Flavin-containing monooxygenase substrates

Cashman, J. R. (2000) Human flavin-containing monooxygenase substrate specificity and role in drug metabolism. Curr. Drug Metab. 1,1037-1045. 

Kim YM, Ziegler DM. Size limits of thiocarbamides accepted as substrates by human flavin-containing monooxygenase 1. Drug Metab Dispos 2000 28 1003-6. 

Poulsen LL. 1981. Organic sulfur substrates for the microsomal flavin-containing monooxygenase. Rev Biochem Toxicol 3 33-49. 

Ziegler DI (1988) Flavin-containing monooxygenases catalytic mechanism and substrate specificities. Dmg Metab Rev 19(l) l-32... 

Tertiary amines such as trimethylamine and dimethylamine had long been known to be metabolized to A -oxides by a microsomal amine oxidase that was not dependent on CYP. This enzyme, now known as the microsomal flavin-containing monooxygenase (FMO), is also dependent on NADPH and 02, and has been purified to homogeneity from a number of species. Isolation and characterization of the enzyme from liver and lung samples provided evidence of clearly distinct physicochemical properties and substrate specificities suggesting the presence of at least two different isoforms. Subsequent studies have verified the presence of multiple forms of the enzyme. 

Monooxygenations are those oxidations in which one atom of molecular oxygen is reduced to water while the other is incorporated into the substrate. Microsomal monooxygenation reactions are catalyzed by nonspecific enzymes such as the flavin-containing monooxygenases (FMOs) or the multienzyme system that has cytochrome P450s (CYPs) as the terminal oxidases. 

TABLE 10.2. Substrates Oxidized by Flavin-Containing Monooxygenases... 

Jones KC, Ballou DP. Reactions of the 4a-hydroperoxide of liver microsomal flavin-containing monooxygenase with nucleophilic and electrophilic substrates. J. Biol. Chem. 1986 261 2553-2559. 

Schlenk, D. A comparison of endogenous and exogenous substrates of the flavin-containing monooxygenases in aquatic organisms. Aquat. Toxicol. 26 157-162, 1993. 

Ziegler, D.M., Flavin-containing monooxygenases Catalytic mechanism and substrate specificities, Drug Metab. Rev., 19,1-32,1988. 

Thiol compounds can be oxidized to sulfenic acids (reaction 1-A), then to sulfmic acids (reaction 1-E), and finally to sulfonic acids (reaction 1-F). Depending on the substrate, the pathway is mediated by cytochrome P450 and/or flavin-containing monooxygenases. Another route of oxidationof thiols is to disulfides either directly (reaction 1-C through thiyl radicals) or by dehy-... 

Tynes, R. E, and Hodgson. E. (1985). Catalytic activity and. substrate specificity of the flavin-containing monooxygenase in microsomal systems Characterization of the hepatic, pulmonary and renal enzymes of the mouse, rabbit, and rat. Arch. Biochem. Biaphys. 240,77-93. 

This approach, as well as other approaches using chemical inhibitor or inhibitory monoclonal antibodies, assumes that the probe substrates behave like the test compound. A simplified approach is to study the test compound in expressed enzymes only and then assume hepatic metabolism is covered by the several expressed enzymes that have been assayed (Venkatakrishnan et al., 2001). In other words, this simplified approach uses the sum of various supersomal clearances instead of the clearance in liver microsomes as 100% of hepatic metabolic clearance. While in most cases several major CYPs may have covered the majority of hepatic metabolism, other enzymes could also contribute significantly to the overall metabolism. Examples of non-CYP microsomal enzymes often involved in drug metabolism include flavin-containing monooxygenase (FMO), UDP—glucuronosyltransferase (UGT), sulfotransfer-ase (SULT), and many others (Parkinson and Ogilvie, 2008). 

Heme-containing monooxygenases catalyze the hydroxylation of various substrates. For example, aryl 4-monooxygenase (liver microsomal cytochrome P-450) hydroxylates aromatic compounds, using reduced flavin as DH [5] ... 

Two classes of monooxygenases are known. Those requiring a cosubstrate (BH2 of Eq. 18-36) in addition to the substrate to be hydroxylated are known as external monooxygenases. In the other group, the internal monooxygenases, some portion of the substrate being hydroxylated also serves as the cosubstrate. Many internal monooxygenases contain flavin cofactors and are devoid of metal ions. 

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