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Solvent Engineering and Other Reaction Design Methods for Favouring Enzyme- Catalysed Synthesis

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Solvent Engineering and Other Reaction Design Methods for Favouring Enzyme- Catalysed Synthesis Downloaded from orbit.dtu.dk on: Oct 08, 2021 Solvent engineering and other reaction design methods for favouring enzyme- catalysed synthesis Zeuner, Birgitte Publication date: 2014 Document Version Peer reviewed version Link back to DTU Orbit Citation (APA): Zeuner, B. (2014). Solvent engineering and other reaction design methods for favouring enzyme-catalysed synthesis. Technical University of Denmark, Department of Chemical and Biochemical Engineering. General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. Users may download and print one copy of any publication from the public portal for the purpose of private study or research. You may not further distribute the material or use it for any profit-making activity or commercial gain You may freely distribute the URL identifying the publication in the public portal If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. PhD thesis Solvent engineering and other reaction design methods for favouring enzyme-catalysed synthesis Birgitte Zeuner December 2013 Center for BioProcess Engineering Department of Chemical and Biochemical Engineering Technical University of Denmark Preface This thesis presents the work carried out during my PhD project at Center for BioProcess Engineering, Department of Chemical and Biochemical Engineering, Technical University of Denmark, from December 2009 to December 2013. The work was carefully supervised by Professor Anne S. Meyer, Center for BioProcess Engineering, and co-supervised by Associate Professor Anders Riisager, Centre for Catalysis and Sustainable Chemistry, Department of Chemistry, Technical University of Denmark. The PhD project was funded by the Technical University of Denmark, Department of Chemical and Biochemical Engineering. First and foremost, I would like to thank Anne Meyer for her incomparable enthusiasm and encouragement, skilful supervision, and for first igniting my interest in enzyme technology back in 2006. Secondly, I want to thank Anders Riisager for valuable insight into the world of ionic liquids and helpful suggestions. Thanks to my colleagues at Center for BioProcess Engineering for sharing the good times as well as the bad, and for making me want to go to work every day. I would like to thank Christian Nyffenegger for showing me how to perform circular dichroism measurements and for numerous constructive discussions and suggestions. I also want to thank Jianquan Luo for performing and reporting the membrane reactor experiments for Paper IV. Thanks to Camilla Arboe Jennum for assisting me in the synthesis of iso-propyl ferulate, and to Karsten Jennum for helping me out with the curved arrows. Also thanks to several people at Centre for Catalysis and Sustainable Chemistry: to Andreas Jonas Kunov-Kruse for providing the COSMO-files and to Tim Ståhlberg, Saravanamurugan Shunmugavel, and Olivier Nguyen van Buu for preparation of the ionic liquids. Finally, I want to thank my parents for never-ending love, trust, and support. Special thanks to Peter for your love, understanding, patience, valuable input, and scientific discussions and to Christian for always putting a smile on my face. Birgitte Zeuner Bispebjerg, December 2013 i ii Summary This thesis investigates different methods for improving reaction yields of enzyme-catalysed synthesis reactions. These methods include the use of non-conventional media such as ionic liquids (ILs) and organic solvents as main solvents or as co-solvents as well as the use of more classical reaction design methods, i.e. enzyme immobilization and the use of an enzymatic membrane reactor. Two different enzyme classes, namely feruloyl esterases (FAEs) and sialidases are employed. Using sinapoylation of glycerol as a model reaction it was shown that both the IL anion nature and the FAE structure were important for FAE activity and stability in IL-buffer (15% v/v) systems. The quantum chemistry-based COSMO-RS method was applied for explaining the IL anion effect in terms of hydrogen bonding capacity. Furthermore, the usefulness of COSMO-RS and other thermodynamically based tools in solvent selection for FAE-catalysed acylation reactions was reviewed. FAE type A from Aspergillus niger and an FAE from a commercial preparation from Humicola insolens, Depol 740L, could not catalyse the esterification of arabinose or xylose with hydroxycinnamates in IL-buffer systems or in surfactantless microemulsion. However, both FAEs catalysed the feruloylation and/or sinapoylation of solvent cation