Synthesis and evaluation of mechanism based inhibitors of kynureninase ; asymmetric reductions of ethynylketones by secondary alcohol dehydrogenase from thermoanaerobacter ethanolicus
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In chapter I of this dissertation, the synthesis of some new inhibitors of the pyridoxal phosphate dependent enzyme kynureninase and the assessment of their kinetic parameters is described. Ten different compounds were prepared and their activity as substrates or as inhibitors was tested. Chapter II presents the enantioselective reduction of ethynylketones and ethynylketoesters by secondary alcohol dehydrogenase from Thermoanaerobacter ethanolicus (SADH). Ethynylhydroxyesters were obtained in optically pure form and represent useful chiral building blocks. The substrate dependence of enantioselectivity was elucidated and a refined active site model was proposed. Chapter III describes the effect of the mutation cysteine 295 to alanine on the enantioselectivity of the reduction of ethynylketones by SADH. In this chapter, the temperature dependence of the enantioselectivity of SADH oxidations of secondary alcohols is also presented. In the appendix, the formation of a benzisoxazole by cyclization of the aminonitrile derived from 2-nitrocinnamaldehyde by Strecker reaction is presented.