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Crystal structure of human cytosolic 5'-nucleotidase II: insights into allosteric regulation and substrate recognition.

Walldén K, Stenmark P, Nyman T, Flodin S, Gräslund S, Loppnau P, Bianchi V, Nordlund P
J Biol Chem 282 17828-36 (2007)
Related entries: 2cn1, 2j2c, 2jcm, 2jga

Cited: 40 times
EuropePMC logo PMID: 17405878

Abstract

Cytosolic 5'-nucleotidase II catalyzes the dephosphorylation of 6-hydroxypurine nucleoside 5'-monophosphates and regulates the IMP and GMP pools within the cell. It possesses phosphotransferase activity and thereby also catalyzes the reverse reaction. Both reactions are allosterically activated by adenine-based nucleotides and 2,3-bisphosphoglycerate. We have solved structures of cytosolic 5'-nucleotidase II as native protein (2.2 Angstrom) and in complex with adenosine (1.5 Angstrom) and beryllium trifluoride (2.15 Angstrom) The tetrameric enzyme is structurally similar to enzymes of the haloacid dehalogenase (HAD) superfamily, including mitochondrial 5'(3')-deoxyribonucleotidase and cytosolic 5'-nucleotidase III but possesses additional regulatory regions that contain two allosteric effector sites. At effector site 1 located near a subunit interface we modeled diadenosine tetraphosphate with one adenosine moiety in each subunit. This efficiently glues the tetramer subunits together in pairs. The model shows why diadenosine tetraphosphate but not diadenosine triphosphate activates the enzyme and supports a role for cN-II during apoptosis when the level of diadenosine tetraphosphate increases. We have also modeled 2,3-bisphosphoglycerate in effector site 1 using one phosphate site from each subunit. By comparing the structure of cytosolic 5'-nucleotidase II with that of mitochondrial 5'(3')-deoxyribonucleotidase in complex with dGMP, we identified residues involved in substrate recognition.

Articles - 2jc9 mentioned but not cited (4)

  1. Structural insights into the inhibition of cytosolic 5'-nucleotidase II (cN-II) by ribonucleoside 5'-monophosphate analogues. Gallier F, Lallemand P, Meurillon M, Jordheim LP, Dumontet C, Périgaud C, Lionne C, Peyrottes S, Chaloin L. PLoS Comput Biol 7 e1002295 (2011)
  2. Ranolazine may exert its beneficial effects by increasing myocardial adenosine levels. Le DE, Davis CM, Wei K, Zhao Y, Cao Z, Nugent M, Scott KLL, Liu L, Nagarajan S, Alkayed NJ, Kaul S. Am J Physiol Heart Circ Physiol 318 H189-H202 (2020)
  3. The dipeptidyl peptidase IV inhibitors vildagliptin and K-579 inhibit a phospholipase C: a case of promiscuous scaffolds in proteins. Chakraborty S, Rendón-Ramírez A, Ásgeirsson B, Dutta M, Ghosh AS, Oda M, Venkatramani R, Rao BJ, Dandekar AM, Goñi FM. F1000Res 2 286 (2013)
  4. Bioactive Compounds in Garlic (Allium sativum) and Black Garlic as Antigout Agents, Using Computer Simulation. Lestari AR, Batubara I, Wahyudi ST, Ilmiawati A, Achmadi SS. Life (Basel) 12 1131 (2022)


Reviews citing this publication (5)

  1. Therapeutic potentials of ecto-nucleoside triphosphate diphosphohydrolase, ecto-nucleotide pyrophosphatase/phosphodiesterase, ecto-5'-nucleotidase, and alkaline phosphatase inhibitors. al-Rashida M, Iqbal J. Med Res Rev 34 703-743 (2014)
  2. Structural genomics and drug discovery: all in the family. Weigelt J, McBroom-Cerajewski LD, Schapira M, Zhao Y, Arrowsmith CH. Curr Opin Chem Biol 12 32-39 (2008)
  3. Genetics and mechanisms of NT5C2-driven chemotherapy resistance in relapsed ALL. Dieck CL, Ferrando A. Blood 133 2263-2268 (2019)
  4. Can one target T-cell ALL? Ferrando A. Best Pract Res Clin Haematol 31 361-366 (2018)
  5. Expanding the clinical relevance of the 5'-nucleotidase cN-II/NT5C2. Jordheim LP. Purinergic Signal 14 321-329 (2018)

Articles citing this publication (31)

