Key regulators in the architecture of substrate access/egress channels in mammalian cytochromes P450 governing flexibility in substrate oxyfunctionalization.

Cytochrome P450s (CYP) represent a superfamily of b-type hemoproteins catalyzing oxifunctionalization of a vast array of endogenous and exogenous compounds. The present review focuses on assessment of the topology of prospective determinants in substrate entry and product release channels of mammalian P450s, steering the conformational dynamics of substrate accessibility and productive ligand orientation toward the iron-oxene core. Based on a generalized, CYP3A4-related construct, the sum of critical elements from diverse target enzymes was found to cluster within the known substrate recognition sites.

Challenges in assignment of allosteric effects in cytochrome P450-catalyzed substrate oxidations to structural dynamics in the hemoprotein architecture.

Cytochrome P450s (CYP) represent a superfamily of b-type hemoproteins catalyzing NAD(P)H-dependent oxidative biotransformation of a vast array of natural and xenobiotic compounds. Many eu- and prokaryotic members of this class of monooxygenases display complex non-Michaelis-Menten saturation kinetics, suggestive of homo-/heterotropic cooperativity arising from substrate-/effector-induced allosteric interactions. Here, the paradigm of multiple-ligand occupancy of the catalytic pocket in combination with enzyme oligomerization provides the most favored explanations for the atypical kinetic patterns.

Mechanistic basis of electron transfer to cytochromes p450 by natural redox partners and artificial donor constructs.

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.

Evaluation of structural features in fungal cytochromes P450 predicted to rule catalytic diversification.

Fungi belong to the large kingdom of lower eukaryotic organisms encompassing yeasts along with filamentous and dimorphic members. Microbial P450 enzymes have contributed to exploration of and adaptation to diverse ecological niches such as conversion of lipophilic compounds to more hydrophilic derivatives or degradation of a vast array of environmental toxicants. To better understand diversification of the catalytic behavior of fungal P450s, detailed insight into the molecular machinery steering oxidative attack on the distinctly structured endogenous and xenobiotic substrates is of preeminent interest.

Insect cytochromes P450: topology of structural elements predicted to govern catalytic versatility.

Among eukaryotic P450s, the greatest expansion has been in insects, providing useful model systems for the study of enzyme evolution in response to natural and anthropogenic pressures such as the chemical warfare against plant toxins and synthetic insecticides. To better understand diversification of the catalytic properties in the various P450 clades, insight into the molecular principles governing biotransformation of the array of endogenous and exogenous compounds is of paramount importance. Based on a general, CYP102A1-related construct, the majority of prospective substrate-docking residues were found to cluster near the distal hemeface within the six known substrate recognition sites (SRSs) made up by the α-helical B′, F, G and I tetrad as well as the B′-C turn and strands of certain β-sheets.