Alternative coenzymes for biocatalysis

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Delft University of Technology

Alternative coenzymes for biocatalysis

Guarneri, Alice; van Berkel, Willem JH; Paul, Caroline E. DOI

10.1016/j.copbio.2019.01.001 Publication date

2019

Document Version Final published version Published in

Current Opinion in Biotechnology

Citation (APA)

Guarneri, A., van Berkel, W. JH., & Paul, C. E. (2019). Alternative coenzymes for biocatalysis. Current Opinion in Biotechnology, 60, 63-71. https://doi.org/10.1016/j.copbio.2019.01.001

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Alternative

coenzymes

for

biocatalysis

Alice

Guarneri

1

,

Willem

JH

van

Berkel

2

and

Caroline

E

Paul

3

CoenzymesareubiquitousinNature,assistingin

enzyme-catalysedreactions.Severalcoenzymes,nicotinamidesand

flavins,havebeenknownforclosetoacentury,whereas

variationsofthoseorganicmoleculeshavemorerecentlycome

tolight.Ingeneral,therequirementofthesecoenzymes

imposescertainconstraintsforinvitroenzymeusein

biocatalyticprocesses.Alternativecoenzymeshaverisento

circumventthecostfactor,tunereactionratesorobtain

differentchemicalreactivity.Thisreviewwillfocusonthese

alternativesandtheirroleandapplicationsinbiocatalysis.

Addresses

1_Laboratory_of_Organic_Chemistry,_Wageningen_University_&_Research,

Stippeneng4,6708WEWageningen,TheNetherlands

2_Laboratory_of_Food_Chemistry,_Wageningen_University_&_Research,

BornseWeilanden9,6708WGWageningen,TheNetherlands

3_Department_of_{Biotechnology,}_Delft_University_of_Technology,_Van_der

Maasweg9,2629HZDelft,TheNetherlands

Correspondingauthor:Paul,CarolineE(c.e.paul@tudelft.nl)

CurrentOpinioninBiotechnology2019,60:63–71

ThisreviewcomesfromathemedissueonChemicalbiotechnology EditedbySvenPankeandThomasWard

ForacompleteoverviewseetheIssueandtheEditorial Availableonline1stFebruary2019

https://doi.org/10.1016/j.copbio.2019.01.001

0958-1669/_ã2019ElsevierLtd.Allrightsreserved.

Introduction

on

coenzymes

Coenzymes are organic molecules that assist certain enzymes in catalysis. Many coenzymes are vitamins or derivativesthereof,andoftencontainanadenosine mono-phosphate(AMP)moietysuchasinb-nicotinamide ade-nine dinucleotide (NAD), flavin adenine dinucleotide (FAD), adenosine triphosphate (ATP) or coenzyme A (CoA).Thecommonevolutionaryoriginofthesecofactors made them indispensable for in vivo cellular metabolic processes.Whenappliedtoinvitrobiocatalyticprocesses, however, cost, instability or restricted reactivity may impedefurtherdevelopment.

Thisreviewaimsatdescribingnewnicotinamideandflavin coenzymederivativesthatwerediscoveredin Nature,as wellasalternativesyntheticcoenzymesandtheirroleand applicationsinbiocatalysis.Nicotinamideandflavin coen-zymesinoxidoreductasesarefirstdiscussed,followedby

S-adenosyl-L-methionine(SAM)intransferases.Aprevious

reviewgivesmoredetailsaboutthefunctionaldiversityof allthedifferentcoenzymes[1].

