Functional interaction of nitrogenous organic bases with cytochrome P450: a critical assessment and update of substrate features and predicted key active-site elements steering the access, binding, and orientation of amines.
The widespread use of nitrogenous organic bases as environmental chemicals, food additives, and clinically important drugs necessitates precise knowledge about the molecular principles governing biotransformation of this category of substrates. In this regard, analysis of the topological background of complex formation between amines and P450s, acting as major catalysts in C- and N-oxidative attack, is of paramount importance. Thus, progress in collaborative investigations, combining physico-chemical techniques with chemical-modification as well as genetic engineering experiments, enables substantiation of hypothetical work resulting from the design of pharmacophores or homology modelling of P450s. Based on a general, CYP2D6-related construct, the majority of prospective amine-docking residues was found to cluster near the distal heme face in the six known SRSs, made up by the highly variant helices B', F and G as well as the N-terminal portion of helix C and certain beta-structures. Most of the contact sites examined show a frequency of conservation < 20%, hinting at the requirement of some degree of conformational versatility, while a limited number of amino acids exhibiting a higher level of conservation reside close to the heme core. Some key determinants may have a dual role in amine binding and/or maintenance of protein integrity. Importantly, a series of non-SRS elements are likely to be operative via long-range effects. While hydrophobic mechanisms appear to dominate orientation of the nitrogenous compounds toward the iron-oxene species, polar residues seem to foster binding events through H-bonding or salt-bridge formation. Careful uncovering of structure-function relationships in amine-enzyme association together with recently developed unsupervised machine learning approaches will be helpful in both tailoring of novel amine-type drugs and early elimination of potentially toxic or mutagenic candidates. Also, chimeragenesis might serve in the construction of more efficient P450s for activation of amine drugs and/or bioremediation.
Hlavica
Peter
P
Walther-Straub-Institut für Pharmakologie und Toxikologie, Goethestrasse 33, D-80336 München, Germany. hlavica@lrz.uni-muenchen.de
D000588:Amines / Q000378:metabolism*; D001665:Binding Sites; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D008958:Models, Molecular; D021281:Quantitative Structure-Activity Relationship
D000588:Amines; D003577:Cytochrome P-450 Enzyme System