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Elucidation of the Catalytic Mechanism of 6-Hydroxymethyl-7,8-dihydropterin pyrophosphokinase using QM/MM Calculations

Abstract

The folate pathway is a recognized intervention point for treating parasitic and bacterial infections in humans. However, the efficacy of treatments targeting dihydropteroate synthase (DHPS) and dihydrofolate reductase (DHFR) have reduced due to disease related mutations. This has prompted interest in other enzyme targets on this clinically validated pathway, including 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK). A challenge in the design of molecules to target this enzyme is that the precise mechanism of reaction, and the role of the active site residues, are not fully understood. In this study we have explored the catalytic pathway of the natural substrate with hybrid quantum mechanical molecular mechanical methods (QM/MM). The reaction profiles associated with three proposed general bases have been investigated, as well as the profile for two mutant enzymes, namely R92A and R82A. We identified R92 as the general base in the wildtype reaction and the predicted barriers are in good agreement with the observed experimental kcat values obtained for wildtype and mutant proteins.

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Publication details

The article was received on 17 Jun 2018, accepted on 03 Aug 2018 and first published on 03 Aug 2018


Article type: Paper
DOI: 10.1039/C8OB01428K
Citation: Org. Biomol. Chem., 2018, Accepted Manuscript
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    Elucidation of the Catalytic Mechanism of 6-Hydroxymethyl-7,8-dihydropterin pyrophosphokinase using QM/MM Calculations

    N. Jongkon, D. Gleeson and M. P. Gleeson, Org. Biomol. Chem., 2018, Accepted Manuscript , DOI: 10.1039/C8OB01428K

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