at metal site 2. Jabalquinto AM, Laivenieks M, González-Nilo FD, Encinas MV, Zeikus G, Cardemil E. J Protein Chem 22 515-519 (2003)
  31. Stereochemistry of the carboxylation reaction catalyzed by the ATP-dependent phosphoenolpyruvate carboxykinases from Saccharomyces cerevisiae and Anaerobiospirillum succiniciproducens. Pérez E, Espinoza R, Laiveniekcs M, Cardemil E. Biochimie 90 1685-1692 (2008)
  32. Saccharomyces cerevisiae phosphoenolpyruvate carboxykinase: the relevance of Glu299 and Leu460 for nucleotide binding. Pérez E, Cardemil E. Protein J 29 299-305 (2010)


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