A Baeyer-Villiger Oxidation Specifically Catalyzed by Human Flavin-Containing Monooxygenase 5

Abstract

ABSTRACT:10-((4-Hydroxypiperidin-1-yl)methyl)chromeno[4,3,2-de]phthalazin-3(2H)-one (E7016), an inhibitor of poly(ADP-ribose) polymerase, is being developed for anticancer therapy. One of the major metabolites identified in preclinical animal studies was the product of an apparent oxidation and ring opening of the 4-hydroxypiperidine. In vitro, this oxidized metabolite could not be generated by incubating E7016 with animal or human liver microsomes. Further studies revealed the formation of this unique metabolite in hepatocytes. In a NAD(P)؉ -dependent manner, this metabolite was also generated by liver S9 fractions and recombinant human flavincontaining monooxygenase (FMO) 5 that was fortified with liver cytosol fractions. In animal and human liver S9, this metabolic pathway could be inhibited by 4-methylpyrazole, bis-p-nitrophenylphosphate (BNPP), or a brief heat treatment at 50°C. Based on these results, the overall metabolic pathway was believed to involve a two-step oxidation process: dehydrogenation of the secondary alcohol in liver cytosol followed by an FMO5-mediated Baeyer-Villiger oxidation in liver microsomes.

Metabolism of MRX-I, a Novel Antibacterial Oxazolidinone, in Humans: The Oxidative Ring Opening of 2,3-Dihydropyridin-4-One Catalyzed by Non-P450 Enzymes

“…Typical FMO-catalyzed reactions have long been recognized, including the monooxygenation of heteroatoms, such as nitrogen, sulfur, and phosphorus (Strolin Benedetti et al, 2006;Cashman 2008). However, recent studies have shown that FMO5 specifically catalyzes the Baeyer-Villiger oxidation of piperidine-4-one (Lai et al, 2011) and cyclic a,b-unsaturated Scheme 2. Proposed metabolic pathway for the formation of MRX445 from MRX-I by analogy with previous studies (Verhoeven et al, 1998;Lai et al, 2011).…”

“…However, recent studies have shown that FMO5 specifically catalyzes the Baeyer-Villiger oxidation of piperidine-4-one (Lai et al, 2011) and cyclic a,b-unsaturated Scheme 2. Proposed metabolic pathway for the formation of MRX445 from MRX-I by analogy with previous studies (Verhoeven et al, 1998;Lai et al, 2011).…”

Auxin Biosynthesis

“…Therefore, flavincontaining monooxygenases are usually promiscuous and the mammalian microsome flavin-containing monooxygenases are known to catalyze the hydroxylation of a large class of nitrogen and sulfur-containing compounds (Ziegler, 1988(Ziegler, , 2002. In addition, mammalian flavin-containing monooxygenases have also been shown to catalyze Baeyer-Villiger type of reactions, in which the C4a intermediate makes a nucleophilic attack on a carbonyl group to form the Criegee intermediate, which then undergoes rearrangement to generate the final products (Lai et al, 2010). The difference between Baeyer-Villiger type of reactions and N-hydroxylation is that the C4a intermediate serves as a nucleophile in Baeyer-Villiger type of reactions while the C4a intermediate is an electrophile in N-hydroxylation reactions.…”

Pictet–Spengler reaction-based biosynthetic machinery in fungi

“…Intermediate 14 undergoes intramolecular cyclization, monooxygenation, and isomerization to form chaetogline G (7), which after decarboxylation gives chaetogline H (8), a precursor of chaetogline B (2). monooxygenase inhibitor (36) (Fig. 2).…”