PT Section Seminar: Dr Samuel De visser
Dr Samuel De visser
C42, Biomedical Sciences
"Enzymatic reaction mechanisms: Computational studies of substrate activation by metalloenzymes"
Dr Samuel De visser, University of Manchester
Metalloenzymes catalyze a range of vital functions for human health, including the biosynthesis of hormones and natural products, the biodegradation of toxic compounds but are also involved in repair mechanisms of DNA. The iron-containing oxygenases, generally, come in two different classes, namely the heme and nonheme enzymes. Hemes are widespread in nature and are involved in oxygen transport, electron transport as well as monoxygenation reactions. Particularly important for human health are the cytochromes P450 that metabolize drug molecules in the body. Over the years, my group has extensively studied heme and nonheme iron oxygenases using computational methods ranging from small model complexes to full protein studies using QM/MM. In this talk I will give a brief overview of recent developments of our group on P450 monoxygenases and peroxygenases. In addition, I will give an overview of recent quantum mechanics/molecular mechanics and density functional theory studies of our group on the mechanism and function of a nonheme iron hydroxylases (prolyl-4-hydroxylase) and a nonheme iron halogenase (hectochlorin biosynthesis protein). Both enzymes contain a nonheme iron active center that is bound to the protein through interactions with two histidine side chains and in addition have an anionic ligand: aspartate in the hydroxylases and halide in the halogenases. The work highlights the importance of the secondary structure of the protein to guide the regio- and stereospecific product formation through proper substrate positioning but also through electrostatic interactions.
1) S. P. de Visser and D. Kumar (Eds.) Iron-containing enzymes: Versatile catalysts of hydroxylation reactions in nature; Royal Society of Chemistry Publishing, Cambridge (UK), 2011.
2) A. Timmins, M. Saint-André and S. P. de Visser, J. Am. Chem. Soc. 2017, 139, 9855–9866.
3) A. Timmins, N. J. Fowler, J. Warwicker, G. D. Straganz and S. P. de Visser, Submitted
Dr Marc Van der Kamp
Research Fellow, School of Biochemistry
Biomedical Sciences Building
Tel: +44(0)117 331 2147