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

Challenges in assignment of allosteric effects in cytochrome P450-catalyzed substrate oxidations to structural dynamics in the hemoprotein architecture. J Inorg Biochem. 2016 Nov 25;167:100-115 Authors: Hlavica P Abstract 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. Making use of available data from crystallographic analyses, homology modeling and site-directed mutagenesis, the present review focuses on assessment of the topology of prospective key players dictating allosterism. Based on a general, CYP3A4-related construct, the majority of determinants were found to cluster within the six known substrate recognition sites (SRSs). Here, the B'/B'-C domains (SRS-1) and the F-helical region (SRS-2) harbor 51% of the critical residues, while SRS-4/5/6 each accommodate about 11-17% of the presumed docking spots. Of note, 12% of the total number of functional amino acids resides in non-SRS ...
Source: Journal of Inorganic Biochemistry - Category: Biochemistry Authors: Tags: J Inorg Biochem Source Type: research