Skip to main content
SpringerLink
Log in

Chemical applications of Class B flavoprotein monooxygenases

  • Concepts in Catalysis
  • Published:
Rendiconti Lincei Aims and scope Submit manuscript

Abstract

Biocatalysis using flavoprotein monooxygenases is coming of age, with intense research and development being carried out within the last decade. The reason behind their popularity is the vast array of reactions which they can catalyze, including Baeyer–Villiger oxidation, sulfoxidation, and epoxidation reactions. Members of Class B flavoprotein monooxygenases, especially Baeyer–Villiger enzymes, are highly selective in their chemo-, regio-, and enantio-selective oxygenation reactions, and are useful in the synthesis of high-value chemicals. Their catalysis products find wide applications in various fields, including fine chemical, cosmetic, as well as pharmaceutical industries. Moreover, in the era of a drive for more environmentally friendly reactions with the use of less toxic reagents and ambient temperatures, these flavoproteins are well suited to the principles of green chemistry. This mini review provides an overview of some stereoselective reactions carried out by Class B flavoprotein monooxygenases and the efforts made to make these biocatalysts suitable for industrial applications.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • Alfieri A, Malito E, Orru R, Fraaije MW, Mattevi A (2008) Revealing the moonlighting role of NADP in the structure of a flavin-containing monooxygenase. Proc Natl Acad of Sci 105:6572–6577

    Article  CAS  Google Scholar 

  • Baeyer A, Villiger V (1899) Einwirkung des caro'schen reagens auf ketone. Ber Dtsch Chem Ges 32(3):3625–3633

    Article  Google Scholar 

  • Ballou DP, Entsch B (2013) The reaction mechanisms of groups A and B flavoprotein monooxygenases. In: Hille R, Miller SM, Palfey B (eds) Handbook of flavoproteins: Complex flavoproteins, dehydrogenases and physical methods. vol II, De Gruyter, Berlin, pp 1–28

    Google Scholar 

  • Beneventi E, Ottolina G, Carrea G, Panzeri W, Fronza G, Lau PCK (2009) Enzymatic Baeyer–Villiger oxidation of steroids with cyclopentadecanone monooxygenase. J Mol Catal B 58:164–168

    Article  CAS  Google Scholar 

  • Berezina N, Alphand V, Furstoss R (2002) Microbiological transformations. Part 51: the first example of a dynamic kinetic resolution process applied to a microbiological Baeyer–Villiger oxidation. Tetrahedron Asymmetry 13:1953–1955. doi:10.1016/S0957-4166(02)00442-1

    Article  CAS  Google Scholar 

  • Bong YK, Clay MD, Collier SJ, Mijts B, Vogel M, Zhang X, Zhu J, Nazor J, Smith D, Song S (2013) Synthesis of prazole compounds. EP2510089 A4

  • Castrignanò S, Sadeghi SJ, Gilardi G (2010) Electro-catalysis by immobilized human flavin-containing monooxygenase isoform 3 (hFMO3). Anal Bioanal Chem 398:1403–1409. doi:10.1007/s00216-010-4014-z

    Article  Google Scholar 

  • Castrignanò S, Sadeghi SJ, Gilardi G (2012) Entrapment of human flavin-containing monooxygenase 3 in the presence of gold nanoparticles: TEM, FTIR and electrocatalysis. Biochim Biophys Acta 1820:2072–2078. doi:10.1016/j.bbagen.2012.09.017

    Article  Google Scholar 

  • Castrignanò S, Gilardi G, Sadeghi SJ (2015) Human flavin-containing monooxygenase 3 on graphene oxide for drug metabolism screening. Anal Chem 87:2974–2980. doi:10.1021/ac504535y

    Article  Google Scholar 

  • Catucci G, Gilardi G, Jeuken L, Sadeghi SJ (2012) In vitro drug metabolism by C-terminally truncated human flavin-containing monooxygenase 3. Biochem Pharm 83:551–558. doi:10.1016/j.bcp.2011.11.029

