Article
Chemistry, Multidisciplinary
Jun Zhang, Daohong Liao, Rongchang Chen, Fangfang Zhu, Yaqing Ma, Lei Gao, Ge Qu, Chengsen Cui, Zhoutong Sun, Xiaoguang Lei, Shu-Shan Gao
Summary: In this study, a concise strategy combining rational design and engineering techniques was developed to enhance the substrate scope and catalytic efficiency of imine reductases (IREDs). The variant M5 exhibited superior performance and broad substrate scope for the synthesis of diverse azacycloalkylamines. This study provides exciting opportunities in medicinal and process chemistry as well as synthetic biology.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2022)
Article
Chemistry, Multidisciplinary
Peiyuan Yao, James R. Marshall, Zefei Xu, Jesmine Lim, Simon J. Charnock, Dunming Zhu, Nicholas J. Turner
Summary: In this study, a new stereoselective biocatalytic synthesis method for N-substituted alpha-amino esters was reported, utilizing diverse metagenomic imine reductases. Both enantiomers of the target products were synthesized with high conversion and excellent enantioselectivity under mild reaction conditions. Furthermore, over 20 different preparative scale transformations were performed, demonstrating the scalability of this system.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2021)
Article
Chemistry, Physical
Jeremy Steflik, Amelia Gilio, Michael Burns, Gideon Grogan, Rajesh Kumar, Russell Lewis, Carlos Martinez
Summary: This study reports a method for biocatalytic reductive amination reactions, which have high potential value in pharmaceutical synthesis. The researchers identified and engineered a RedAm enzyme to catalyze the synthesis of a key intermediate for a cyclin-dependent kinase (CDK) inhibitor. The optimized enzyme variant showed high productivity at high substrate concentrations (50-fold improvement over the wild-type). Crystal structures of both the wild-type and mutant enzymes were solved to elucidate the structural changes that improved the performance of the RedAm under process conditions. This work demonstrates the versatility and industrial utility of RedAm-catalyzed reductive amination by enabling the synthesis of a chiral intermediate on a multikilogram scale.
Article
Chemistry, Physical
Eric J. Ma, Elina Siirola, Charles Moore, Arkadij Kummer, Markus Stoeckli, Michael Faller, Caroline Bouquet, Fabian Eggimann, Mathieu Ligibel, Dan Huynh, Geoffrey Cutler, Luca Siegrist, Richard A. Lewis, Anne-Christine Acker, Ernst Freund, Elke Koch, Markus Vogel, Holger Schlingensiepen, Edward J. Oakeley, Radka Snajdrova
Summary: This study evaluated machine-directed evolution as an enzyme engineering strategy and found that within one cycle, it yielded a library of high-activity mutants with a significantly different activity distribution compared to traditional directed evolution. Structure-guided analysis suggested that linear additivity might provide a simple explanation for the effectiveness of machine-directed evolution in accessing chiral molecules.
Article
Chemistry, Physical
Ewald P. J. Jongkind, Aurelie Fossey-Jouenne, Ombeline Mayol, Anne Zaparucha, Carine Vergne-Vaxelaire, Caroline E. Paul
Summary: Accessing chiral amines with high enantiomeric and diastereomeric excess was achieved through the development of a bi-enzymatic cascade using Old Yellow Enzyme family enzymes. Different unsaturated carbonyl substrates were successfully converted with up to 99% selectivity, showcasing the potential of this approach for diverse alkene substrates.
Article
Chemistry, Physical
Itziar Penafiel, Robert A. W. Dryfe, Nicholas J. Turner, Michael F. Greaney
Summary: The integration of electro and bio-catalysis offers new ways of making molecules under very mild, environmentally benign conditions. The combined process offers a new approach to amine alkylation with native alcohols, a key bond formation in the chemical economy that is currently achieved via precious metal-catalyzed hydrogen-borrowing technologies.