Alternative

coenzymes

for

oxidoreductases

Oxidoreductasesaccountforaquarterofallenzymesinthe Enzymenomenclaturedatabase(ExPaSy).Theirsubstrate scope and largepoolof diverse reactionslead to awide rangeofapplicationsandhavebroughtoxidoreductasesat the forefront in biotechnology and the pharmaceutical sector, where two-thirdsof chiralproducts are obtained by enzymatic catalysis [2]. A remarkable proportion of oxidoreductasesrequireb-nicotinamideadenine dinucleo-tides(NAD/NADP)orflavins(FAD/FMN)ascoenzymes. NAD,avitaminB3derivative, is aubiquitous redoxcofactor

inlivingcellscentraltomanycellularprocessesthatcanact as an electron donor or acceptorthrough the releaseor acceptanceofahydride(Figure1).Recently,anewnickel pincer cofactor was discovered in a lactate racemase enzyme. This (SCS)Ni(II)pincer complex (Figure 1) is derivedfromnicotinic acidandis involvedin ahydride transferfortheracemisationofL-lactate[3].

NAD(P)-dependent enzymes representhalf of the oxi-doreductase activities registered in the Braunschweig Enzyme Database (BRENDA) [4]. The current price of these coenzymes can range from s 1400 (NAD) to s 70000 (NADPH) per mole [5]. To reduce costs of biocatalysed redox reactions, several well-established methods for NAD(P)H regeneration are available (see Table1foracomparison)[6,7].Nevertheless,significant effortsareundertakentodevelopsimpler,moreefficient alternatives [5,8].Natural-basedNADHanalogues have beenusedtoinvestigatetheinfluenceofsubstituentson the dihydropyridine ring, and synthetic nicotinamide coenzymebiomimetics(NCBs)wereproducedto inves-tigatethehydridetransfermechanism,butmorerecently wereattractive toprovide inexpensivealternative coen-zymes(Figure 1)[5,9–11].

Natural-basedandsugar-based(nicotinamideriboseNR, nicotinamide mononucleotide NMN) NAD analogues canbeexpensivealternativesto use inbiocatalytic pro-cesses,whereasNCBscanbeeasilysynthesisedingood yields starting from cost-effective pyridine derivatives [5]. NCBs have been used in stoichiometric amounts sincetheirinsiturecyclingiscurrentlyanopenchallenge. Nonetheless,whencomparedtothecostsand disadvan-tages ofenzymaticNAD(P)Hrecyclingmethods,which uptonowaretheonlyonesappliedatindustrialscale[7], stoichiometric amountsof biomimetics areshown to be viable (Table1).

Availableonlineatwww.sciencedirect.com

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Flavin cofactors are omnipresent in Nature and are involved in a wide variety of chemical reactions [12,13]. The most common flavin cofactors, FAD and FMN, are derived from vitamin B2 (riboflavin;

Figure2),andoccur asredox-active prosthetic groups in about two percent of all proteins [14]. In many flavoenzymes, including dehydrogenases, reductases

and monooxygenases, the flavin cofactor exchanges electronswithNAD(P)(H).In mostoftheseenzymes, the NAD(P)(H) co-substrate binds in an elongated conformation, and its nicotinamide moiety meets the isoalloxazineringoftheflavinforhydridetransferatthe interfacebetweentheNAD-bindingandFAD-binding domains[15–17]. 64 Chemicalbiotechnology Figure1 Nicotinamides NR NMN NADH NADPH

Nickel-pincer cofactor Natural-based analogues NCBs

His₂₀₀

CONH_2,CO₂-

, COCH3, CN alkyl, aryl

Schematicstructuresofnicotinamidecoenzymesandderivatives(reducedforms;NR=nicotinamideribose,NMN=nicotinamidemononucleotide).

Table1

MainnicotinamidecoenzymeregenerationstrategiesandtheuseofstoichiometricamountsofNCBsa

Approach Pros Cons Selectedreagentsandcoenzymesinvolved

Enzymatic Coupledenzyme

HighTTNandselectivity Enzymeinstabilityandadditionalcost Interactionbetweenspecies Productisolation

