CYTOCHROME-P-450 CATALYZED INSECTICIDE METABOLISM - PREDICTION OF REGIOSELECTIVITY AND STEREOSELECTIVITY IN THE PRIMER METABOLISM OF CARBOFURAN - A THEORETICAL-STUDY

The molecular mechanism of carbofuran metabolism was investigated by m olecular modeling using the energy-minimized active site of cytochrome P-450(cam). A feasible binding conformation of carbofuran was subject ed to Monte Carlo (MC) conformational search and molecular dynamics (M D) simulation in the active site to obtain the global minimum of the e nzyme-substrate complex. For exploring its conformational space, MC wa s found to be more effective than simple MD. Enzyme-substrate interact ions were examined in detail in all low-energy states. Distances betwe en the active ferryl oxygen of the central heme unit and the reactive centers of carbofuran involved in oxidative metabolism were monitored. H-bonding interaction between the carbamate group of carbofuran and t he Tyr96-OH group, as well as the steric effects of Val247 and Val295, were found to be crucial for the orientation of carbofuran. The prefe rred formation of 3-hydroxycarbofuran, the major primer metabolite, co uld be rationalized by the model. The configuration at the C3 atom was predicted to be S in accordance with the stereospecificity reported f or the natural substrate.