Review
Chemistry, Physical
Kai Wu, Junhai Huang, Lei Shao
Summary: The synthesis of chiral amines is important in the pharmaceutical industry. IRED, a promising biocatalyst, has been found to catalyze direct asymmetric reductive amination and conjugate reduction, producing valuable amine diastereomers. This review provides insights into the catalytic mechanisms of IREDs and highlights their potential for industrial applications.
Review
Biotechnology & Applied Microbiology
Andras Telek, Zsofia Molnar, Beata G. Vertessy, Gabor Tasnadi
Summary: This review summarizes the current knowledge of opines and opine-type chemicals, highlighting their diverse biochemical roles and potential as synthetic building blocks of bioactive compounds. The synthesis of opines involves the reductive amination of ketoacids with amino acids, which has high synthetic potential in producing enantiopure secondary amines. While only one enzyme has been used as a biocatalyst for this transformation, analysis suggests that more enzymes can be exploited in synthetic organic chemistry.
BIOTECHNOLOGY AND BIOENGINEERING
(2023)
Review
Chemistry, Organic
Tingting Li, Qian Zhou, Fanjing Meng, Wenhui Cui, Qian Li, Jiang Zhu, Yang Cao
Summary: This review provides a summary of the recent advances in organocatalytic and biocatalytic asymmetric reductive amination (ARA), which is a challenging but significant topic for drug discovery and the pharmaceutical industry. ARA can be categorized into three types: metal catalysis, organic catalysis, and biocatalysis. Transition metal-catalyzed ARA has been well-established, while organocatalytic ARA has emerged as a powerful alternative. Biocatalytic ARA has also shown remarkable progress in the past decade, with the successful utilization of various enzymes.
EUROPEAN JOURNAL OF ORGANIC CHEMISTRY
(2023)
Article
Chemistry, Physical
Qi Chen, Bo-Bo Li, Lilan Zhang, Xin-Ru Chen, Xin-Xin Zhu, Fei-Fei Chen, Min Shi, Chun-Chi Chen, Yu Yang, Rey-Ting Guo, Weidong Liu, Jian-He Xu, Gao-Wei Zheng
Summary: An engineered IRED with significantly improved activity and stability was developed through three rounds of evolution. The use of this engineered enzyme allowed for complete reduction of a cyclic imine, resulting in high yield and high enantiomeric excess of an important chiral intermediate.
Article
Chemistry, Physical
Amelia K. Gilio, Thomas W. Thorpe, Alex Heyam, Mark R. Petchey, Balazs Pogranyi, Scott P. France, Roger M. Howard, Michael J. Karmilowicz, Russell Lewis, Nicholas Turner, Gideon Grogan
Summary: Imine reductases (IREDs) catalyze the reduction of cyclic imines and the coupling of ketones and amines, forming secondary amine products. IR77 enzyme was found to catalyze the coupling of larger bicyclic amines with cyclohexanone. Mutant IR77-A208N with improved activity for amine product formation was successfully synthesized using structure-guided mutagenesis.
Article
Chemistry, Physical
Amelia K. Gilio, Thomas W. Thorpe, Alex Heyam, Mark R. Petchey, Balazs Pogranyi, Scott P. France, Roger M. Howard, Michael J. Karmilowicz, Russell Lewis, Nicholas Turner, Gideon Grogan
Summary: Imine reductases (IREDs) can catalyze the reduction of cyclic imines and the coupling of ketones and amines to form secondary amine products. The larger amines used in the coupling reactions were likely recruited from solution for enzyme reduction. Mutant IR77-A208N showed improved activity for amine product formation.
Article
Chemistry, Physical
Amelia K. Gilio, Thomas W. Thorpe, Alex Heyam, Mark R. Petchey, Balazs Pogranyi, Scott P. France, Roger M. Howard, Michael J. Karmilowicz, Russell Lewis, Nicholas Turner, Gideon Grogan
Summary: Imine reductases (IREDs) can catalyze the reduction of cyclic imines and the coupling of ketones and amines to form secondary amine products. Previous studies mainly focused on using small hydrophobic amines, but for certain pharmaceutical targets, larger amines are required. In this study, the enzyme IR77 from Ensifer adhaerens was found to be a promising biocatalyst for the reductive amination of cyclohexanone with pyrrolidine. The mutant IR77-A208N showed improved activity for amine product formation, leading to isolated yields of up to 93% for the amination of cyclohexanone with larger amines.