  1. Relapse-specific mutations in NT5C2 in childhood acute lymphoblastic leukemia. Meyer JA, Wang J, Hogan LE, Yang JJ, Dandekar S, Patel JP, Tang Z, Zumbo P, Li S, Zavadil J, Levine RL, Cardozo T, Hunger SP, Raetz EA, Evans WE, Morrison DJ, Mason CE, Carroll WL. Nat Genet 45 290-294 (2013)
  2. Gemcitabine and cytosine arabinoside cytotoxicity: association with lymphoblastoid cell expression. Li L, Fridley B, Kalari K, Jenkins G, Batzler A, Safgren S, Hildebrandt M, Ames M, Schaid D, Wang L. Cancer Res 68 7050-7058 (2008)
  3. ASD v2.0: updated content and novel features focusing on allosteric regulation. Huang Z, Mou L, Shen Q, Lu S, Li C, Liu X, Wang G, Li S, Geng L, Liu Y, Wu J, Chen G, Zhang J. Nucleic Acids Res 42 D510-6 (2014)
  4. Structural basis for the allosteric regulation and substrate recognition of human cytosolic 5'-nucleotidase II. Walldén K, Nordlund P. J Mol Biol 408 684-696 (2011)
  5. Intracellular cytarabine triphosphate production correlates to deoxycytidine kinase/cytosolic 5'-nucleotidase II expression ratio in primary acute myeloid leukemia cells. Yamauchi T, Negoro E, Kishi S, Takagi K, Yoshida A, Urasaki Y, Iwasaki H, Ueda T. Biochem Pharmacol 77 1780-1786 (2009)
  6. NT5DC2 promotes tumor cell proliferation by stabilizing EGFR in hepatocellular carcinoma. Li KS, Zhu XD, Liu HD, Zhang SZ, Li XL, Xiao N, Liu XF, Xu B, Lei M, Zhang YY, Shi WK, Cao MQ, Xu YF, Tang ZY, Sun HC. Cell Death Dis 11 335 (2020)
  7. Structure and Mechanisms of NT5C2 Mutations Driving Thiopurine Resistance in Relapsed Lymphoblastic Leukemia. Dieck CL, Tzoneva G, Forouhar F, Carpenter Z, Ambesi-Impiombato A, Sánchez-Martín M, Kirschner-Schwabe R, Lew S, Seetharaman J, Tong L, Ferrando AA. Cancer Cell 34 136-147.e6 (2018)
  8. The TP0796 lipoprotein of Treponema pallidum is a bimetal-dependent FAD pyrophosphatase with a potential role in flavin homeostasis. Deka RK, Brautigam CA, Liu WZ, Tomchick DR, Norgard MV. J Biol Chem 288 11106-11121 (2013)
  9. Relapsed acute lymphoblastic leukemia-specific mutations in NT5C2 cluster into hotspots driving intersubunit stimulation. Hnízda A, Fábry M, Moriyama T, Pachl P, Kugler M, Brinsa V, Ascher DB, Carroll WL, Novák P, Žaliová M, Trka J, Řezáčová P, Yang JJ, Veverka V. Leukemia 32 1393-1403 (2018)
  10. Cell proliferation and drug sensitivity of human glioblastoma cells are altered by the stable modulation of cytosolic 5'-nucleotidase II. Cividini F, Cros-Perrial E, Pesi R, Machon C, Allegrini S, Camici M, Dumontet C, Jordheim LP, Tozzi MG. Int J Biochem Cell Biol 65 222-229 (2015)
  11. Identification of Drosophila and human 7-methyl GMP-specific nucleotidases. Buschmann J, Moritz B, Jeske M, Lilie H, Schierhorn A, Wahle E. J Biol Chem 288 2441-2451 (2013)
  12. Active and regulatory sites of cytosolic 5'-nucleotidase. Pesi R, Allegrini S, Careddu MG, Filoni DN, Camici M, Tozzi MG. FEBS J 277 4863-4872 (2010)
  13. Mechanisms of NT5C2-Mediated Thiopurine Resistance in Acute Lymphoblastic Leukemia. Moriyama T, Liu S, Li J, Meyer J, Zhao X, Yang W, Shao Y, Heath R, Hnízda A, Carroll WL, Yang JJ. Mol Cancer Ther 18 1887-1895 (2019)
  14. Allosteric regulation and substrate activation in cytosolic nucleotidase II from Legionella pneumophila. Srinivasan B, Forouhar F, Shukla A, Sampangi C, Kulkarni S, Abashidze M, Seetharaman J, Lew S, Mao L, Acton TB, Xiao R, Everett JK, Montelione GT, Tong L, Balaram H. FEBS J 281 1613-1628 (2014)
  15. Crystal structures of the novel cytosolic 5'-nucleotidase IIIB explain its preference for m7GMP. Monecke T, Buschmann J, Neumann P, Wahle E, Ficner R. PLoS One 9 e90915 (2014)
  16. Expression of bovine cytosolic 5'-nucleotidase (cN-II) in yeast: nucleotide pools disturbance and its consequences on growth and homologous recombination. Allegrini S, Filoni DN, Galli A, Collavoli A, Pesi R, Camici M, Tozzi MG. PLoS One 8 e63914 (2013)
