STRUCTURE AND FUNCTION OF CYTOCHROMES-P450 - A COMPARATIVE-ANALYSIS OF 3 CRYSTAL-STRUCTURES

Background: Cytochromes P450 catalyze the oxidation of a variety of hydrophobic substrates. Sequence identities between P450 families are generally low (10-30%), and consequently, the structure-function correlations among P450s are not clear. The crystal structures of P450(terp) and the hemoprotein domain of P450(BM-3) were recently determined, and are compared here with the previously available structure of P450(cam). Results: The topology of all three enzymes is quite similar. The heme-binding core structure is well conserved, except for local differences in the I helices. The greatest variation is observed in the substrate-binding regions. The structural superposition of the proteins permits an improved sequence alignment of other P450s. The charge distribution in the three structures is similarly asymmetric and defines a molecular dipole. Conclusions: Based on this comparison we believe that all P450s will be found to possess the same tertiary structure. The ability to precisely predict other P450 substratecontact residues is limited by the extreme structural heterogeneity in the substrate-recognition regions. The central I-helix structures of P450(terp) and P45O(BM-3) suggest a role for helix-associated solvent molecules as a source of catalytic protons, distinct from the mechanism for P450(cam). We suggest that the P450 molecular dipole for P450 might aid in both redox-partner docking and proton recruitment for catalysis.