    Article  CAS  Google Scholar 

  • Catucci G, Occhipinti A, Maffei M, Gilardi G, Sadeghi SJ (2013) Effect of human flavin-containing monooxygenase 3 polymorphism on the metabolism of aurora kinase inhibitors. Int J Mol Sci 14:2707–2716. doi:10.3390/ijms14022707

    Article  CAS  Google Scholar 

  • Catucci G, Zgrablic I, Lanciani F, Valetti F, Minerdi D, Ballou PD, Gilardi G, Sadeghi SJ (2016) Characterization of a new Baeyer–Villiger monooxygenase and conversion to a solely N- or S-oxidizing enzyme by a single R292 mutation. BBA-Proteins Proteom 1864:1177–1187. doi:10.1016/j.bbapap.2016.06.010

    Article  CAS  Google Scholar 

  • Ceccoli RD, Bianchi DA, Rial DV (2014) Flavoprotein monooxygenases for oxidative biocatalysis: recombinant expression in microbial hosts and applications. Front Microbiol 5:25. doi:10.3389/fmicb.2014.00025

    Article  Google Scholar 

  • Chen YCJ, Peoples OP, Walsh CT (1988) Acinetobacter cyclohexanone monooxygenase-gene cloning and sequence determination. J Bacteriol 170:781–789

    Article  Google Scholar 

  • Choi HS, Kim JK, Cho EH, Kim YC, Kim JI, Kim SW (2003) A novel flavin-containing monooxygenase from Methylophaga sp. strain SK1 and its indigo synthesis in E. coli. Biochem Biophys Res Commun 306:930–936. doi:10.1016/S0006-291X(03)01087-8

    Article  CAS  Google Scholar 

  • Colonna S, Gaggero N, Pasta P, Ottolina G (1996) Enantioselective oxidation of sulfides to sulfoxides catalysed by bacterial cyclohexanone monooxygenases. Chem Commun 20:2303–2307. doi:10.1039/CC9960002303

    Article  Google Scholar 

  • Colonna S, Gaggero N, Carrea G, Pasta P (1998) Oxidation of organic cyclic sulfites to sulfates: a new reaction catalyzed by cyclohexanone monooxygenase. Chem Commun 3:415–416. doi:10.1039/A707749A

    Article  Google Scholar 

  • Colonna S, Gaggero N, Carrea G, Pasta P, Alphand V, Furstoss R (2001) Enantioselective synthesis of tert-butyl tert-butanethiosulfinate catalyzed by cyclohexanone monooxygenase. Chirality 13:40–42. doi:10.1002/1520-636X(2001)13:1<40:AID-CHIR8>3.0.CO;2-M

    Article  CAS  Google Scholar 

  • De Gonzalo G, Torres Pazmiño DE, Ottolina G, Fraaije MW, Carrea G (2006) 4-hydroxyacetophenone monooxygenase from Pseudomonas fluorescens ACB as an oxidative biocatalyst in the synthesis of optically active sulfoxides. Tetrahedron Asymmetry 17:130–135. doi:10.1016/j.tetasy.2005.11.024

    Article  Google Scholar 

  • Donoghue NA, Trudgill PW (1975) The metabolism of cyclohexanol by Acinetobacter NCIB 9871. Eur J Biochem 60:1–7

    Article  CAS  Google Scholar 

  • Dudek HM, Popken P, van Bloois E, Duetz WA, Fraaije MW (2013) A generic, whole-cell-based screening method for Baeyer–Villiger monooxygenases. J Biomol Screen 18:678–687

    Article  Google Scholar 

  • Dundas J, Ouyang Z, Tseng J, Binkowski A, Turpaz Y, Liang J (2006) CASTp: computed atlas of surface topography of proteins with structural and topographical mapping of functionally annotated residues. Nucleic Acid Res 34:W116–W118

    Article  CAS  Google Scholar 

  • Eswaramoorthy S, Bonanno JB, Burley SK, Swaminathan S (2006) Mechanism of action of a flavin-containing monooxygenase. Proc Natl Acad Sci 103:9832–9837

