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Two-Component FAD-Dependent Monooxygenases: Current Knowledge and Biotechnological Opportunities

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Two-Component FAD-Dependent Monooxygenases: Current Knowledge and Biotechnological Opportunities biology Review Two-Component FAD-Dependent Monooxygenases: Current Knowledge and Biotechnological Opportunities Thomas Heine 1 ID , Willem J. H. van Berkel 2 ID , George Gassner 3, Karl-Heinz van Pée 4 and Dirk Tischler 1,5,* ID 1 Institute of Biosciences, Environmental Microbiology, TU Bergakademie Freiberg, Leipziger Str. 29, 09599 Freiberg, Germany; [email protected] 2 Laboratory of Biochemistry, Wageningen University & Research, Stippeneng 4, 6708 WE Wageningen, The Netherlands; [email protected] 3 Department of Chemistry and Biochemistry, San Francisco State University, 1600 Holloway Avenue, San Francisco, CA 94132, USA; [email protected] 4 Allgemeine Biochemie, Technische Universität Dresden, 01062 Dresden, Germany; [email protected] 5 Microbial Biotechnology, Ruhr University Bochum, Universitätsstr. 150, 44780 Bochum, Germany * Correspondence: [email protected]; Tel.: +49-234-32-22656 Received: 31 May 2018; Accepted: 1 August 2018; Published: 2 August 2018 Abstract: Flavoprotein monooxygenases create valuable compounds that are of high interest for the chemical, pharmaceutical, and agrochemical industries, among others. Monooxygenases that use flavin as cofactor are either single- or two-component systems. Here we summarize the current knowledge about two-component flavin adenine dinucleotide (FAD)-dependent monooxygenases and describe their biotechnological relevance. Two-component FAD-dependent monooxygenases catalyze hydroxylation, epoxidation, and halogenation reactions and are physiologically involved in amino acid metabolism, mineralization of aromatic compounds, and biosynthesis of secondary metabolites. The monooxygenase component of these enzymes is strictly dependent on reduced FAD, which is supplied by the reductase component. More and more representatives of two-component FAD-dependent monooxygenases have been discovered and characterized in recent years, which has resulted in the identification of novel physiological roles, functional properties, and a variety of biocatalytic opportunities. Keywords: hydroxylation; epoxidation; halogenation; heteroatom oxidation; biocatalysis; flavoprotein monooxygenases; flavin reductase 1. Introduction Enzymatic reactions are often highly chemo-, regio- and enantioselective and are therefore of high interest for biotechnological applications. However, many enzymes require a certain cofactor to realize a catalytic reaction. These cofactors can be divided into prosthetic groups and coenzymes/co-substrates. Cofactors can be inorganic (metal ions), organic (e.g., flavin, pterin), or organometallic (e.g., heme, cobalamin). A huge set of organic cofactors are employed by enzymes, which can be vitamins and derivatives, sugars, small peptides and lipids (e.g., adenosine triphosphate (ATP), nicotinamide adenine dinucleotide (phosphate) (NAD(P)), coenzyme A, pyridoxal phosphate, flavin adenine dinucleotide (FAD), flavin mononucleotide (FMN), vitamin K, glutathione). Cofactors allow the transfer of chemical groups as well as electron transfer in redox reactions. Further, they can build Biology 2018, 7, 42; doi:10.3390/biology7030042 www.mdpi.com/journal/biology Biology 2018, 7, 42 2 of 35 Biology 2018, 7, x 2 of 34 together with the protein a three-dimensional space and thus form the catalytic active site, fostering together with the protein a three-dimensional space and thus form the catalytic active site, fostering substrate binding and/or conversion. substrate binding and/or conversion. Amongst the most versatile cofactors are the riboflavin (vitamin B2) derivatives, flavin adenine Amongst the most versatile cofactors are the riboflavin (vitamin B2) derivatives, flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN) [1]. They can occur in flavoproteins in covalently dinucleotide (FAD) and flavin mononucleotide (FMN) [1]. They can occur in flavoproteins in bound (~10%) as well as dissociable forms [2,3]. They are able to perform one- and two-electron covalently bound (~10%) as well as dissociable forms [2,3]. They are able to perform one- and two-electron transfertransferreactions, reactions, whichwhich enableenable themthem toto supportsupport a wide range of catalytic reactions reactions and and biological biological processesprocesses [ 4[4,5].,5]. The The catalytically catalytically important important moiety moiety is theis the isoalloxazine isoalloxazine ring ring (Figure (Figure1), which 1), which can adopt can severaladopt several redox states redox [ 6states]. [6]. FigureFigure 1.1. ((leftleft)) Chemical Chemical structure structure of ofthe the oxidized oxidized form form of the of flavin the flavin isoalloxazine isoalloxazine ring system ring system with withindication indication of the of atom the atomnumbering. numbering. (middle (middle) Chemical) Chemical structure structure of the C4a-hydroperoxyflavin. of the C4a-hydroperoxyflavin. (right) (rightChemical) Chemical structure structure of the of theflavin flavin-N5-oxide.