Cytochromes P450: structure, function and mechanism.

Abstract

Part 1 Introduction: historical background isolation, purification and characterization spectral and related physiochemical properties substrate-binding spectra polarized optical spectroscopy vibrational spectroscopy magnetic resonance spectroscopy Mossbauer spectroscopy EXAFS spectroscopy other physical methods x-ray crystallography redox potentials and their equilibria other physiochemical and structural studies. Part 2 Evolution of the P450 superfamily: the P450 phylogenetic tree evolutionary aspects of P450 function conclusion P450 nomenclature. Part 3 The P450 catalytic cycle: the P450 catalytic cycle nature of the oxygenating species participation of active site amino acids in P450 oxygenations thermodynamics of P450 substrate binding and spin state equilibrium the coupling of redox and spin equilibria redox potential and redox interactions in the P450 system interactions between redox components protein-lipid interactions in the P450 system a proposed mechanistic scheme for the P450 catalytic cycle. Part 4 P450 substrate specificity and metabolism: endogenous metabolism exogenous metabolism the CYP1 family the CYP2 family the CYP3 family exogenous metabolism by other CYP enzymes. Part 5 Induction, regulation and inhibition: induction and regulation of P450 genes regulatory elements in P450 genes the toxic consequences of induction heterologous expression systems and in vitro models inhibition of cytochrome P450 competitive inhibitors irreversible and mechanism-based inhibitors therapeutic and agrochemical uses of P450 inhibitors metal ions as P450 inhibitors. Part 6 Structural models of P450s and related topics: P450 modelling physical methods P450 sequence alignment general features of P450 crystal structures and sequences recommended procedure for homology modelling of P450s eukaryotic P450s modelled from P450 BM3 (CYP 102) evaluation of P450-mediated toxicity by the COMPACT approach conclusions and future prospects.