    Article  CAS  Google Scholar 

  • Fink MJ, Schön M, Rudroff F, Schnürch M, Mihovilovic MD (2013) Single operation stereoselective synthesis of aerangis lactones: combining continuous flow hydrogenation and biocatalysts in a chemoenzymatic sequence. ChemCatChem 5:724–727

    Article  CAS  Google Scholar 

  • Fraaije MW, Kamerbeek NM, van Berkel WJH, Janssen DB (2002) Identification of a Baeyer–Villiger monooxygenase sequence motif. FEBS Lett 518:43–47

    Article  CAS  Google Scholar 

  • Fraaije MW, Kamerbeek NM, Heidekamp AJ, Fortin R, Janssen DB (2004) The prodrug activator EtaA from Mycobacterium tuberculosis is a Baeyer–Villiger monooxygenase. J Biol Chem 279:3354–3360

    Article  CAS  Google Scholar 

  • Furnes B, Schlenk D (2004) Evaluation of xenobiotic N- and S-oxidation by variant flavin-containing monooxygenase 1 (FMO1) enzymes. Toxicol Sci 78:196–203. doi:10.1093/toxsci/kfh079

    Article  CAS  Google Scholar 

  • Gao C, Catucci G, Di Nardo G, Gilardi G, Sadeghi SJ (2016) Human flavin-containing monooxygenase 3: structural mapping of gene polymorphisms and insights into molecular basis of drug binding. Gene 593:91–99. doi:10.1016/j.gene.2016.08.020

    Article  CAS  Google Scholar 

  • Gutiérrez M-C, Furstoss R, Alphand V (2005) Microbiological transformations 60. enantioconvergent Baeyer–Villiger oxidation via a combined whole cells and ionic exchange resin-catalysed dynamic kinetic resolution process. Adv Synth Catal 347:1051–1059. doi:10.1002/adsc.200505048

    Article  Google Scholar 

  • Hamman MA, Haehner-Daniels BD, Wrighton SA, Rettie AE, Hall SD (2000) Stereoselective sulfoxidation of sulindac sulfide by flavin-containing monooxygenases. Biochem Pharm 60:7–17

    Article  CAS  Google Scholar 

  • Hanlon SP, Camattari A, Bda S, Glieder A, Kittelmann M, Lutz S, Wirz B, Winkler M (2012) Expression of recombinant human flavin monooxygenase and moclobemide-N-oxide synthesis on multi-mg scale. Chem Commun 48:6001–6003

    Article  CAS  Google Scholar 

  • Held M, Schmid A, Kohler H-P, Suske W, Witholt B, Wubbolts MG (1999) An integrated process for the production of toxic catechols from toxic phenols based on a designer biocatalyst. Biotechnol Bioeng 62:641–648. doi:10.1002/(SICI)1097-0290(19990320)62:6<641:AID-BIT3>3.0.CO;2-H

    Article  CAS  Google Scholar 

  • Higson FK, Focht DD (1990) Degradation of 2-bromobenzoic acid by a strain of Pseudomonas aeruginosa. Appl Environ Microbiol 56:3678–3685

    CAS  Google Scholar 

  • Hilker I, Gutierrez MC, Furstoss R, Ward J, Wohlgemuth R, Alphand V (2008) Preparative scale Baeyer–Villiger biooxidation at high concentration using recombinant Escherichia coli and in situ substrate feeding and product removal process. Nat Protoc 3:546–554

    Article  CAS  Google Scholar 

  • Hollmann F, Schmid A, Steckhan E (2001) The first synthetic application of a monooxygenase employing indirect electrochemical NADH regeneration. Angew Chem 40:169–171

    Article  CAS  Google Scholar 

  • Hollmann F, Witholt B, Schmid A (2002) Cp*Rh(bpy)(H2O) (2+): a versatile tool for efficient and non-enzymatic regeneration of nicotinamide and flavin coenzymes. J Mol Cat B 19:167–176

