Baeyer-Villiger monooxygenases

Discovery, redesign and applications of Baeyer-Villiger monooxygenases 

Laboratory of Biochemistry, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Nijenborgh, Groningen, The Netherlands 

The Baeyer-Villiger oxidation reaction was discovered more than 100 years ago by Adolf von Baeyer and Victor Villiger. By this reaction, ketones are converted into the corresponding esters. In organic chemistry, peracids are commonly used as catalyst to perform this atypical oxidation reaction that results in oxygen insertion into a carbon—carbon bond (Fig. 1). 

All characterized BVMOs contain a flavin cofactor that is crucial for catalysis while NADH or NADPH is needed as electron donor. An interesting observation is the fact that most reported BVMOs are soluble proteins. This is in contrast to many other monooxygenase systems that often are found to be membrane-bound or membrane-associated. In 1997, Willetts concluded from careful inspection of 

Most biochemical and biocatalytic studies have been performed with type I B VMOs. This is partly because of the fact that they represent relatively uncomplicated monooxygenase systems. These monooxygenases are typically soluble and composed of only one polypeptide chain. Expression systems have been developed for a number of type I BVMOs while no recombinant expression has been reported for a type II BVMO. Cyclohexanone monooxygenase (CHMO) from an Acinetobacter sp. NCIMB9871 was the only recombinant available BVMO 

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

Baeyer-Villiger monooxygenase (BVMOMtbs) Mycobacterium tuberculosis H37Rv 2006 [140] 2006 [140] [140,141]... 

Fraaije MW, NM Kammerbeek, AJ Heidkamp, R Fortin, DB Janssen (2004) The prodrug activator EtaA from Mycobacterium tuberculosis is a Baeyer-Villiger monooxygenase. J Biol Chem 279 3354-3360. 

Alphand, V., Carrea, G., Wohlgemuth, R. et al. (2003) Towards large-scale synthetic applications of Baeyer-Villiger monooxygenases. Trends in Biotechnology, 21 (7), 318-323. 

Enantioselective Kinetic Resolution of Racemic 3-Phenylbutan-2-one Using a Baeyer-Villiger Monooxygenase... 

Kirschner, A. and Bornscheuer, U.T., Kinetic resolution of 4-hydroxy-2-ketones catalyzed by a Baeyer-Villiger monooxygenase. Angew. Chem. Int. Ed., 2006,45, 7004. 

Geitner, K., Kirschner, A., Rehdorf, J., Schmidt, M., Mihovilovic, M.D. and Bornscheuer, U.T., Enantioselective kinetic resolution of 3-pheny 1-2-ketones using Baeyer-Villiger monooxygenases. Tetrahedron Asymm., 2007,18, 892. 

Kirschner, A., Altenbuchner, J. and Bornscheuer, U.T., Cloning, expression, and characterization of a Baeyer-Villiger monooxygenase from Pseudomonas fluorescens DSM 50106 in E. coli. Appl. Microbiol. Biotechnol. 2007, 73, 1065. 

Rodriguez, C., de Gonzalo, G., Eraaije, M.W. and Gotor, V., Enzymatic kinetic resolution of racemic ketones catalyzed by Baeyer-Villiger monooxygenases. Tetrahedron Asymm., 2007, 18, 1338. 

BV monooxygenase Baeyer-Villiger monooxygenase CHMO cyclohexanone monooxygenase COMT catechol O-methyltransferase PDC pyruvate decarboxylase PRAI phosphoribosyl anthranilate isomerase. 

Among the most popular oxidative biotransformations, Baeyer-Villiger monooxygenases (BVMOs) belong to the main fields of research. Nowadays, manifold enzymes catalyzing the Baeyer-Villiger oxidation are expressed in common recombinant organisms, such as E. coli or S. cerevisiae. The mechanism of the enzymatic... 

Fig. 24 Mechanism of flavin-dependent Baeyer-Villiger monooxygenases...

Sicard, R., Chen, LS Marsaioli, A.J. and Reymond, J.L (2005) A fluorescence-based assay for Baeyer-Villiger monooxygenases, hydroxylases and lactonases. Advanced Synthesis ef Catalysis, 347,1041-1050. 

Towards large-scale synthetic applications of Baeyer-Villiger monooxygenases. Trends in Biotechnology, 21, 318-323. 

Wang, C., Gibson, M., Rohr, J. and Oliveira, M.A. (2005) Crystallization and X-ray dififaction properties of Baeyer-Villiger monooxygenase MtmOlV from the mithramycin biosynthetic pathway in Streptomyces argillaceus. 

Kamerbeek, N.M., Janssen, D.B., van Berkel, W.J.H. and Fraaije, M.W. (2003) Baeyer-Villiger monooxygenases, an emerging family of flavin-dependent biocatalysts. Advanced Synthesis Catalysis, 345, 667-678. 

Here, NADP-h stays bound throughout the entire reaction cycle. Furthermore, Baeyer-Villiger monooxygenases usually promote the deprotonation of the flavin C4a-peroxide (Fig. 6), which thereby facilitates nucleophilic substitution reactions... 

Figure 6 General mechanism for flavoprotein monooxygenases. With Baeyer-Villiger monooxygenases (nucleophilic oxygenation), NADP+ stays bound during the entire reaction cycle.

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