Flavin-containing

Oxidation of P-nicotinamide adenine dinucleotide (NADH) to NAD+ has attracted much interest from the viewpoint of its role in biosensors reactions. It has been reported that several quinone derivatives and polymerized redox dyes, such as phenoxazine and phenothiazine derivatives, possess catalytic activities for the oxidation of NADH and have been used for dehydrogenase biosensors development [1, 2]. Flavins (contain in chemical structure isoalloxazine ring) are the prosthetic groups responsible for NAD+/NADH conversion in the active sites of some dehydrogenase enzymes. Upon the electropolymerization of flavin derivatives, the effective catalysts of NAD+/NADH regeneration, which mimic the NADH-dehydrogenase activity, would be synthesized [3]. 

Ubiquitous mitochondrial monoamine oxidase [monoamine oxygen oxidoreductase (deaminating) (flavin-containing) EC 1.4.3.4 MAO] exists in two forms, namely type A and type B [ monoamine oxidase (MAO) A and B]. They are responsible for oxidative deamination of primary, secondary, and tertiary amines, including neurotransmitters, adrenaline, noradrenaline, dopamine (DA), and serotonin and vasoactive amines, such as tyramine and phenylethylamine. Their nonselec-tive and selective inhibitors ( selective MAO-A and -B inhibitors) are employed for the treatment of depressive illness and Parkinson s disease (PD). 

Flavin-containing Baeyer-Villiger monooxygenases (BVMOs) represent nature s equivalent of conventional peracids or de novo designed metal complexes... 

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

Branchaud BP, CT Walsh (1985) Functional group diversity in enzymatic oxygenation reactions catalyzed by bacterial flavin-containing cyclohexanone oxygenase. J Amer Chem Soc 107 2153-2161. 

Schlenk D, DR Buhler (1991) Role of flavin-containing monooxygenase in the in vitro biotransformation of aldicarb in rainbow trout (Oncorhyncus mykiss). Xenobiotica 21 1583-1589. 

Chen YP, DE Lincol, SA Woodin, CR Lovell (1991) Purification and properties of a unique flavin-containing chloroperoxidase from the capitellid polychaete Notomastus lobatus. J Biol Chem 266 23909-23915. 

There have been a number of reports of electrocatalysis of alcohol oxidation using immobilized PQQ-dependent alcohol dehydrogenases or flavin-containing alcohol dehydrogenases or oxidases with dissolved mediators in solution. Co-immobihzing the mediator with the enzyme is advantageous, as set out in Section 17.1, and several such strategies have been employed for electrocatalytic alcohol oxidation. 

The assessment of clearance is complicated by the numerous mechanisms by which compounds may be cleared from the body. These mechanisms include oxidative metabolism, most commonly by CYP enzymes, but also in some cases by other enzymes including but not limited to monoamine oxidases (MAO), flavin-containing monooxygenases (FMO), and aldehyde oxidase [45, 46], Non-oxidative metabolism such as conjugation or hydrolysis may be effected by enzymes such as glucuronyl transferases (UGT), glutathione transferases (GST), amidases, esterases, or ketone reductases, as well as other enzymes [47, 48], In addition to metabolic pathways, parent compound may be excreted directly via passive or active transport processes, most commonly into the urine or bile. 

SGAs = second-generation antipsychotics (SGAs) FM03 = flavin-containing monooxygenase TCAs = tricyclic antidepressants Adapted from de Leon et al., 2005b... 

Cashman, J. R. etal. (2001). Population distribution ofhuman flavin-containing monooxygenase form 3 gene polymorphisms. Drug Metab. Dispos., 29, 1629-37. 

Cashman, J.R. (2005) Some distinctions between flavin-containing and cytochrome P450 monooxygenases. Biochemical and Biophysical Research Communications, 338, 599-604. 

Itagaki, K., Carver, G.T. andPhilpot, R.M. (1996) Expression and characterization ofa modified flavin-containing monooxygenase 4 from humans. The Journal of Biological Chemistry, 271, 2012—20107. 

Such a process is supposed to occur within the limits of Q-cycle mechanism (Figure 23.2). In accord with this scheme ubihydroquinone reduced dioxygen in Complex III, while superoxide producers in Complex I could be FMN or the FeS center [12]. Zhang et al. [24] also suggested that the Q-cycle mechanism is responsible for the superoxide production by the succinate-cytochrome c reductase in bovine heart mitochondria and that FAD of succinate dehydrogenase is another producer of superoxide. Young et al. [25] concluded that, in addition to Complex III, flavin-containing enzymes and FeS centers are also the sites of superoxide production in liver mitochondria. 

Monoamine oxidase (MAO) is a mammalian flavin-containing enzyme that catalyzes oxidation of primary amines. While the neurotransmitter amines are... 

Cocaine-mediated hepatotoxicity has been associated with the conversion of cocaine to norcocaine and further oxidation products. The enzymes involved in in vitro hepatic oxidative N-demethylation of cocaine (192) were investigated (237), and two different enzymatic pathways appear to be important in the formation of the hepatotoxic metabolite. Cytochrome P-450 monooxygenases accomplish the direct N-demethylation of cocaine to norcocaine (194) as confirmed by induction and inhibition studies (Scheme 42). The second pathway for cocaine N-demethylation involves formation of cocaine /V-oxide (193) as an intermediate and two enzymes. A flavin-containing monooxygenase is first thought to convert cocaine to cocaine /V-oxide, followed by cytochrome P-450-... 

Cashman JR, Zhang J. Interindividual differences of human flavin-containing monooxygenase 3 genetic polymorphisms and functional variation. Drug Metab Dispos 2002 30(10) 1043-1052. 

Ziegler DM. Recent studies on the structure and function of multisubstrate flavin-containing monooxygenases. Annu Rev Pharmacol Toxicol 1993 33 179-199. 

Cashman JR, Xiong YN, Xu L, et al. N-oxygenation of amphetamine and methamphetamine by the human flavin-containing monooxygenase (form 3) role in bioactivation and detoxication. J Pharmacol Exp Ther 1999 288(3) 1251—1260. 

Hamman MA, Haehner-Daniels BD, Wrighton SA, et al. Stereoselective sulfoxidation of sulin-dac sulfide by flavin-containing monooxygenases. Comparison of human liver and kidney microsomes and mammalian enzymes. Biochem Pharmacol 2000 60(1) 7-17. 

Rettie, A., Bogucki, B., Lim, I. and Meier, P. (1990). Steroselective sulfadioxidation of a series of alkyl P-tolyl sulfides hy microsomal and purified flavin-containing monooxygenases. Mol. Pharmacol. 37 643-651. 

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

Tynes RE, Hodgson E. 1985. Magnitude of involvement of the mammalian flavin-containing monooxygenase in the microsomal oxidation of pesticides. J Agric Food Chem 33 471-479. 

Figure 6.27 Passage of reducing power from NADPEH to form water. One atom of oxygen is incorporated into the toxic compound ( oxidation). NADPEI-cytochrome P-450 reductase is a flavin-containing protein...

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