Flavoprotein monooxygenases: Versatile biocatalysts

Paul, Caroline E.; Eggerichs, Daniel; Westphal, Adrie H.; Tischler, Dirk; Berkel, Willem J.H. van

doi:10.1016/j.biotechadv.2021.107712

Cited by 90 publications

(125 citation statements)

References 327 publications

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“…The question, whether the first electron transfer is coupled to the proton transfer remains open. Differently from flavin monooxygenases (Paul et al 2021;Toplak et al 2021) and some flavin oxidases (Sucharitakul et al 2008;Wongnate and Chaiyen 2013), a C4a-hydroperoxyflavin is not stabilized in PeAAO (Serrano et al 2020).…”

Section: Structure and Mechanismmentioning

confidence: 84%

Pecularities and applications of aryl-alcohol oxidases from fungi

Urlacher

Koschorreck

2021

Appl Microbiol Biotechnol

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Aryl-alcohol oxidases (AAOs) are FAD-containing enzymes that oxidize a broad range of aromatic as well as aliphatic allylic alcohols to aldehydes. Their broad substrate spectrum accompanied by the only need for molecular oxygen as cosubstrate and production of hydrogen peroxide as sole by-product makes these enzymes very promising biocatalysts. AAOs were used in the synthesis of flavors, fragrances, and other high-value-added compounds and building blocks as well as in dye decolorization and pulp biobleaching. Furthermore, AAOs offer a huge potential as efficient suppliers of hydrogen peroxide for peroxidase- and peroxygenase-catalyzed reactions. A prerequisite for application as biocatalysts at larger scale is the production of AAOs in sufficient amounts. Heterologous expression of these predominantly fungal enzymes is, however, quite challenging. This review summarizes different approaches aiming at enhancing heterologous expression of AAOs and gives an update on substrates accepted by these promising enzymes as well as potential fields of their application. Key points • Aryl-alcohol oxidases (AAOs) supply ligninolytic peroxidases with H2O2. • AAOs accept a broad spectrum of aromatic and aliphatic allylic alcohols. • AAOs are potential biocatalysts for the production of high-value-added bio-based chemicals.

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Section: Structure and Mechanismmentioning

confidence: 84%

Pecularities and applications of aryl-alcohol oxidases from fungi

Urlacher

Koschorreck

2021

Appl Microbiol Biotechnol

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“…3a). CtdE belongs to group A FPMOs, which do not contain a separate dinucleotide-binding domain 19 .…”

Section: Resultsmentioning

confidence: 99%

“…4c). These distances are appropriate for the proposed C(4a)-hydroperoxide flavin (Fl OOH ) 50 , which has been characterized as an active intermediate for oxygen activation in many group A FPMOs 19 , to perform epoxidation on C2=C3 bond in substrate 3. Similarly, in FPMOs HpxO 47 and TetX 20 , the distances from the C4a of the flavin to the hydroxylation sites of the substrates are 4.9 and 5.9 Å in the "in" conformation, respectively.…”

Section: Resultsmentioning

confidence: 99%

“…Subsequently, various enzymatic modifications, including the construction of spirocycles, further enrich their structural complexity 18 . The flavoprotein monooxygenases (FPMOs) 19 are widespread and perform a variety of oxygenations, including hydroxylations 20 , Baeyer-Villiger oxidations 21 , and epoxidations 22 , each incorporating a single oxygen atom into the substrate. A few FPMOs have been reported to perform indole 2,3epoxidation in the biosynthesis of PIAs [23][24][25][26] , which could act before or after the formation of the bicyclo[2.2.2]diazaoctane ring by the intramolecular [4 + 2] hetero-Diels-Alder (IMDA) reaction (Supplementary Fig.…”

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confidence: 99%

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Structural basis of the stereoselective formation of the spirooxindole ring in the biosynthesis of citrinadins

Liu

Zhao

et al. 2021

Nat Commun

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Prenylated indole alkaloids featuring spirooxindole rings possess a 3R or 3S carbon stereocenter, which determines the bioactivities of these compounds. Despite the stereoselective advantages of spirooxindole biosynthesis compared with those of organic synthesis, the biocatalytic mechanism for controlling the 3R or 3S-spirooxindole formation has been elusive. Here, we report an oxygenase/semipinacolase CtdE that specifies the 3S-spirooxindole construction in the biosynthesis of 21R-citrinadin A. High-resolution X-ray crystal structures of CtdE with the substrate and cofactor, together with site-directed mutagenesis and computational studies, illustrate the catalytic mechanisms for the possible β-face epoxidation followed by a regioselective collapse of the epoxide intermediate, which triggers semipinacol rearrangement to form the 3S-spirooxindole. Comparing CtdE with PhqK, which catalyzes the formation of the 3R-spirooxindole, we reveal an evolutionary branch of CtdE in specific 3S spirocyclization. Our study provides deeper insights into the stereoselective catalytic machinery, which is important for the biocatalysis design to synthesize spirooxindole pharmaceuticals.

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“…Tmm is a bacterial flavin-containing monooxygenase (FMO), which belongs to the class B flavoprotein monooxygenases (Chen et al, 2011;Paul et al, 2021). FMOs are a widespread class of enzymes that are involved in the metabolism of xenobiotics (Cho et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Structural and Mechanistic Insights Into Dimethylsulfoxide Formation Through Dimethylsulfide Oxidation

et al. 2021

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Dimethylsulfide (DMS) and dimethylsulfoxide (DMSO) are widespread in marine environment, and are important participants in the global sulfur cycle. Microbiol oxidation of DMS to DMSO represents a major sink of DMS in marine surface waters. The SAR11 clade and the marine Roseobacter clade (MRC) are the most abundant heterotrophic bacteria in the ocean surface seawater. It has been reported that trimethylamine monooxygenase (Tmm, EC 1.14.13.148) from both MRC and SAR11 bacteria likely oxidizes DMS to generate DMSO. However, the structural basis of DMS oxidation has not been explained. Here, we characterized a Tmm homolog from the SAR11 bacterium Pelagibacter sp. HTCC7211 (Tmm7211). Tmm7211 exhibits DMS oxidation activity in vitro. We further solved the crystal structures of Tmm7211 and Tmm7211 soaked with DMS, and proposed the catalytic mechanism of Tmm7211, which comprises a reductive half-reaction and an oxidative half-reaction. FAD and NADPH molecules are essential for the catalysis of Tmm7211. In the reductive half-reaction, FAD is reduced by NADPH. In the oxidative half-reaction, the reduced FAD reacts with O2 to form the C4a-(hydro)peroxyflavin. The binding of DMS may repel the nicotinamide ring of NADP+, and make NADP+ generate a conformational change, shutting off the substrate entrance and exposing the active C4a-(hydro)peroxyflavin to DMS to complete the oxidation of DMS. The proposed catalytic mechanism of Tmm7211 may be widely adopted by MRC and SAR11 bacteria. This study provides important insight into the conversion of DMS into DMSO in marine bacteria, leading to a better understanding of the global sulfur cycle.

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Flavoprotein monooxygenases: Versatile biocatalysts

Cited by 90 publications

References 327 publications

Pecularities and applications of aryl-alcohol oxidases from fungi

Pecularities and applications of aryl-alcohol oxidases from fungi

Structural basis of the stereoselective formation of the spirooxindole ring in the biosynthesis of citrinadins

Structural and Mechanistic Insights Into Dimethylsulfoxide Formation Through Dimethylsulfide Oxidation

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