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

Biochimica Et Biophysica Acta
Peter Hlavica

Abstract

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 ...Continue Reading

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Citations

Jul 17, 2009·The Journal of Biological Chemistry·Larissa M PodustPaul R Ortiz de Montellano
Jul 30, 2010·The Journal of Biological Chemistry·Natalia MastC David Stout
May 8, 2010·Antioxidants & Redox Signaling·Thomas C PochapskyMarina Dang
Oct 14, 2010·Archives of Biochemistry and Biophysics·Kip P ConnerWilliam M Atkins
Dec 16, 2006·Bioorganic & Medicinal Chemistry Letters·Kuo-Long YuNicholas A Meanwell
Jan 9, 2013·Inorganic Chemistry·Júlio S Rebouças, Brian R James

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