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Dr Samuel De visser - research

Research interests

Oxidative properties of heme and nonheme enzymes. Nature contains many enzymes that utilize molecular oxygen on an iron center, namely there a large group of enzymes with a heme central ligand but also many enzymes with non-heme ligands. Often the active species that performs the oxidation reactions is an oxo-iron(IV) species, which has been trapped and characterized in the nonheme enzyme taurine/alpha-ketoglutarate dioxygenase but is elusive in the cytochromes P450. Thus, theoretical modeling as done in our group gives important answers to questions such as: What is the active oxidant in the enzyme and what are the mechanisms of substrate monoxygenation? In the past we have done many detailed density functional theory and quantum mechanics/molecular mechanics studies into the nature of substrate oxidation by heme and nonheme enzymes. Among the heme-ligated oxo-iron species are enzymes such as the cytochromes P450, catalases and peroxidases. These enzymes all have seemingly similar active sites but totally different functions in biosystems. Thus, the P450s catalyze the metabolism of drugs and are involved in the detoxification of xenobiotics and the biosynthesis of hormones. By contrast, the catalases reduce hydrogen peroxide to water. In our group we extensively studied the electronic factors that influence the catalytic properties of heme and non-heme enzymes using model complexes and quantum mechanical / molecular mechanical (QM/MM) techniques. Our studies have shown how small structural differences in the active site of enzymes result in dramatic differences in reactivity patterns. Recently, a valence bond curve crossing model was set-up that describes the hydroxylation mechanism of substrates by the oxo-iron(IV) oxidant of P450 enzymes. Other heme enzymes, we recently started working on are the nitric oxide synthase class of enzymes that are involved in the biosynthesis of NO in the body through oxidation of arginine. We have established a new mechanism and assigned a possible oxidant of the reaction.Other studies in our group focused on the differences and comparisons of substrate monoxygenation by heme and nonheme oxo-iron(IV) oxidants. Thus, in order to make a fair comparison we studied the same reaction mechanism by models of taurine/α-ketoglutarate dioxygenase (TauD) and cytochrome P450 using propene as a substrate. As shown, both models give competing C-H hydroxylation and C=C epoxidation mechanisms. However, the barriers as obtained for α-ketoglutarate dioxygenase are lower by 7.5 kcal mol-1 with respect to cytochrome P450. Those studies implied that non-heme oxo-iron complexes as appear in α-ketoglutarate dioxygenase are much more aggressive oxidants than oxo-iron heme enzymes. Therefore, our studies have given insight into the nature of high valent oxo-iron oxidants and their reactivity patterns with respect to a broad range of substrates. These studies give insight into the way nature catalyzes important reaction mechanisms.