NAD(P)H:FDHb₊_formate;_GDHc₊_glucose NAD(P):GLDHd

Enzymatic Coupledsubstrate

HighTTNandselectivity Productisolation Co-substrateinexcess

NAD(P)H:isopropanol NAD(P):acetone

Chemical Lowcost LowTTN

Lowselectivity

NAD(P)andNAD(P)H:NCBs;Me_;_Na

2S2O4

Electrochemical Electricalenergyas electronsource

LowTTNandselectivity Electrodefouling Mediatorrequired

NAD(P)H:modifiedelectrodesurface+Me_or methyleneblue

NAD:modifiedelectrodesurface+ABTS2f Photochemical Solarenergyaselectron

source

Mediatorandphotosensitiserrequired Lowefficiencywithvisiblelight

NADH:carbon-dopedTiO2+Me+

2-mercaptoethanol+H2

NAD(P)H:oligothiophene+methyl viologen+EDTA+FDRg

Stoichiometric amountofNCBh

Lowcost ApplicableonlywithNCB-accepting enzymes

BNAH

a_Adapted_from_Ref._[₆_];_TTN₌_total_turnover_number. b_Formate_{dehydrogenase.} c_Glucose_{dehydrogenase.} d_Glutamate_{dehydrogenase.} e M=[Cp*Rh(bpy)(H2O)]2+. f_{2,2-Azinobis(3-ethylbenzothiazoline-6-sulfonate).} g_{Ferrodoxin-NADP}_reductase.

h_Enzymatic_and_{(photo)chemical}_recycling_available_however_not_currently_efficient,_see_Ref._[₁₁_].

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Coenzymes

for

FMN-dependent

ene-reductases

and

other

reductases

Flavin-dependentene-reductases(ERs)oftheoldyellow enzyme(OYE)familycatalyseawiderangeof asymmet-richydrogenationreactions[18].NCBsarewellaccepted byOYEs,withvariations.Sincethefirststudypublished in2013[19],twomainstudieswerecarriedout[20,21]. Several NCBs (BNAH, BuNAH, BAPH, CO2NAH,

CNNAH, Figure 3) were screened against a panel of OYEs for the asymmetric reductionof a,b-unsaturated ketonesandaldehydes(Figure4a),leadingtoconversions

and enantiomeric excess (ee) as good as those with the preferred natural coenzyme NADPH and even better conversion than with NADH [20]. It is worth noting that a substituted hydride donor such as the Hantzsch ester (HEH) does not seem to be accepted for steric reasons [19].

For three OYEs, PETNR, TOYE and XenA, the kcat

values were comparable and slightly higher for NCBs compared to NADPH, whereas the KM values varied

depending on the OYE and NCB: with PETNR and XenA, BNAH and BuNAH had a higher affinity than NADPH,butaloweraffinitywithTOYE.Interestingly, the rates of reduction of the flavin cofactor by these NCBs were orders of magnitude higher than with the natural coenzyme, research to explain this effect is ongoing [22]. For the nitrile-substituted analogue (CNNAH), XenA was one of the few enzymes found (alongwithTsOYEandRmOYE)thatgavehigh conver-sion[20].AccordingtotheOYEclassificationproposed by Scholtissek et al., XenA belongs to classIII OYEs, whichcontainstheonlyERsshowingactivity withthis mimic[23].TheBNAH-mediatedreductionof ketoiso-phoronebyTsOYEwasalso coupledwith[CpRh(bpy) (H2O)]2+asaregenerationsystem forthemimic[20].

An iridium-based artificial metalloprotein was used to recycleMNAH,BNAH,BAPH,CO2NAHandCNNAH

fortheTsOYE-catalysedreductionofcyclicenonesanda maleimide [24].

Inanotherstudy,BNAHanditsderivativesPhNAHand HPNAH(Figure3)weretestedonfourOYEs,MR,NCR, OYE1andOYE3,withenalsubstrates.Allthreesynthetic coenzymeswereacceptedandHPNAHperformedbest withNCR[21].Notably,thesemimicsshowedefficient AlternativecoenzymesforbiocatalysisGuarneri,vanBerkelandPaul 65

Figure2 Flavins isoalloxazine riboflavin FMN FAD

Schematicstructuralrepresentationofflavincoenzymes.

