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Leaving group activation by aromatic stacking: an alternative to general acid catalysis.

Versées W, Loverix S, Vandemeulebroucke A, Geerlings P, Steyaert J
J Mol Biol 338 1-6 (2004)
Cited: 30 times
EuropePMC logo PMID: 15050818

Abstract

General acid catalysis is a powerful and widely used strategy in enzymatic nucleophilic displacement reactions. For example, hydrolysis/phosphorolysis of the N-glycosidic bond in nucleosides and nucleotides commonly involves the protonation of the leaving nucleobase concomitant with nucleophilic attack. However, in the nucleoside hydrolase of the parasite Trypanosoma vivax, crystallographic and mutagenesis studies failed to identify a general acid. This enzyme binds the purine base of the substrate between the aromatic side-chains of Trp83 and Trp260. Here, we show via quantum chemical calculations that face-to-face stacking can raise the pKa of a heterocyclic aromatic compound by several units. Site-directed mutagenesis combined with substrate engineering demonstrates that Trp260 catalyzes the cleavage of the glycosidic bond by promoting the protonation of the purine base at N-7, hence functioning as an alternative to general acid catalysis.

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  1. Gap junction intercellular communication and cytotoxicity in normal human cells after exposure to smoke condensates from cigarettes that burn or primarily heat tobacco. McKarns SC, Bombick DW, Morton MJ, Doolittle DJ. Toxicol In Vitro 14 41-51 (2000)


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  1. The place of metabolism in the origin of life. Anet FA. Curr Opin Chem Biol 8 654-659 (2004)
  2. Structure, Oligomerization and Activity Modulation in N-Ribohydrolases. Degano M. Int J Mol Sci 23 2576 (2022)

