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dc.contributor.authorRichter, Florian-
dc.contributor.authorBlomberg, Rebecca-
dc.contributor.authorKhare, Sagar D.-
dc.contributor.authorKiss, Gert-
dc.contributor.authorKuzin, Alexandre P.-
dc.contributor.authorSmith, Adam J. T.-
dc.contributor.authorGallaher, Jasmine-
dc.contributor.authorPianowski, Zbigniew-
dc.contributor.authorHelgeson, Roger C.-
dc.contributor.authorGrjasnow, Alexej-
dc.contributor.authorXiao, Rong-
dc.contributor.authorSeetharaman, Jayaraman-
dc.contributor.authorSu, Min-
dc.contributor.authorVorobiev, Sergey-
dc.contributor.authorLew, Scott-
dc.contributor.authorForouhar, Farhad-
dc.contributor.authorKornhaber, Gregory J.-
dc.contributor.authorHunt, John F.-
dc.contributor.authorMontelione, Gaetano T.-
dc.contributor.authorTong, Liang-
dc.contributor.authorHouk, K. N.-
dc.contributor.authorHilvert, Donald-
dc.contributor.authorBaker, David-
dc.date.accessioned2018-08-27T06:47:25Z-
dc.date.available2018-08-27T06:47:25Z-
dc.date.issued2012-
dc.identifier.issn0002-7863de_CH
dc.identifier.issn1520-5126de_CH
dc.identifier.urihttps://digitalcollection.zhaw.ch/handle/11475/9665-
dc.description.abstractNucleophilic catalysis is a general strategy for accelerating ester and amide hydrolysis. In natural active sites, nucleophilic elements such as catalytic dyads and triads are usually paired with oxyanion holes for substrate activation, but it is difficult to parse out the independent contributions of these elements or to understand how they emerged in the course of evolution. Here we explore the minimal requirements for esterase activity by computationally designing artificial catalysts using catalytic dyads and oxyanion holes. We found much higher success rates using designed oxyanion holes formed by backbone NH groups rather than by side chains or bridging water molecules and obtained four active designs in different scaffolds by combining this motif with a Cys-His dyad. Following active site optimization, the most active of the variants exhibited a catalytic efficiency (k(cat)/K(M)) of 400 M(-1) s(-1) for the cleavage of a p-nitrophenyl ester. Kinetic experiments indicate that the active site cysteines are rapidly acylated as programmed by design, but the subsequent slow hydrolysis of the acyl-enzyme intermediate limits overall catalytic efficiency. Moreover, the Cys-His dyads are not properly formed in crystal structures of the designed enzymes. These results highlight the challenges that computational design must overcome to achieve high levels of activity.de_CH
dc.language.isoende_CH
dc.publisherAmerican Chemical Societyde_CH
dc.relation.ispartofJournal of the American Chemical Societyde_CH
dc.rightsLicence according to publishing contractde_CH
dc.subjectCatalytic domainde_CH
dc.subjectEsterasesde_CH
dc.subjectEstersde_CH
dc.subjectHydrogen bondingde_CH
dc.subjectHydrolysisde_CH
dc.subjectKineticsde_CH
dc.subjectBiocatalysisde_CH
dc.subjectDrug designde_CH
dc.subjectMolecular modelsde_CH
dc.subject.ddc540: Chemiede_CH
dc.titleComputational design of catalytic dyads and oxyanion holes for ester hydrolysisde_CH
dc.typeBeitrag in wissenschaftlicher Zeitschriftde_CH
dcterms.typeTextde_CH
zhaw.departementLife Sciences und Facility Managementde_CH
dc.identifier.doi10.1021/ja3037367de_CH
dc.identifier.pmid22871159de_CH
zhaw.funding.euNode_CH
zhaw.issue39de_CH
zhaw.originated.zhawNode_CH
zhaw.pages.end16206de_CH
zhaw.pages.start16197de_CH
zhaw.publication.statuspublishedVersionde_CH
zhaw.volume134de_CH
zhaw.publication.reviewPeer review (Publikation)de_CH
Appears in collections:Publikationen Life Sciences und Facility Management

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Richter, F., Blomberg, R., Khare, S. D., Kiss, G., Kuzin, A. P., Smith, A. J. T., Gallaher, J., Pianowski, Z., Helgeson, R. C., Grjasnow, A., Xiao, R., Seetharaman, J., Su, M., Vorobiev, S., Lew, S., Forouhar, F., Kornhaber, G. J., Hunt, J. F., Montelione, G. T., et al. (2012). Computational design of catalytic dyads and oxyanion holes for ester hydrolysis. Journal of the American Chemical Society, 134(39), 16197–16206. https://doi.org/10.1021/ja3037367
Richter, F. et al. (2012) ‘Computational design of catalytic dyads and oxyanion holes for ester hydrolysis’, Journal of the American Chemical Society, 134(39), pp. 16197–16206. Available at: https://doi.org/10.1021/ja3037367.
F. Richter et al., “Computational design of catalytic dyads and oxyanion holes for ester hydrolysis,” Journal of the American Chemical Society, vol. 134, no. 39, pp. 16197–16206, 2012, doi: 10.1021/ja3037367.
RICHTER, Florian, Rebecca BLOMBERG, Sagar D. KHARE, Gert KISS, Alexandre P. KUZIN, Adam J. T. SMITH, Jasmine GALLAHER, Zbigniew PIANOWSKI, Roger C. HELGESON, Alexej GRJASNOW, Rong XIAO, Jayaraman SEETHARAMAN, Min SU, Sergey VOROBIEV, Scott LEW, Farhad FOROUHAR, Gregory J. KORNHABER, John F. HUNT, Gaetano T. MONTELIONE, Liang TONG, K. N. HOUK, Donald HILVERT und David BAKER, 2012. Computational design of catalytic dyads and oxyanion holes for ester hydrolysis. Journal of the American Chemical Society. 2012. Bd. 134, Nr. 39, S. 16197–16206. DOI 10.1021/ja3037367
Richter, Florian, Rebecca Blomberg, Sagar D. Khare, Gert Kiss, Alexandre P. Kuzin, Adam J. T. Smith, Jasmine Gallaher, et al. 2012. “Computational Design of Catalytic Dyads and Oxyanion Holes for Ester Hydrolysis.” Journal of the American Chemical Society 134 (39): 16197–206. https://doi.org/10.1021/ja3037367.
Richter, Florian, et al. “Computational Design of Catalytic Dyads and Oxyanion Holes for Ester Hydrolysis.” Journal of the American Chemical Society, vol. 134, no. 39, 2012, pp. 16197–206, https://doi.org/10.1021/ja3037367.


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