Figure3

BNAH BuNAH

MNAH

PhNAH

HPNAH P2NAH P3NAH

BAPH CNNAH HEH

CO2NAH

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conversions with both isomers of citral, whereas this terpene isnot efficiently reduced by NCRin presence ofNADH [21].

Interestingly,a non-flavinreductasefrom Nicotina taba-cum(NtDBR) couldcatalyse thereductionof cinnamal-dehyde with mimics BNAH, BAPH, CO2NAH and

BuNAH, albeit with low conversions [20]. An azore-ductaseAzoRowasusedwithBNAH,displayingahigher activity for the degradation of the dye methyl red at neutralpH[25].

CoenzymesforNAD(P)-dependentdehydrogenases,

enzymaticNCBrecycling,andstability

Todate, theregenerationof NCBshasbeenlimitedto chemical, chemoenzymatic and electrochemical meth-ods,becauseofthelackofdehydrogenasesabletoaccept those biomimetics [5,11,24]. Recently, a glucose dehy-drogenase from Sulfolobus sulfataricus (SsGDH) and its variants were tested with BNA, P2NA and P3NA (Figures 3 and 4b). The best kinetics results with the mimicswereachievedwithadoublemutantthatshowed improved catalytic efficienciesfor all the analogues, in particularP2NA[26].Basedontheseresults,the reduc-tion of 2-methylbut-2-enal by TsOYE and P2NAH as coenzymewascoupledwiththeSsGDHdoublemutant fortheregenerationofP2NAHwithaturnoverfrequency (TOF) of 99h1. Control reactions revealed trace amounts of natural NADH present after purification of themutant[26].Thesamemimicsweretestedwithother commerciallyavailablerecyclingenzymesandhorseliver alcohol dehydrogenase (HLADH) but no activity was detectedwith purifiedenzyme[26].

Knausetal.usedaNADPHoxidasefromBacillussubtilis with mimics BNAH, BAPH, CO2NAH and BuNAH

[20],whilethegroupofSieberusedanNADHoxidase fromLactobacilluspentosus(LpNox)fortherecyclingofthe oxidised form of BNAH and MNAH [27]. LpNox was activewithP2NAHandP3NAHaswell,withacatalytic efficiencyof upto 0.49mM1s1withP3NAH [28].

NCBsarenotnecessarilymorestable thantheirnatural counterpartsandarealsosensitivetospecificpHranges, buffers and temperatures. Thus, efforts have recently beenmadetoovercomethehighinstabilityofthemimic modelBNAH.ThederivativeP2NAH wasdescribedto beasstableasNADHduetoapotentialstackingofthe phenylgroupagainstthedihydronicotinamide ring[28].

BNAH

with

two-component

FAD-dependent

monooxygenases

Two-component flavin-dependentmonooxygenasesuse a reductase component (StyB) for generating reduced flavin[29].TheNCBmodelBNAHwasusedtodirectly reduce free FAD, which then could bind to styrene monooxygenase StyA1 from Rhodococcus opacus 1CP to generate the flavin hydroperoxide oxygenation species (Figure4c).StyA1wasshowntocatalysetheoxidationof styrene derivatives to their corresponding epoxides, retaining (S)-enantioselectivity. For styrene, a 433h1 TF was obtained compared to a 175h1 TF with the naturalbi-enzymaticStyA1/StyBsystem[30].Upscaling of the sulfoxidation of thioanisole in the presence of BNAH gave 53% yield in two hoursand 99% ee [30]. Therefore, the natural reductase partner StyB is not needed for the generation of FADH2. The coenzyme

66 Chemicalbiotechnology Figure4 ER SsGDH StyA1, FAD, BNAH P2NA+ O2 NCBs (a) (b) (c)

NAD-dependentoxidoreductase-catalysedreactionswithNCBs.(a)ER-catalysedasymmetricreductionofactivatedalkenes.(b)GDH-catalysed oxidationofglucoseandspontaneoushydrolysisofgluconolactone.(c)Styrenemonooxygenase-catalysedasymmetricepoxidationor

sulfoxidation.

