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Substrate-Enzyme Interactions from Modeling and Isotope Effects

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Molecular Materials with Specific Interactions – Modeling and Design

Part of the book series: Challenges and Advances in Computational Chemistry and Physics ((COCH,volume 4))

Abstract

Isotope effects provide a powerful tool for learning structures of transition states, species that are not amenable for direct observation. In the case of enzymatic processes, however, their application for the purpose of transition state structure elucidation is often obscured by reaction complexity. However, experimental measurements of isotope effects, enhanced by theoretical QM/MM modeling of the chemical step of enzymatic catalysis, allows study of the changes that occur upon conversion of substrates to transition states. Information obtained about the nature of specific interactions within the active site of an enzyme may be used for practical purposes. In this communication we will summarize studies of haloacid dehalogenases, ornithine decarboxylase, and methylmalonyl-CoA mutase to exemplify these studies. Studies of transition state structure will also be presented for purine nucleoside phosphorylases (PNP). Experimental measurements of kinetic IEs for this enzyme together with theoretical analysis of their values led to rational synthesis of new inhibitors of this enzyme. The application of transition state theory to PNP has led to the most potent and specific inhibitors known for this important enzyme

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Authors and Affiliations

  1. Institute of Applied Radiation Chemistry, Department of Chemistry, Technical University, Zeromskiego 116, Lodz, 90-924, Poland

    Renata A. Kwiecień & Piotr Paneth

  2. International Institute of Molecular and Cell Biology, Warsaw, 02-109, Trojdena 4 Street, Poland

    Andrzej Lewandowicz

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  1. Department of Chemistry, Wrocław University of Technology, Poland

    W. Andrzej Sokalski

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Kwiecień, R.A., Lewandowicz, A., Paneth, P. (2007). Substrate-Enzyme Interactions from Modeling and Isotope Effects. In: Sokalski, W.A. (eds) Molecular Materials with Specific Interactions – Modeling and Design. Challenges and Advances in Computational Chemistry and Physics, vol 4. Springer, Dordrecht. https://doi.org/10.1007/1-4020-5372-X_7

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