-N5-oxide. R = R =ribityl ribityl (Riboflavin), (Riboflavin), ribitylphosphate ribitylphosphate (flavin (flavin mononucleotide,mononucleotide, FMN)FMN) or ribityl- ribityl-ADPADP (flavin (flavin adenine adenine dinucleotide, dinucleotide, FAD); FAD); R* R*= ribitylphosphate = ribitylphosphate or orribityl-ADP. ribityl-ADP. One specific group of flavoproteins that has received increasing attention in biotechnology concernsOne specificthe flavin-dependent group of flavoproteins monooxygenases. that has Thes receivede enzymes increasing act on many attention different in biotechnologysubstrates by concernsutilization the and flavin-dependent activation of molecular monooxygenases. oxygen via the These reduced enzymes form act of onthe many flavin differentcofactor (Figure substrates 1) by[7–11]. utilization Flavoprotein and activation monooxygenases of molecular (EC 1.14.13, oxygen EC via1.14.14, the reducedEC 1.13.12) form are ofwidespread the flavin in cofactornature (Figureand can1) be[7 –classified11]. Flavoprotein in several monooxygenases groups according (EC to their 1.14.13, fold EC and 1.14.14, function EC 1.13.12)[7,8]: are widespread in natureSingle and can component be classified monooxygenases, in several groups belonging according to groups to their A foldand andB, contain function a tightly [7,8]: bound FAD cofactorSingle and component are dependent monooxygenases, on NAD(P)H belonging as the exte tornal groups electron A and donor. B, contain A notable a tightly exception bound is FADthe cofactorrecently anddiscovered are dependent 2-aminobenzoylacetate on NAD(P)H N as-hydroxylase the external (PqsL) electron from donor. Pseudomonas A notable aeruginosa exception. PqsL is thecontains recently a FAD discovered cofactor 2-aminobenzoylacetate but depends on free reducN-hydroxylaseed flavin as (PqsL) external from electronPseudomonas donor instead aeruginosa of . PqsLNAD(P)H contains [12]. a FADSingle-component cofactor but depends Baeyer-Villiger on free reducedmonooxygenases flavin as (group external B) electron are especially donor insteaduseful offor NAD(P)H biocatalytic [12 ].applications, Single-component because Baeyer-Villiger they catalyze monooxygenasesa wide range of (group reactions B) are with especially high usefulenantioselectivity for biocatalytic [10,13–16]. applications, because they catalyze a wide range of reactions with high enantioselectivityTwo-component [10,13 flavoprotein–16]. monooxygenases use either reduced FMN (group C) or reduced FADTwo-component (groups D, E and flavoprotein F) for molecular monooxygenases oxygen activation. use either The reduced reduced FMN flavin (group that C)binds or reduced in the FADmonooxygenase (groups D, Eactive and F)site for is moleculardelivered oxygenby a NA activation.D(P)H-dependent The reduced flavin flavinreductase that [8,17]. binds inBoth the monooxygenaseprotein components active are site usually is delivered encoded by a next NAD(P)H-dependent to each other on flavinthe genome reductase in [a8 ,17respective]. Both protein gene componentscluster. Direct are interaction usually encoded between next monooxygenase to each other on and the reductase genome inis aoften respective not required gene cluster. and supply Direct interactionof reduced between flavin can monooxygenase be as well compensated and reductase by othe isr often reductases, not required for instance and supply in whole of reduced cell systems. flavin can beFurther, as well compensatedin single component by other internal reductases, flavop forrotein instance monooxygenase in whole cell (groups systems. G and H), flavin reductionFurther, can in be single accomplished component via internalthe substrate flavoprotein [7,10,18]. monooxygenase (groups G and H), flavin reductionDuring can the be accomplishedenzymatic activation via the substrateof molecular [7,10 ,oxygen,18]. a C4a-(hydro)peroxyflavin is formed (FigureDuring 1), which the enzymatic can act as activation nucleophile of or molecular electrophile oxygen, [11,19]. a C4a-(hydro)peroxyflavinSubsequently, one oxygen is atom formed is (Figureinserted1), into which the can substrate act as nucleophilewhile the other or electrophile one is reduced [ 11 ,19to ].water. Subsequently, Insertion oneof oxygen oxygen into atom the is insertedsubstrate into is thein many substrate cases while chemo-, the other regio- one and is reduced enantioselective to water. Insertion[20–22]. Stabilization of oxygen into of the the substrate highly isreactive in many C4a-(hydro)peroxyflavin cases chemo-, regio- and intermediate enantioselective within [ 20the–22
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