Evaluating the Role of an Active-Site Methionine in Coenzyme Binding by Human Carbonyl Reductase

Document Type

Student Presentation

Presentation Date

April 2016

Faculty Sponsor

Henry Charlier


Of the many chemotherapy drugs used to treat cancer, anthracyclines are among the most widely used. Human Carbonyl Reductase 1 (HCBR1) catalyzes the NADPH-dependent reduction of these anthracyclines creating an alcohol metabolite that lacks anti-cancer properties and are known cardiotoxins. Anthracycline compounds that do not react with HCBR1 have the potential to reduce the risks of the cardiotoxic effects that are associated with anthracycline chemotherapy. A key step in developing such anthracyclines is to better understand how they bind and interact with HCBR1. Toward this end, a methionine located it the enzyme active site has been mutated to an alanine in order to assess the role of this amino acid in substrate specificity. Earlier studies with this mutant enzyme suggest the active-site structure is perturbed with respect to carbonyl substrate binding, but little is known about the impact that this structural change has on NADPH binding. The work presented will be a further evaluation of the impact of the mutation on HCBR1 function with respect to NADPH and NADP+ binding.

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