title: Insect cytochromes P450: topology of structural elements predicted to govern catalytic versatility.
abstract: 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. Highest proportion of contact sites, having a mean frequency of conservation of not more than 10%, was detected to be housed in the variable SRS-1 and SRS-2 domains, affording conformational mobility to meet the structural diversity in the bulk of substrates. Some key determinants may have a function in governing substrate access, positioning ligands toward the catalytic center to allow regioselective attack, and promoting dioxygen activation. Moreover, non-SRS elements occupying regions on the bowl-like proximal heme face may serve in recognition of electron delivery partners. Physico-chemical factors interfering with substrate anchoring mainly relate to the variably expressed lipophilicity/hydrophilicity profile of the diverse binding sites and bulkiness of the side chains of critical amino acids. Detailed knowledge about structure–function relationships in insect P450s, thus, may offer an incentive to tailoring of novel insecticides and synergistic enzyme inhibitors to more efficiently control insect pests.
authors.affiliation: Walther-Straub-Institut für Pharmakologie und Toxikologie, Goethestrasse 33, Munich, Germany. hlavica@lrz.uni-muenchen.de.
authors.forename: Peter
authors.initials: P
authors.lastname: Hlavica
mesh_terms: D000818:Animals; D002384:Catalysis; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry* / Q000378:metabolism*; D019476:Insect Proteins / Q000737:chemistry* / Q000378:metabolism*; D008958:Models, Molecular; D017433:Protein Structure, Secondary; D013329:Structure-Activity Relationship
chemical_list: D019476:Insect Proteins; D003577:Cytochrome P-450 Enzyme System