Baeyer–Villiger Monooxygenases, an Emerging Family of Flavin‐Dependent Biocatalysts

Kamerbeek, NM; Janssen, Dick B.; Berkel, Wjh van; Fraaije, Marco W.; Berkel, W.J.H. van

doi:10.1002/adsc.200303014

Cited by 261 publications

(168 citation statements)

References 123 publications

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“…These proteins are extensively studied for their exploitation in biocatalytic applications (2,3). This interest follows the problems related to the toxicity and instability of the oxidizing reactants that are currently being used in chemical processes.…”

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Crystal structure of a Baeyer–Villiger monooxygenase

Malito

Alfieri²,

Fraaije³

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

280

305

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Flavin-containing Baeyer-Villiger monooxygenases employ NADPH and molecular oxygen to catalyze the insertion of an oxygen atom into a carbon-carbon bond of a carbonylic substrate. These enzymes can potentially be exploited in a variety of biocatalytic applications given the wide use of Baeyer-Villiger reactions in synthetic organic chemistry. The catalytic activity of these enzymes involves the formation of two crucial intermediates: a flavin peroxide generated by the reaction of the reduced flavin with molecular oxygen and the ''Criegee'' intermediate resulting from the attack of the flavin peroxide onto the substrate that is being oxygenated. The crystal structure of phenylacetone monooxygenase, a Baeyer-Villiger monooxygenase from the thermophilic bacterium Thermobifida fusca, exhibits a two-domain architecture resembling that of the disulfide oxidoreductases. The active site is located in a cleft at the domain interface. An arginine residue lays above the flavin ring in a position suited to stabilize the negatively charged flavin-peroxide and Criegee intermediates. This amino acid residue is predicted to exist in two positions; the ''IN'' position found in the crystal structure and an ''OUT'' position that allows NADPH to approach the flavin to reduce the cofactor. Domain rotations are proposed to bring about the conformational changes involved in catalysis. The structural studies highlight the functional complexity of this class of flavoenzymes, which coordinate the binding of three substrates (molecular oxygen, NADPH, and phenylacetone) in proximity of the flavin cofactor with formation of two distinct catalytic intermediates.flavoenzyme ͉ mechanism of catalysis ͉ biocatalysis ͉ Baeyer-Villiger reaction ͉ crystallography A t the end of the 19th century, Baeyer and Villiger (1) discovered that cyclic ketones react with oxidants, such as peroxymonosulfuric acid, to yield lactones. The mechanism of the Baeyer-Villiger reaction involves a nucleophilic attack of a peroxide to the ketone reagent to generate the so-called ''Criegee'' intermediate ( Fig. 1), which is followed by an intramolecular rearrangement that leads to the migration of an alkyl group to an oxygen atom, generating the lactone product. Baeyer-Villiger reactions are of enormous value in synthetic organic chemistry, and the number of their applications is countless.Several microorganisms produce enzymes capable to catalyze Baeyer-Villiger reactions. These proteins are extensively studied for their exploitation in biocatalytic applications (2, 3). This interest follows the problems related to the toxicity and instability of the oxidizing reactants that are currently being used in chemical processes. In addition, enzymatic reactions exhibit a superior degree of enantio-and regioselectivity. Baeyer-Villiger monooxygenases are classified depending on the nature of their flavin cofactor (4). The type I enzymes are the most extensively investigated (5). They are FAD-dependent proteins that use NADPH and molecular oxygen to insert an oxygen atom into th...

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confidence: 99%

“…We have expressed and purified several monooxygenases (2,8), and the only protein that so far produced crystals suited for x-ray analysis is phenylacetone monooxygenase (PAMO) from the moderate thermophilic bacterium Thermobifida fusca. PAMO is a monomeric 62-kDa enzyme that catalyses the conversion of phenylacetone to phenylacetate ( Fig.…”

mentioning

confidence: 99%

Crystal structure of a Baeyer–Villiger monooxygenase

Malito

Alfieri²,

Fraaije³

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

280

305

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“…However, this cascade is currently limited to NADPH due to the strict cofactor recognition of the CHMO from Acinetobacter sp. NCIMB 9871 (CHMO Acineto ), [4] a well-known BaeyerVilliger monooxygenase (BVMO) for lactone synthesis. From an industrial perspective, NADH is the preferred cofactor as it is cheaper (up to 30 times) and more stable than NADPH.…”