C2OHMIm+, thus underlining the broad acceptor specificity of FAEs and their potential for future solvent reactions. An engineered sialidase from Trypanosoma rangeli, Tr6, catalyses trans-sialylation but the yield is hampered by substrate and product hydrolysis. The formation of 3’-sialyllactose from lactose and casein glycomacropeptide was used as a model reaction. Addition of 20-25% (v/v) t-butanol improved the trans-sialylation yield 1.4-fold and the synthesis/hydrolysis ratio 1.2-fold. Using ILs as co-solvents, the synthesis/hydrolysis ratio was also improved, but the trans-sialylation yield decreased, probably due to destabilization of Tr6 caused by the ILs. Returning to the conventional aqueous medium, immobilization of Tr6 on magnetic nanoparticles improved the synthesis/hydrolysis ratio 2.1-fold and increased the biocatalytic productivity of 2.5-fold. However, the recyclability of the immobilized enzyme was low. Reusing Tr6 seven times in a membrane reactor increased the trans-sialylation yield on the limiting substrate 1.3-fold, emphasizing the importance of the continuous product removal. Furthermore, the biocatalytic productivity was increased more than 9-fold as a result of the enzyme recovery. In conclusion, where the use of non-conventional media is required for catalysis, e.g. in the thermodynamically controlled FAE-catalysed esterification, careful selection of both solvent system and the FAE itself is required to obtain adequate reaction yields. In contrast, for Tr6 the most promising results were obtained when keeping the reaction in aqueous medium and employing other reaction design methods such as continuous product removal and enzyme immobilization. iii iv Dansk sammenfatning Afhandlingen undersøger forskellige metoder til at øge reaktionsudbyttet i enzymkatalyserede syntesereaktioner. Først undersøges brugen af ukonventionelle reaktionsmedier som ioniske væsker og organiske solventer, både som hovedsolvent og co-solvent. Til sidst undersøges brugen af mere klassiske metoder i reaktionsdesign såsom enzymimmobilisering og brug af en membranreaktor. To forskellige enzymtyper anvendes, nemlig ferulinsyreesteraser og sialidaser. Med sinapoylering af glycerol som eksempel blev det vist, at både anionen i den ioniske væske og ferulinsyreesterasernes struktur havde betydning for ferulinsyreesteraseaktivitet og -stabilitet i ionisk væske-systemer med 15 % (v/v) vand (buffer). Den kvantekemibaserede software COSMO-RS kunne forklare den observerede anioneffekt som et resultat af anionens tendens til at danne hydrogenbindinger med enzymstrukturen. Anvendeligheden af COSMO-RS og andre termodynamiske modeller i forbindelse med valg af solventer til ferulinsyreesterase- katalyserede reaktioner blev undersøgt. Ferulinsyreesterase type A fra Aspergillus niger og ferulinsyreesterasene i den kommercielle enzympreparation fra Humicola insolens, Depol 740L, kunne ikke katalysere esterificeringen af arabinose eller xylose med hydroxycinnamater i systemer af ionisk væske og buffer eller i mikroemulsioner. Dog kunne begge ferulinsyreesteraser katalysere feruloylering og/eller sinapoylering af kationen C2OHMIm+; dette understreger at ferulinsyreesteraserne har en bred acceptorspecificitet og således har potentiale for at kunne gøre nytte i andre, mere brugbare reaktioner med solventet. En modificeret sialidase fra Trypanosoma rangeli, Tr6, kan katalysere trans-sialylering, fx produktion af 3’-sialyllaktose fra laktose og kaseinglykomakropeptid (CGMP), men reaktionsudbyttet trækkes ned af substrat- og produkthydrolyse. Ved at tilsætte 20-25 % (v/v) t-butanol blev trans-sialyleringsudbyttet øget 1,4 gange, og forholdet mellem syntese og hydrolyse blev øget 1,2 gange. Forholdet mellem syntese og hydrolyse blev også øget ved at tilsætte ioniske væsker som co-solventer, men på bekostning af enzymaktiviteten. Tilbage i vandigt miljø kunne immobilisering af Tr6 på magnetiske nanopartikler øge forholdet mellem syntese og hydrolyse 2,1 gange og desuden give en 2,5 gange forøget biokatalytisk produktivitet (mg produkt pr. mg enzym). Desværre tabte de magnetiske nanopartikler en stor del af enzymaktiviteten i brug og kunne kun genbruges få gange. I stedet kunne frit Tr6 bruges i en membranreaktor med et 1,3 gange højere udbytte på sialyldonoren (CGMP) til følge; dette understreger, at kontinuert fjernelse af produktet vha. en membranreaktor er en brugbar metode til at undgå produkthydrolyse. Stabiliteten af Tr6 var høj i membranreaktoren, og 7 ganges genbrug resulterede i mere end 9 ganges forøgelse af den biokatalytiske produktivitet. Det kan konkluderes, at omhyggelig udvælgelse af både enzymstrukturer og solventsystemer nødvendig i reaktioner hvor ukonventionelle solventer
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