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mimic showed moderate to excellent electron transfer efficiency for both epoxidation and sulfoxidation reactions.

Artificial

flavins

for

flavin-dependent

enzymes

Kinetic studies on apoflavoproteins reconstituted with artificial flavins have provided valuable information on theaccessibilityof theflavinringintheseproteins[31]. Initially,artificialflavinswereeither usedaschemically reactive or mechanistic probes. More recent work has

shown that these compounds, especially when used in combinationwithproteinengineeringstrategies,canalso beusefulforbiocatalysis [13,32].

Martinoli et al. showed that 1-deaza-FAD and a set of monochlorinated and dichlorinated FADs (Figure 5a) canreplacethenaturalFADcofactorinthephenylacetone monooxygenase(PAMO)-mediatedconversionofracemic bicyclo[3.2.0]hept-2-en-6-one[33].InthisBaeyer–Villiger oxidation reaction, which theoretically can yield four AlternativecoenzymesforbiocatalysisGuarneri,vanBerkelandPaul 67

Figure5 Artificial flavins 7-Cl-8-nor-FAD 7,8-diCl-FAD 8-Cl-FAD 1-deaza-FAD 8-fFAD 5-deaza-FMN Flavin-N5-oxide prFMN RoFMN Naturally-occurring flavins 5-Deazaflavins Fo F4200 F420 (a) (b)

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stereo- andregiodivergent products, the naturalPAMO first preferentiallyconvertsthe(1R,5S)-ketonetothe‘normal’ lactone with an ee in favour of the (1S,5R)-enantiomer (Figure6a).Afterdepletionofthe(1R,5S)-substrate, the (1S,5R)-ketone is also converted, yielding mainly the ‘abnormal’lactone.ThePAMOvariantsreconstitutedwith artificial flavins gave virtually similar reaction patterns, althoughtheirreactionratesweresomewhatsloweddown. NADPH wasalso replacedwiththe acetylpyridine ana-logue APADPH (Figure 1 natural-based analogue, R1= COCH3,X=PO3

2_),_which_led_to_inefficient

phenylace-toneconversion.

Su etal. showed thatexchangeof theFMNcofactor of iodotyrosine deiodinase with a 5-deaza-FMN analogue (Figure 5a) suppresses the dehalogenase activity and leadsto nitroreductaseactivitythatsupportsfull reduc-tionof2-nitrotyrosinetotheamineproductinthe pres-enceofsodium borohydride[34].

Alternative

artificial

flavins

in

organic

chemistry

Severalstudiesreportedthepreparationofflavinadducts includingflavinpeptidepolymerhybridsthatmightactas organocatalystsinbiomimeticoxygenationreactions[35– 37]. Bou-Nader et al. synthesised a flavin-methylene iminiumcompoundthatcouldactasacatalytically com-petent coenzyme intermediate of reconstituted RNA methyltransferaseandthymidylate synthase[38].

Naturally

occurring

flavin

derivatives

Recently,severalnewflavin-basedcofactorswere discov-ered (Figure 5b) [39]. 8-Formyl-FAD (8-fFADH) appeared to be the native cofactor in formate oxidase (FOX)[40].Aflavin-N5-oxidecofactorwasencountered inEncM[41],whileaprenylatedformofFMN(prFMN) wasfoundin (de)carboxylases(Figure 6b)[42].

Next to the FAD and FMN scaffolds, there is another natural flavin-like cofactor. This rare F420 deazaflavin

cofactor,containinganoligoglutamate sidechainof dif-ferentlengths(Figure5b),hasrecentlybeendetectedina broad range of aerobic bacteria and therefore is more widespread than previously thought [43]. The redox potentialoffreeF420(340mV)issomewhatlowerthan

thatoffreeNAD(P)H(320mV) andmuchlowerthan thatoffreeFMN/FAD(220mV).ThismakesF420an

