Flavin-dependent monooxygenase

Yang W, IF Moore, KP Koteva, DC Bareich, DW Hughe, GD Wright (2004) TetX is a flavin-dependent monooxygenase conferring resiatence to tetracycline antibiotics. J Biol Chem 279 52346-52352. 

The systems where this type of reaction is produced may be metal-, heme- or flavin-dependent. In flavin-dependent monooxygenases, a flavin-oxygen intermediate reacts with the substrate, producing water in a second step and requiring cofactors for regeneration of the flavin moiety. The non-heme-dependent oxygenases include the... 

Other metabolic enzymes that show polymorphic differences in that they can occur as genetic high-activity and low-activity variants include acetylcholinesterase, butyrylcholinesterases, flavin-dependent monooxygenase, alcohol dehydrogenase, epoxide hydrolase, and arylesterase (Beltoft et al. 2001). 

Mishina, T.E., Zeier, J. The Arabidopsis flavin-dependent monooxygenase FMOl is an essential component of biologically induced systemic acquired resistance. Plant Physiol 141 (2006) 1666-1675. 

Modelling can pinpoint functional groups and analyse catalytic interactions. In several enzymes, catalytic interactions have been identified via calculation. For example, in the flavin-dependent monooxygenases, para-hydroxybenzoate hydroxylase and phenol hydroxylase, a conserved proline residue was found from QM/MM modelling, which specifically stabilizes the transition state for aromatic hydroxy-lation.12,13... 

NAUMANN, C., HARTMANN, T., OBER, D., Evolutionary recruitment of a flavin-dependent monooxygenase for the detoxification of host plant-acquired pyrrolizidine alkaloids in the alkaloid-defended arctiid moth Tyria jacobaeae. Proc. Natl. Acad. Sci. U. S. A., 2002,99, 6085-6090. 

In another system, the [Cp Rhm(bpy)(H20)]2+ complex was used for the regeneration of NADH in combination with an isolated flavine-dependent monooxygenase (2-hydroxybiphenyl-3-monooxygenase) from P. azelaica [120]. This enzyme catalyzes the specific ort/m-hydroxylation of several a-substituted phenol derivatives with simultaneous oxidation of NADH (Fig. 25). 

Fig. 4.15 Mechanism of the Baeyer-Villiger oxidation of cyclohexanone using flavin-dependent monooxygenase.

Table 3 Examples of important reactions catalyzed by microsomal flavin-dependent monooxygenases...

Flavin-dependent monooxygenases function through a reaction cycle that is schematically presented in Fig. 4.79. These enzymes perform their catalytic reaction through the generation of a reactive form of the flavin cofactor, formed by 2-electron reduction of the flavin followed by its reaction with molecular oxygen. As a result, the so-called C(4a)-peroxyflavin intermediate is formed, whose electrophilic reactivity is further increased by protonation of the distal oxygen of the peroxide to yield the C(4a)-hydroperoxyflavin form of the cofactor (Fig. 4.80). 

Thus, these flavin-dependent monooxygenases demonstrate the capacity of enzymes to modify the pK of reactants through specific interactions of amino acid residue side-chains with the substrate. In principle, the catalytic process depicted in Fig. 4.81 is impossible outside the active site of the enzyme, since in solution at any given pH the simultaneous generation of both the protonated C(4a)-hydroperoxyflavin and the deprotonated para-hydroxybenzoate substrate would be impossible due to the pK values of these two reactants. The enzyme provides a way for simultaneous generation of the activated protonated C(4a)-hydroperoxyflavin cofactor and the activated deprotonated substrate. 

Flavin-dependent monooxygenase-mediated Baeyer-Villiger oxidations leading to chiral lactones 02EJO3711. 

Apart from the asymmetric metal catalysis, enantioselective Baeyer-Villiger oxidations mediated by enzymes have been known for some time [32,33,34]. Both whole-cell cultures and isolated enzymes, usually flavin-dependent monooxygenases, can be used to oxidize ketones enantioselectively. For future improvements in the asymmetric Baeyer-VilHger oxidation the use of chiral Lewis acids in combination with an appropriate oxidant seems worthy of intensive investigation. 

Enzymatic Baeyer-Villiger Oxidations by Flavin Dependent Monooxygenases" Walsh. C.T. Chen, Y.-C.J. Angew. Chem. Int Ed., Engl, 1988, 27, 333. 

---