Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.724653
Title: Biocatalytic studies of cytochrome P450 decarboxylase, related enzymes and biomimetic complexes
Author: Faponle, Abayomi
ISNI:       0000 0004 6425 5221
Awarding Body: University of Manchester
Current Institution: University of Manchester
Date of Award: 2016
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Abstract:
The biochemistry of cytochrome P450 is an interesting topic in biology and chemistry due to the importance of their functions to human health, but also has relevance to biotechnology. As such, understanding the catalytic mechanism of the P450s is crucial to assigning their applications. In this regard, it is often required to develop biomimetic models or synthetic analogues of their active sites for chemical investigation. In this thesis, I have investigated the mechanistic details of a novel cytochrome P450 Peroxygenase, OleTJE whose reaction with long chain fatty acids gives a mixture of alpha- and beta-hydroxy fatty acids and terminal alkenes. Our QM/MM calculation on its reaction mechanism reveals regioselective formation of these products and suggests how it can be bioengineered to alter the product distribution towards terminal alkene. We also studied the reactions of cytochrome P450 in drug metabolism and reveal the factors that determine the regioselectivity of substrate hydroxylation over desaturation in P450 isozymes. Spin-selective products formation was observed; the energy gaps between O-H and C-O bonds formed, and the pi-conjugation energy determines the extent of desaturation in addition to perturbations by environmental influences in the binding pocket as revealed by QM/MM study. The reaction of [(L52)FeIII(OOH)]2+ biomimetic model with aromatic compounds such as benzene and anisole as studied with DFT shows that hydroxylation occurs by direct C-O bond formation rather than an initial low-energy homolytic O-O bond cleavage which is slightly higher in energy. Moreover, the homolytic cleavage activates the oxidant toward reaction unlike in the heme where heterolytic cleavage occurs to form an active oxidant. This was followed by determining why phenol is a dominant product over ketone which is the primary product in reaction with aryl compounds. We also investigated the chemical and reactivity differences between nonheme iron(IV)-tosylimido and iron(IV)-oxo oxidants as biomimetic models of reactive intermediates in certain enzyme reactions. The iron(IV)-tosylimido complex has larger electron affinity and will react better with sulfides in an electrophilic addition than the iron(IV)-oxo which react faster in hydrogen atom transfer. These studies have employed computational analysis in most cases, and used to provide support for experimentally-obtained data where they exist; and have revealed fascinating bio(chemistry) of heme and nonheme iron-containing enzymes and oxidants with various substrates.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.724653  DOI: Not available
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