title: Computational studies of the regioselectivities of COMT-catalyzed meta-/para-O methylations of luteolin and quercetin.
abstract: Catechol-O-methyltransferase (COMT, EC 2.1.1.6) plays a central role in the inactivation of neurotransmitters sharing a catecholic motif by transferring a methyl group from AdoMet. Methylation of the meta-hydroxyl is much more common than that of the para-hydroxyl in many COMT substrates, such as dopamine and norepinephrine. Our experimental data showed that quercetin preferred meta-methylation but luteolin favored a para-methylation. To elucidate the mechanism for different preferences of methylations of quercetin and luteolin, we performed a theoretical investigation on the different regioseletivities of COMT-catalyzed methylations for quercetin and luteolin by a combined approach of MD simulations, ab initio calculations, and QM/MM computations. The ab initio calculation results showed that both quercetin and luteolin have more negative charge distributions on the meta-O atom than the para-O atom, which indicated that meta-O preferred SN2 reaction for their methylation. Our QM/MM computations also confirmed that these two flavonoids have lower reaction energetic barriers for COMT-catalyzed meta-O-methylation than para-O-methylation. On the other hand, our binding free energy computation results indicated that quercetin has a more stable binding mode for meta-O-methylation than para-O-methylation but luteolin has a more stable binding mode for para-O-methylation than meta-O-methylation. We gave a comprehensive explanation considering both thermodynamics and reaction kinetics aspects and discussed the protein-inhibitor interactions as well as the O-methylation mechanism in our present work.
authors.affiliation: Institute of Materia Medica, College of Pharmaceutical Sciences, Zhejiang University , Hangzhou, Zhejiang 310058, P. R. China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Cao
authors.forename: Zhong-Jian
authors.initials: ZJ
authors.lastname: Chen
authors.forename: Hui-Di
authors.initials: HD
authors.lastname: Jiang
authors.forename: Jian-Zhong
authors.initials: JZ
authors.lastname: Chen
mesh_terms: D001665:Binding Sites; D055162:Biocatalysis; D002394:Catechol O-Methyltransferase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D005419:Flavonoids / Q000737:chemistry; D006801:Humans; D047311:Luteolin / Q000737:chemistry* / Q000378:metabolism; D008274:Magnesium / Q000737:chemistry; D008745:Methylation; D056004:Molecular Dynamics Simulation; D017434:Protein Structure, Tertiary; D011789:Quantum Theory; D011794:Quercetin / Q000737:chemistry* / Q000378:metabolism; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics; D013237:Stereoisomerism; D013816:Thermodynamics
chemical_list: D005419:Flavonoids; D011994:Recombinant Proteins; D011794:Quercetin; D002394:Catechol O-Methyltransferase; D008274:Magnesium; D047311:Luteolin