  17. Backbone conformational dependence of peptide acidity. Anderson JS, Hernández G, LeMaster DM. Biophys Chem 141 124-130 (2009)
  18. The purine analog fludarabine acts as a cytosolic 5'-nucleotidase II inhibitor. Cividini F, Pesi R, Chaloin L, Allegrini S, Camici M, Cros-Perrial E, Dumontet C, Jordheim LP, Tozzi MG. Biochem Pharmacol 94 63-68 (2015)
  19. Oligomeric interface modulation causes misregulation of purine 5´-nucleotidase in relapsed leukemia. Hnízda A, Škerlová J, Fábry M, Pachl P, Šinalová M, Vrzal L, Man P, Novák P, Řezáčová P, Veverka V. BMC Biol 14 91 (2016)
  20. Cytosolic 5'-Nucleotidase II Silencing in Lung Tumor Cells Regulates Metabolism through Activation of the p53/AMPK Signaling Pathway. Pesi R, Allegrini S, Garcia-Gil M, Piazza L, Moschini R, Jordheim LP, Camici M, Tozzi MG. Int J Mol Sci 22 7004 (2021)
  21. Functional and small-angle X-ray scattering studies of a new stationary phase survival protein E (SurE) from Xylella fastidiosa--evidence of allosteric behaviour. Saraiva AM, Reis MA, Tada SF, Rosselli-Murai LK, Schneider DR, Pelloso AC, Toledo MA, Giles C, Aparicio R, de Souza AP. FEBS J 276 6751-6762 (2009)
  22. Cytosolic 5'-Nucleotidase II Is a Sensor of Energy Charge and Oxidative Stress: A Possible Function as Metabolic Regulator. Pesi R, Allegrini S, Balestri F, Garcia-Gil M, Cividini F, Colombaioni L, Jordheim LP, Camici M, Tozzi MG. Cells 10 182 (2021)
  23. Structural basis of substrate specificity and selectivity of murine cytosolic 5'-nucleotidase III. Grobosky CL, Lopez JB, Rennie S, Skopelitis DJ, Wiest AT, Bingman CA, Bitto E. J Mol Biol 423 540-554 (2012)
  24. The Legionella pneumophila effector Ceg4 is a phosphotyrosine phosphatase that attenuates activation of eukaryotic MAPK pathways. Quaile AT, Stogios PJ, Egorova O, Evdokimova E, Valleau D, Nocek B, Kompella PS, Peisajovich S, Yakunin AF, Ensminger AW, Savchenko A. J Biol Chem 293 3307-3320 (2018)
  25. Initial studies to define the physiologic role of cN-II. Filoni DN, Pesi R, Careddu MG, Camici M, Allegrini S, Collavoli A, Scarfone I, Zucchi F, Galli A, Tozzi MG. Nucleosides Nucleotides Nucleic Acids 30 1155-1160 (2011)
  26. Pharmacologic Inhibition of NT5C2 Reverses Genetic and Nongenetic Drivers of 6-MP Resistance in Acute Lymphoblastic Leukemia. Reglero C, Dieck CL, Zask A, Forouhar F, Laurent AP, Lin WW, Albero R, Miller HI, Ma C, Gastier-Foster JM, Loh ML, Tong L, Stockwell BR, Palomero T, Ferrando AA. Cancer Discov 12 2646-2665 (2022)
  27. Pyrimidine-5'-nucleotidase Campinas, a new mutation (p.R56G) in the NT5C3 gene associated with pyrimidine-5'-nucleotidase type I deficiency and influence of Gilbert's Syndrome on clinical expression. Santos Ad, Dantas LE, Traina F, Albuquerque DM, Chaim EA, Saad ST. Blood Cells Mol Dis 53 246-252 (2014)
  28. A rare mutation (p.F149del) of the NT5C3A gene is associated with pyrimidine 5'-nucleotidase deficiency. Bogusławska DM, Skulski M, Bartoszewski R, Machnicka B, Heger E, Kuliczkowski K, Sikorski AF. Cell Mol Biol Lett 27 104 (2022)
  29. Conformationally constrained nucleoside phosphonic acids--potent inhibitors of human mitochondrial and cytosolic 5'(3')-nucleotidases. Šimák O, Pachl P, Fábry M, Buděšínský M, Jandušík T, Hnízda A, Skleničková R, Petrová M, Veverka V, Řezáčová P, Brynda J, Rosenberg I. Org Biomol Chem 12 7971-7982 (2014)
  30. Pharmacogenetic characterization of naturally occurring germline NT5C1A variants to chemotherapeutic nucleoside analogs. Saliba J, Zabriskie R, Ghosh R, Powell BC, Hicks S, Kimmel M, Meng Q, Ritter DI, Wheeler DA, Gibbs RA, Tsai FT, Plon SE. Pharmacogenet Genomics 26 271-279 (2016)
  31. TRAIL-induced apoptosis of FHIT-negative lung cancer cells is inhibited by FHIT re-expression. Mirandola P, Gobbi G, Sponzilli I, Malinverno C, Cavazzoni A, Alfieri R, Petronini PG, Vitale M. J Cell Physiol 220 492-498 (2009)


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