title: Brain chemistry: how does P450 catalyze the O-demethylation reaction of 5-methoxytryptamine to yield serotonin?
abstract: Density functional theory has been applied to elucidate the mechanism of the O-demethylation reaction that generates serotonin from 5-methoxytryptamine (5-MT); a process that is efficiently catalyzed by P450 CYP2D6. Two substrates, the neutral 5-MT and the protonated 5-MTH(+), were used to probe the reactivity of CYP2D6 compound I. Notably, the H-abstraction process is found to be slightly more facile for 5-MT. However, our DFT augmented by docking results show that the amino acid Glu216 in the active site holds the NH(3)(+) tail of the 5-MTH(+) substrate in an upright conformation and thereby controls the regioselectivity of the bond activation. Thus, the substrate protonation serves an important function in maximizing the yield of serotonin. This finding is in accord with experimental conclusions that 5-MTH(+) serves as the substrate for the CYP2D6 enzyme. The study further shows that the H-abstraction follows two-state reactivity (TSR), whereas the rebound path may involve more states due to the appearance of both Fe(IV) and Fe(III) electromers during the reaction of 5-MTH(+).
authors.affiliation: Institute of Chemistry and The Lise Meitner-Minerva Center for Computational Quantum Chemistry, The Hebrew University of Jerusalem, 91940 Jerusalem, Israel.
authors.forename: Patric
authors.initials: P
authors.lastname: Schyman
authors.forename: Dandamudi
authors.initials: D
authors.lastname: Usharani
authors.forename: Yong
authors.initials: Y
authors.lastname: Wang
authors.forename: Sason
authors.initials: S
authors.lastname: Shaik
mesh_terms: D008735:5-Methoxytryptamine / Q000378:metabolism*; D000818:Animals; D055162:Biocatalysis; D001921:Brain / Q000201:enzymology*; D020134:Catalytic Domain; D003198:Computer Simulation; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism*; D006900:Hydroxylation; D051379:Mice; D012701:Serotonin / Q000378:metabolism*; D013237:Stereoisomerism; D013816:Thermodynamics
chemical_list: D012701:Serotonin; D008735:5-Methoxytryptamine; D019389:Cytochrome P-450 CYP2D6