engleski

Experimental and theoretical models for the reaction pathways of radical enzymes

Some of the most ‘ difficult’ chemical reactions in Nature are catalysed by ‘ radical enzymes’ , which effect reaction pathways that feature protein-bound organic radicals as intermediates [1]. These enzymes are remarkable because of their ability to control highly reactive radical intermediates. This prevents attack by the radicals on protein components and also shields the radicals from dioxygen. Radical enzymes participate in metabolic pathways in all cells, e.g. in the biosynthesis of many medicinally important molecules including alkaloids, antibiotics and coenzymes. In humans, the conversion of methyl-malonyl-CoA to succinyl-CoA, a process that aids the detoxification of propionate, is catalysed by the coenzyme B12-dependent radical enzyme called methylmalonyl-CoA mutase. Some critical issues for which our understanding of radical enzymes is at an early stage are: • What are the general principles enabling radical enzymes to control the intrinsic, high reactivity of radicals? • How do enzymes channel radical intermediates through specific reaction pathways? • How do enzymes lower the energy barriers of reactions within those specific pathways? This lecture will discuss the mechanism of action of selected radical enzymes including diol dehydratase and ethanolamine ammonia lyase, glutamate and 2-methyleneglutarate mutase and 4-hydroxybutyrl-CoA dehydratase. Experimental model systems for these enzymes will be described, as well the application of ab initio molecular orbital calculations for assessing the energetics of putative reaction pathways.

radical enzymes

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