obligate two-electron carrier that can perform a wide rangeofchemicallydemanding redoxreactions[44,45]. Kumar et al. isolated and characterised a thermostable F420:NADPH oxidoreductase (FNO) from Thermobifida

fusca [46]. Greening et al. showed that F420-dependent

reductases (FDRs) can reduce a,b-unsaturated alkenes [47].Followingthisconcept,Mathewetal.reportedthat FDRsfromRhodococcusjostii RHA1canregioselectively reducea,b-unsaturatedketonesandaldehydeswithhigh yields and excellentenantioselectivity (Figure 6c)[48]. They also found that the enantioselectivity of FDRs differsfromthatofFMN-dependentenereductases[18]. The antibiotic roseoflavin (8-amino-8-demethyl-ribofla-vin)is anothernatural flavinthat hasbeen testedas an alternativecoenzymeforflavoproteins[49].Roseo-FMN (RoFMN, Figure 5b) bound with high affinity to apo azobenzene reductase, and the reconstituted enzyme showedabout30% activityofthenativeenzyme.

Other

alternative

coenzymes

S-Adenosyl-L-methionine(SAM)isacoenzymerequired

forthetrans-methylationof biomolecules,playinga sig-nificant role in epigeneticregulation, cellularsignalling and metabolite degradation [50]. SAM-dependent methyltransferases (MTases) are turning into versatile catalysts and advances of MTase in biocatalysis have been recently reviewed [51]. Several SAM analogues havebeensynthesisedtotransfertheactivatedgroupson MTasesubstrates(Figure 7).Astheinsituformationof theSAMcoenzymerequiresATP,complexregeneration systemsarebeingdeveloped[52].Aswell,an

S-adenosyl-L-homocysteine hydrolase, providing the adenosine for

SAM,requiresNADasacofactor.AttemptstouseNCBs resultedin findingapotentialinhibitor[53].

MTaseswerealsousedfor anenzymaticFriedel–Crafts alkylationreaction.Althoughthesubstratespecificity of theenzymesrangedfromhightomoderate,thecofactor 68 Chemicalbiotechnology Figure6 PAMO, EcAroY, FDR O2 CO2 F420H2 artificial flavins prFMN ‘normal’ (1R,5S) ‘abnormal’ (a) (b) (c)

Flavin-dependentoxidoreductase-catalysedreactionswithflavin derivatives.(a)PAMO-catalysedoxidationof bicyclo[3.2.0]hept-2-en-6-onetothe‘normal’or‘abnormal’lactone.(b)Reaction catalysedbydecarboxylaseAroYfromEnterobactercloacaeusing theprenylatedFMN;c)F420H2-dependentreductase-catalysed

reductionofactivatedalkenes,givingoppositestereochemistryto thatwithOYEs.

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scope isbroad. Modified SAMs withalkyl groups other than methyl were used for biocatalytic Friedel–Crafts alkylation, achievingexcellentconversions[54].

Conclusions

and

perspectives

The recent discovery of new coenzymes such as the nickel pincercomplex andprenylated flavinshows that Nature is resourceful and stimulates research towards unravellingnewreactionmechanisms.The useof alter-nativesyntheticcoenzymesforbiocatalysisispromising: costaside,theabilitytochangereactionratesorthetype of reactionenablesto catalysehighlyselectivereactions previously thought overly challenging. We hypothesise thatNCBsarescarcelyacceptedbydehydrogenasesdue totheirlackofanadenosinemoietyrequiredforenzyme recognition. This line of research wouldgreatly benefit from a quality structure-activity relationship analysis, withtheremainingchallengetoaltercofactorspecificity throughproteinengineering.

Conflict

of

interest

statement

Nothing declared.

Acknowledgements

CEPgratefullyacknowledgesfundingfromtheNetherlandsOrganization forScientificResearchVENI[grantagreement722.015.011].Thisproject hasreceivedfundingfromtheEuropeanUnion’sHorizon2020researchand innovationprogrammeundertheMarieSkłodowska-Curie[grantagreement 764920]forAG.

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Delft University of Technology