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confidence: 99%

“…[6] The majority of BVMOs including CHMO Acineto belongs to the NADPH-dependent type I BVMOs. [4] Up to date, there are several studies devoted to change the cofactor specificity of BVMOs through protein engineering. [7] One recent study on switching the cofactor specificity of CHMO Acineto has been reported by the group of Bornscheuer.…”

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Nicotinamide Adenine Dinucleotide‐Dependent Redox‐Neutral Convergent Cascade for Lactonizations with Type II Flavin‐Containing Monooxygenase

et al. 2017

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A nicotinamide adenine dinucleotide (NADH)-dependent redox-neutral convergent cascade composed of a recently discovered type II flavin-containing monooxygenase (FMOÀE) and horse liver alcohol dehydrogenase (HLADH) has been established. Two model reaction cascades were analyzed for the synthesis of g-butyrolactone and chiral bicyclic lactones. In the former cascade, all substrates were converted into one single product g-butyrolactone with high atom efficiency. More than 130 mM g-butyrolactone were obtained when applying 100 mM cyclobutanone and 50 mM 1,4-butanediol in this cascade. In the second cascade where bicyclo[4.2.0]octan-7-one and cis-1,2-cyclohexanedimethanol were coupled, the ketone substrate was converted to the corresponding normal lactone with an ee value of 89-74% (3aS, 7aS) by FMOÀE alone and the abnormal lactone with an ee value of > 99% (3aR, 7aS) was formed by both HLADH and FMOÀE.

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“…However, the conversion of 9 into 11 by G. candidium CCT 1205 in aqueous phosphate (pH 6.5) did not even reach 3% within 48 h. On the other, the lower pH was found essential to activate the BVMO of T. cutaneum CCT 1903, as almost 30% of the starting 9 was converted into 11 within 48 h. In both cases the intermediate 10 was never detected, probably due to the action of hydrolytic enzymes such as lipases or esterases, as previously mentioned. 14 As reviewed recently, BVMOs are classified according to substrate specificity, 18 therefore BVMOs of G. candidum CCT 1205 and T. cutaneum CCT 1903 belong to different groups. Therefore, probe-substrates for enzyme activity must be carefully selected as "you get what you screen for".…”

Section: Screening For Bvmomentioning

confidence: 99%

Studies on whole cell fluorescence-based screening for epoxide hydrolases and Baeyer-Villiger monoxygenases

Bicalho¹,

Chen²,

Grognux³

et al. 2004

J. Braz. Chem. Soc.

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Reações de biocatálise foram realizadas em microplacas (200 µL) visando a utilização de substratos fluorogênicos (100 µmol L -1 ) para prospecção rápida de epóxido hidrolases (EHs) e Baeyer-Villiger monoxigenases (BVMOs) em microrganismos (células inteiras). Um protocolo final foi alcançado para EHs, com a detecção de 3 novas fontes enzimáticas (Agrobacterium tumefaciens, Pichia stipitis, Trichosporom cutaneum). O ensaio fluorogênico para BVMO não ocorreu como esperado. A abordagem de algumas variáveis envolvidas (aeração; pH) proporcionou a detecção inédita da atividade enzimática de BVM em T. cutaneum.Biocatalysis reactions were performed on microtiter plates (200 µL) aiming at the utilization of fluorogenic substrates (100 µmol L -1 ) for rapid whole cell screening for epoxide hydrolases (EHs) and Baeyer-Villiger monoxygenases (BVMOs). A final protocol was achieved for EHs, with 3 new enzymatic sources being detected (Agrobacterium tumefaciens, Pichia stipitis, Trichosporom cutaneum). The fluorogenic assay for BVMO did not work as expected. However, an approach to possible variables involved (aeration; pH) provided the first detection of a BVMO activity in T. cutaneum.

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Baeyer–Villiger Monooxygenases, an Emerging Family of Flavin‐Dependent Biocatalysts

Cited by 261 publications

References 123 publications

Crystal structure of a Baeyer–Villiger monooxygenase

Crystal structure of a Baeyer–Villiger monooxygenase

Nicotinamide Adenine Dinucleotide‐Dependent Redox‐Neutral Convergent Cascade for Lactonizations with Type II Flavin‐Containing Monooxygenase

Studies on whole cell fluorescence-based screening for epoxide hydrolases and Baeyer-Villiger monoxygenases

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