De visser, Samuel - University of Manchester - School of Chemical Engineering and Analytical Science

研究领域

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.

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Barman, P., Upadhyay, P., Faponle, A., Kumar, J., Nag, S. S., Kumar, D., ... De Visser, S. (2016). Deformylation reaction by a nonheme manganese(III)-peroxo complex via initial hydrogen atom abstraction. Angewandte Chemie (International Edition), 55(37), 11257‒11261. DOI: 10.1002/ange.201604412. Publication link: fb0e2467-3492-4861-93e0-3069a394f2a0 Fellner, M., Siakkou, E., Faponle, A., Tchesnokov, E. P., De Visser, S., Wilbanks, S. M., & Jameson, G. N. L. (2016). Influence of cysteine 164 on active site structure in rat cysteine dioxygenase. Journal of Biological Inorganic Chemistry, 21(4), 501–510. DOI: 10.1007/s00775-016-1360-0. Publication link: f799ff81-0123-4671-bd4b-09e89b36f0ff | PubMed:27193596 Tchesnokov, E. P., Faponle, A., Davies, C. G., Quesne, M. G., Turner, R., Fellner, M., ... Jameson, G. N. L. (2016). An iron-oxygen intermediate formed during the catalytic cycle of cysteine dioxygenase. Chemical Communications, 52(57), 8814-8817. DOI: 10.1039/c6cc03904a. Publication link: f1fd4c41-fefb-405c-8bda-b84a63940653 Cantú Reinhard, F. G., Sainna, M. A., Upadhyay, P., Balan, G. A., Kumar, D., Fornarini, S., ... de Visser, S. P. (2016). A Systematic Account on Aromatic Hydroxylation by a Cytochrome P450 Model Compound I: A Low-Pressure Mass Spectrometry and Computational Study. Chemistry - A European Journal, 22(51), 18608-18619. DOI: 10.1002/chem.201604361. Publication link: dd8128f8-0f1c-47bd-985d-21a1eb87166d Faponle, A., Banse, F., & De Visser, S. (2016). Arene activation by a nonheme iron(III)-hydroperoxo complex: Pathways leading to phenol and ketone products: pathways leading to phenol and ketone products. Journal of Biological Inorganic Chemistry, 21(4), 453–462. DOI: 10.1007/s00775-016-1354-y. Publication link: b8af0cc1-099e-42f7-b5fe-ed641f252ffd | PubMed:27099221 Yang, T., Quesne, M. G., Neu, H. M., Reinhard, F. G. C., Goldberg, D. P., & De Visser, S. (2016). Singlet versus Triplet Reactivity in an Mn(V)-Oxo Species: Testing Theoretical Predictions Against Experimental Evidence. Journal of the American Chemical Society, 138(38), 12375-12386. DOI: 10.1021/jacs.6b05027. Publication link: 017a4b62-aea1-4bc0-a623-56b2f49465c0 Faponle, A., Quesne, M., & De Visser, S. (2016). Origin of the regioselective fatty acid hydroxylation versus decarboxylation by a cytochrome P450 peroxygenase: What drives the reaction to biofuel production?: What Drives the Reaction to Biofuel Production?Chemistry - A European Journal, 22(16), 5478-5483. DOI: 10.1002/chem.201600739. Publication link: 9c93daba-97ff-401e-b385-23947e954a2a | PubMed:26918676 Quesne, M. G., Senthilnathan, D., Singh, D., Kumar, D., Maldivi, P., Sorokin, A. B., & De Visser, S. (2016). Origin of the enhanced reactivity of -nitrido-bridged diiron(IV)-oxo porphyrinoid complexes over cytochrome P450 Compound I.A C S Catalysis, 6(4), 2230-2243. . Publication link: 7c91bddb-1011-4f35-8463-c2455053b918 Barman, P., Faponle, A. S., Vardhaman, A. K., Angelone, D., Löhr, A. M., Browne, W. R., ... De Visser, S. (2016). Influence of Ligand Architecture in Tuning Reaction Bifurcation Pathways for Chlorite Oxidation by Non-Heme Iron Complexes. Inorganic Chemistry: including bioinorganic chemistry , 55(20), 10170-10181. DOI: 10.1021/acs.inorgchem.6b01384. Publication link: 6d60e537-ef4f-470f-af36-7f625d8e7095