    Article  Google Scholar 

  • Hollmann F, Taglieber A, Sculz F, Reetz MT (2007) A light-driven stereoselective biocatalytic oxidation. Angew Chem 46:2903–2906. doi:10.1002/anie.200605169

    Article  CAS  Google Scholar 

  • Iwaki H, Hasegawa Y, Wang S, Kayser MM, Lau PCK (2002) Cloning and characterization of a gene cluster involved in cyclopentanol metabolism in Comamonas sp. strain NCIMB 9872 and biotransformations effected by Escherichia coli-expressed cyclopentanone 1,2-monooxygenase. Appl Environ Microbiol 68:5671–5684. doi:10.1128/AEM.68.11.5671-5684.2002

    Article  CAS  Google Scholar 

  • Iwaki H, Wang S, Grosse S, Bergeron H, Nagahashi A, Lertvorachon J, Yang J, Konishi Y, Hasegawa Y, Lau PCK (2006) Pseudomonad cyclopentadecanone monooxygenase displaying an uncommon spectrum of Baeyer–Villiger oxidations of cyclic ketones. Appl Environ Microbiol 72:2707–2720

    Article  CAS  Google Scholar 

  • Jensen CN, Cartwright J, Ward J, Hart S, Turkenburg JP, Ali ST et al (2012) A flavoprotein monooxygenase that catalyses a Baeyer–Villiger reaction and thioether oxidation using NADH as nicotinamide cofactor. ChemBioChem 13:872–878. doi:10.1002/cbic.201200006

    Article  CAS  Google Scholar 

  • Kamerbeek NM, Janssen DB, van Berkel WJH, Fraaije MW (2003) Baeyer–Villiger monooxygenases, an emerging family of flavin-dependent biocatalysts. Adv Synth Catal 345:667–678

    Article  CAS  Google Scholar 

  • Kim YH, Yoo YJ (2009) Regeneration of the nicotinamide cofactor using a mediator-free electrochemical method with a tin oxide electrode. Enzym Microbol Technol 44:129–134

    Article  CAS  Google Scholar 

  • Labet M, Thielemans W (2009) Synthesis of polycaprolactone: a review. Chem Soc Rev 38:3484–3504

    Article  CAS  Google Scholar 

  • Lebreton J, Alphand V, Furstoss R (1997) Chemoenzymatic synthesis of marine brown algae pheromones. Tetrahedron 53:145–160

    Article  CAS  Google Scholar 

  • Leisch H, Morley K, Lau PCK (2011) Baeyer–Villiger monooxygenases: more than just green chemistry. Chem Rev 111:4165–4222

    Article  CAS  Google Scholar 

  • Light DR, Waxman DJ, Walsh C (1982) Studies on the chirality of sulfoxidation catalyzed by bacterial flavoenzyme cyclohexanone monooxygenase and hog liver FAD-containing monooxygenase. Biochemistry 21:2490–2498. doi:10.1021/bi00539a031

    Article  CAS  Google Scholar 

  • Malito E, Alfieri A, Fraaije MW, Mattevi A (2004) Crystal structure of a Baeyer–Villiger monooxygenase. Proc Natl Acad Sci 101:13157–13162

    Article  CAS  Google Scholar 

  • Massey V (1994) Activation of molecular-oxygen by flavins and flavoproteins. J Biol Chem 269:22459–22462

    CAS  Google Scholar 

  • Mihovilovic MD, Muller B, Stanetty P (2002) Monooxygenase-mediated Baeyer–Villiger oxidations. Eur J Org Chem 22:3711–3730. doi:10.1002/1099-0690(200211)2002:22<3711:AID-EJOC3711>3.0.CO;2-5

    Article  Google Scholar 

  • Minerdi D, Zgrablic I, Sadeghi SJ, Gilardi G (2012) Identification of a novel Baeyer–Villiger monooxygenase from Acinetobacter radioresistens: close relationship to the Mycobacterium tuberculosis prodrug activator EtaA. Microb Biotechnol 5:700–716. doi:10.1111/j.1751-7915.2012.00356.x