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  2. Transition state analogues in structures of ricin and saporin ribosome-inactivating proteins. Ho MC, Sturm MB, Almo SC, Schramm VL. Proc Natl Acad Sci U S A 106 20276-20281 (2009)
  3. Aromatic stacking between nucleobase and enzyme promotes phosphate ester hydrolysis in dUTPase. Pecsi I, Leveles I, Harmat V, Vertessy BG, Toth J. Nucleic Acids Res 38 7179-7186 (2010)
  4. Theoretical study revealing the functioning of a novel combination of catalytic motifs in histone deacetylase. Vanommeslaeghe K, De Proft F, Loverix S, Tourwé D, Geerlings P. Bioorg Med Chem 13 3987-3992 (2005)
  5. Covalent and noncovalent intermediates of an NAD utilizing enzyme, human CD38. Liu Q, Kriksunov IA, Jiang H, Graeff R, Lin H, Lee HC, Hao Q. Chem Biol 15 1068-1078 (2008)
  6. Mechanism and cellular kinetic studies of the enhancement of antioxidant activity by using surface-functionalized gold nanoparticles. Du L, Suo S, Wang G, Jia H, Liu KJ, Zhao B, Liu Y. Chemistry 19 1281-1287 (2013)
  7. Transition-state complex of the purine-specific nucleoside hydrolase of T. vivax: enzyme conformational changes and implications for catalysis. Versées W, Barlow J, Steyaert J. J Mol Biol 359 331-346 (2006)
  8. Accurate interaction energies at density functional theory level by means of an efficient dispersion correction. Krishtal A, Vanommeslaeghe K, Olasz A, Veszprémi T, Van Alsenoy C, Geerlings P. J Chem Phys 130 174101 (2009)
  9. The thermodynamics of thiol sulfenylation. Billiet L, Geerlings P, Messens J, Roos G. Free Radic Biol Med 52 1473-1485 (2012)
  10. The use of atomic intrinsic polarizabilities in the evaluation of the dispersion energy. Olasz A, Vanommeslaeghe K, Krishtal A, Veszprémi T, Van Alsenoy C, Geerlings P. J Chem Phys 127 224105 (2007)
  11. Modeling the chemical step utilized by human alkyladenine DNA glycosylase: a concerted mechanism AIDS in selectively excising damaged purines. Rutledge LR, Wetmore SD. J Am Chem Soc 133 16258-16269 (2011)
  12. The activation of electrophile, nucleophile and leaving group during the reaction catalysed by pI258 arsenate reductase. Roos G, Loverix S, Brosens E, Van Belle K, Wyns L, Geerlings P, Messens J. Chembiochem 7 981-989 (2006)
  13. Leaving group activation and pyrophosphate ionic state at the catalytic site of Plasmodium falciparum orotate phosphoribosyltransferase. Zhang Y, Deng H, Schramm VL. J Am Chem Soc 132 17023-17031 (2010)
  14. Mechanisms and energetics for N-glycosidic bond cleavage of protonated 2'-deoxyguanosine and guanosine. Wu RR, Chen Y, Rodgers MT. Phys Chem Chem Phys 18 2968-2980 (2016)
  15. N-Arylmethyl substituted iminoribitol derivatives as inhibitors of a purine specific nucleoside hydrolase. Goeminne A, Berg M, McNaughton M, Bal G, Surpateanu G, Van der Veken P, De Prol S, Versées W, Steyaert J, Haemers A, Augustyns K. Bioorg Med Chem 16 6752-6763 (2008)
  16. Synthesis and biochemical evaluation of guanidino-alkyl-ribitol derivatives as nucleoside hydrolase inhibitors. Goeminne A, McNaughton M, Bal G, Surpateanu G, Van Der Veken P, De Prol S, Versées W, Steyaert J, Haemers A, Augustyns K. Eur J Med Chem 43 315-326 (2008)
  17. Structures of purine nucleosidase from Trypanosoma brucei bound to isozyme-specific trypanocidals and a novel metalorganic inhibitor. Giannese F, Berg M, Van der Veken P, Castagna V, Tornaghi P, Augustyns K, Degano M. Acta Crystallogr D Biol Crystallogr 69 1553-1566 (2013)
  18. Cooperativity of pi-stacking and hydrogen bonding interactions and substituent effects on X-ben//pyr...H-F complexes. Ebrahimi A, Habibi M, Neyband RS, Gholipour AR. Phys Chem Chem Phys 11 11424-11431 (2009)
  19. Synthesis of 2-substituted tryptophans via a C3- to C2-alkyl migration. Mari M, Lucarini S, Bartoccini F, Piersanti G, Spadoni G. Beilstein J Org Chem 10 1991-1998 (2014)
  20. Probing the catalytic mechanism of bovine CD38/NAD+ glycohydrolase by site directed mutagenesis of key active site residues. Kuhn I, Kellenberger E, Cakir-Kiefer C, Muller-Steffner H, Schuber F. Biochim Biophys Acta 1844 1317-1331 (2014)
  21. Structural and biochemical characterization of the nucleoside hydrolase from C. elegans reveals the role of two active site cysteine residues in catalysis. Singh RK, Steyaert J, Versées W. Protein Sci 26 985-996 (2017)
  22. Self-replication: spelling it out in a chemical background. Ma W, Yu C, Zhang W, Zhou P, Hu J. Theory Biosci 130 119-125 (2011)
  23. The impact of protonation and deprotonation of 3-methyl-2'-deoxyadenosine on N-glycosidic bond cleavage. Ebrahimi A, Habibi-Khorassani M, Bazzi S. Phys Chem Chem Phys 13 3334-3343 (2011)
  24. Structure of Patt1 human proapoptotic histone acetyltransferase. Jędrzejewski RP, Kaźmierkiewicz R. J Mol Model 19 5533-5538 (2013)
  25. Intramolecular hydrogen bonding, π-π stacking interactions, and substituent effects of 8-hydroxyquinoline derivative supermolecular structures: a theoretical study. Zhang J, Li X. J Mol Model 25 241 (2019)
  26. Loop motion and base release in purine-specific nucleoside hydrolase: a molecular dynamics study. Chen N, Ge H, Xu J, Cao Z, Wu R. Biochim Biophys Acta 1834 1117-1124 (2013)
  27. Structural explanation for the tunable substrate specificity of an E. coli nucleoside hydrolase: insights from molecular dynamics simulations. Lenz SAP, Wetmore SD. J Comput Aided Mol Des 32 1375-1388 (2018)


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