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Mechanistic Basis of Electron Transfer to Cytochromes P450 by Natural Redox Partners and Artificial Donor Constructs

  • Peter HlavicaEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 851)

Abstract

Cytochromes P450 (P450s) are hemoproteins catalyzing oxidative biotransformation of a vast array of natural and xenobiotic compounds. Reducing equivalents required for dioxygen cleavage and substrate hydroxylation originate from different redox partners including diflavin reductases, flavodoxins, ferredoxins and phthalate dioxygenase reductase (PDR)-type proteins. Accordingly, circumstantial analysis of structural and physicochemical features governing donor-acceptor recognition and electron transfer poses an intriguing challenge. Thus, conformational flexibility reflected by togging between closed and open states of solvent exposed patches on the redox components was shown to be instrumental to steered electron transmission. Here, the membrane-interactive tails of the P450 enzymes and donor proteins were recognized to be crucial to proper orientation toward each other of surface sites on the redox modules steering functional coupling. Also, mobile electron shuttling may come into play. While charge-pairing mechanisms are of primary importance in attraction and complexation of the redox partners, hydrophobic and van der Waals cohesion forces play a minor role in docking events. Due to catalytic plasticity of P450 enzymes, there is considerable promise in biotechnological applications. Here, deeper insight into the mechanistic basis of the redox machinery will permit optimization of redox processes via directed evolution and DNA shuffling. Thus, creation of hybrid systems by fusion of the modified heme domain of P450s with proteinaceous electron carriers helps obviate the tedious reconstitution procedure and induces novel activities. Also, P450-based amperometric biosensors may open new vistas in pharmaceutical and clinical implementation and environmental monitoring.

Keywords

P450 Redox machinery Key determinants Genetic engineering Biotechnological exploitation 

Notes

Reviews

Abbreviations: AdR NADPH-adrenodoxin reductase, Adx adrenodoxin, Arx [2Fe-2S]-type ferredoxin, b 5 cytochrome b 5, BMR Bacillus megaterium (CYP102A1) reductase component, CC carbon cloth electrode, CYP or P450 cytochrome P450, FdR NAD(P)H-ferredoxin reductase, Fdx ferredoxin, GC glassy carbon electrode, PCNA proliferating cell nuclear antigen, PdR NADH-putidaredoxin reductase, PDR phthalate dioxygenase reductase, Pdx putidaredoxin, POR NADPH-P450 oxidoreductase, Pux palustrisredoxin, r.m.s. root mean square deviation, SP screen-printed electrode.

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Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  1. 1.Walther-Straub-Institut für Pharmakologie und Toxikologie der LMUMünchenGermany

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