    Article  Google Scholar 

  • Minerdi D, Sadeghi SJ, Di Nardo G, Rua F, Castrignanò S, Allegra P, Gilardi G (2015) CYP116B5: a new class VII catalytically self-sufficient cytochrome P450 from Acinetobacter radioresistens that enables growth on alkanes. Mol Microbiol 95:539–554. doi:10.1111/mmi.12883

    Article  CAS  Google Scholar 

  • Minerdi D, Zgrablic I, Castrignanò S, Catucci G, Medana C, Terlizzi ME, Gribaudo G, Gilardi G, Sadeghi SJ (2016) Escherichia coli overexpressing a Baeyer–Villiger monooxygenase from Acinetobacter radioresistens become resistant to Imipenem. Antimicrob Agent Chemother 60:64–74. doi:10.1128/AAC.01088-15

    Article  CAS  Google Scholar 

  • Mirza IA, Yachnin BJ, Wang S, Grosse S, Bergeron H, Imura A, Iwaki H, Hasegawa Y, Lau PC, Berghuis AM (2009) Crystal structures of cyclohexanone monooxygenase reveal complex domain movements and a sliding cofactor. J Am Chem Soc 131:8848–8854

    Article  CAS  Google Scholar 

  • Moonen MJH, Fraaije MW, Rietjens I, Laane C, van Berkel WJH (2002) Flavoenzyme-catalyzed oxygenations and oxidations of phenolic compounds. Adv Synth Catal 344:1023–1035

    Article  CAS  Google Scholar 

  • Raja R, Thomas JM, Xu MC, Harris KDM, Greenhill-Hooper M, Quill K (2006) Highly efficient one-step conversion of cyclohexane to adipic acid using single-site heterogeneous catalysts. Chem Commun 4:448–450

    Article  Google Scholar 

  • Rettie AE, Lawton MP, Sadeque AJM, Meier GP, Philpot RM (1994) Prochiral sulfoxidation as a probe for multiple forms of the microsomal flavin-containing monooxygenase: studies with rabbit FMO1, FMO2, FMO3, and FMO5 expressed in Escherichia coli. Arch Biochem Biophys 311:369–377

    Article  CAS  Google Scholar 

  • Rial DV, Cernuchova P, van Beilen JB, Mihovilovic MD (2008) Biocatalyst assessment of recombinant whole-cells expressing the Baeyer–Villiger monooxygenase from Xanthobacter sp. ZL5. J Mol Cat B-Enzym 50:61–68

    Article  CAS  Google Scholar 

  • Rioz-Martínez A, Kopacz M, de Gonzalo G, Torres Pazmiño DE, Gotor V, Fraaije MW (2011) Exploring the biocatalytic scope of a bacterial flavin-containing monooxygenase. Org Biomol Chem 9:1337–1341. doi:10.1039/c0ob00988a

    Article  Google Scholar 

  • Riva S, Fassi P, Allegrini P, Razzetti G (2007) A process for the preparation of (−) modafinil. EP1777295A2

  • Rodriguez C, de Gonzalo G, Pazmino DET, Fraaije MW, Gotor V (2009) Baeyer–Villiger monooxygenase-catalyzed kinetic resolution of racemic alpha-alkyl benzyl ketones: enzymatic synthesis of alpha-alkyl benzylketones and alpha-alkyl benzylesters. Tetrahedron-Asymmetry 20:1168–1173

    Article  CAS  Google Scholar 

  • Rodriguez C, de Gonzalo G, Rioz-Martinez A, Torres Pazmino DE, Fraaije MW, Gotor V (2010) BVMO-catalysed dynamic kinetic resolution of racemic benzyl ketones in the presence of anion exchange resins. Org Biomol Chem 8:1121–1125. doi:10.1039/b922693a

    Article  CAS  Google Scholar 

  • Sadeghi SJ, Gilardi G, Cass AEG (1997) Mediated electrochemistry of peroxidases—effects of variations in protein and mediator structures. Biosens Bioelectron 12:1191–1198. doi:10.1016/S0956-5663(97)00089-4

    Article  CAS  Google Scholar 

  • Sadeghi SJ, Meirinhos R, Catucci G, Dodhia VR, Di Nardo G, Gilardi G (2010) Direct electrochemistry of drug metabolising hFMO3: electrochemical turnover of benzydamine and tamoxifen. J Am Chem Soc 132:458–459. doi:10.1021/ja909261p

    Article  CAS  Google Scholar 

  • Sheng DW, Ballou DP, Massey V (2001) Mechanistic studies of cyclohexanone monooxygenase: chemical properties of intermediates involved in catalysis. Biochemistry 40:11156–11167

    Article  CAS  Google Scholar 

  • Stewart JD (1988) Cyclohexanone monooxygenase: a useful reagent for asymmetric Baeyer–Villiger reactions. Curr Org Chem 2:195–216

    Google Scholar 

  • Summers BD, Omar M, Ronson TO, Cartwright J, Lloyd M, Grogan G (2015) E. coli cells expressing the Baeyer–Villiger monooxygenase ‘MO14’ (ro03437) from Rhodococcus jostii RHA1 catalyse the gram-scale resolution of a bicyclic ketone in a fermentor. Org Biomol Chem 13:1897–1903

    Article  CAS  Google Scholar 

  • Torres Pazmino DE, Riebel A, de Lange J, Rudroff F, Mihovilovic MD, Fraaije MW (2009) Efficient biooxidations catalyzed by a new generation of self-sufficient Baeyer–Villiger monooxygenases. ChemBioChem 10:2595–2598. doi:10.1002/cbic.200900480

    Article  CAS  Google Scholar 

  • Torres Pazmino DE, Winkler M, Glieder A (2010) Monooxygenases as biocatalysts: classification, mechanistic aspects and biotechnological applications. J Biotechnol 146:9–24

    Article  CAS  Google Scholar 

  • van Berkel WJH, Kamerbeek NM, Fraaije MW (2006) Flavoprotein monooxygenases, a diverse class of oxidative biocatalysts. J Biotechnol 124:670–689

    Article  Google Scholar 

  • Virkel G, Lifschitz J, Sallovitz J, Pis A, Lanusse C (2004) Comparative hepatic and extrahepatic enantioselective sulfoxidation of albendazole and fenbendazole in sheep and cattle. Drug Metab Dispos 32:536–544. doi:10.1124/dmd.32.5.536

    Article  CAS  Google Scholar 

  • Walsh CT, Chen Y-C (1988) Enzymic Baeyer–Villiger oxidations by flavin-dependent monooxygenases. Angew Chem Int Ed Engl 27:333–343

    Article  Google Scholar 

Download references

Acknowledgements

G.C. acknowledges support from the Compagnia di San Paolo for participation to the Conference “Concepts in catalysis: from heterogeneous to homogeneous and enzymatic catalysis” held at Accademia dei Lincei in Rome on February 25, 26, 2016.

Author information

Author notes

    Authors and Affiliations

    1. Department of Life Sciences and Systems Biology, University of Torino, Via Accademia Albertina 13, 10123, Turin, Italy

      Gianluca Catucci, Chongliang Gao, Sheila J. Sadeghi & Gianfranco Gilardi

    Authors
    1. Gianluca Catucci
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Chongliang Gao
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Sheila J. Sadeghi
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Gianfranco Gilardi
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to Gianfranco Gilardi.

    Additional information

    G. Catucci and C. Gao contributed equally to this work.

    This contribution is the written, peer-reviewed version of a paper presented by a participant to the Conference "Concepts in catalysis: from heterogeneous to homogeneous and enzymatic catalysis" held at Accademia Nazionale dei Lincei in Rome on February 25–26, 2016.

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Catucci, G., Gao, C., Sadeghi, S.J. et al. Chemical applications of Class B flavoprotein monooxygenases. Rend. Fis. Acc. Lincei 28 (Suppl 1), 195–206 (2017). https://doi.org/10.1007/s12210-016-0583-x

    Download citation

    • Received:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s12210-016-0583-x

    Keywords

    Search

    Navigation