Article
Chemistry, Multidisciplinary
Joan Citoler, Vanessa Harawa, James R. Marshall, Han Bevinakatti, James D. Finnigan, Simon J. Charnock, Nicholas J. Turner
Summary: The efficient biocatalytic approach for the synthesis of 2-aminotetralin and 3-aminochroman derivatives was reported, achieving high yields and enantioselectivity for over 15 examples. Additionally, a chemo-enzymatic total synthesis of the Parkinson's disease therapy Rotigotine was successfully accomplished with a 63% overall yield and 92% ee.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2021)
Article
Chemistry, Multidisciplinary
Fengwei Chang, Chengyi Wang, Qipeng Chen, Yongjin Zhang, Guohua Liu
Summary: The combination of biocatalysis and transition-metal catalysis can bridge synthetic gaps in chemical or biological processes, but the deactivation between enzymatic and chemical species poses a significant challenge. Researchers developed an encapsulated Au/carbene and free amine dehydrogenase co-catalyst system, enabling efficient hydration/amination enantioselective cascade reaction.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2022)
Article
Biochemistry & Molecular Biology
Peter Stockinger, Luca Schelle, Benedikt Schober, Patrick C. F. Buchholz, Juergen Pleiss, Bettina M. Nestl
Article
Chemistry, Multidisciplinary
Ludwig L. Bengel, Benjamin Aberle, Alexander-N. Egler-Kemmerer, Samuel Kienzle, Bernhard Hauer, Stephan C. Hammer
Summary: Selective alkylation of pyrazoles using a catalyst-controlled enzymatic system allows for the efficient synthesis of important molecules with unprecedented regioselectivity. The use of a computational enzyme-library design tool enabled the conversion of a promiscuous enzyme into a small enzyme family of pyrazole-alkylating enzymes in one round of mutagenesis and screening. This enzymatic system demonstrates high selectivity and achieves different alkylations of pyrazoles with remarkable regiodivergence.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2021)
Article
Biochemistry & Molecular Biology
Kai H. Schuelke, Felipe Ospina, Kathrin Hoernschemeyer, Sebastian Gergel, Stephan C. Hammer
Summary: SAM-dependent methyltransferases (MTs) and SAM analogs can be used for biocatalytic alkylation reactions with high selectivity. Halide methyltransferases (HMTs) enable the synthesis and recycling of SAM analogs using easily available haloalkanes. Anion MTs show promiscuity towards alkyl chains and halide leaving groups, and they cluster in sequence space. This study expands the application of SAM analogs in regioselective reactions using haloalkanes as substrates.
Article
Chemistry, Physical
Peter Stockinger, Niels Borlinghaus, Mahima Sharma, Benjamin Aberle, Gideon Grogan, Juergen Pleiss, Bettina M. Nestl
Summary: Enzyme engineering was used to switch the selectivity of NADH-IRED-Ms, leading to a variant with (S)-selectivity in asymmetric reductions; the quintuple variant exhibited high catalytic efficiency and reverse stereopreference in the reduction of cyclic imine, achieving >99% conversion and 91% enantiomeric excess.
Review
Chemistry, Multidisciplinary
Felipe Ospina, Kai H. Schuelke, Stephan C. Hammer
Summary: Biocatalysis has traditionally been used for obtaining chiral centers, but recent research has focused on developing enzymes that catalyze sp(3) bond formations, providing a new way to build molecules with high activity and selectivity. This shift highlights the success of designing new enzyme functions, particularly when utilizing off-the-shelf synthetic reagents to access non-natural reactive intermediates.
Article
Chemistry, Multidisciplinary
Felipe Ospina, Kai H. Schuelke, Jordi Soler, Alina Klein, Benjamin Prosenc, Marc Garcia-Borras, Stephan C. Hammer
Summary: This study reports a new method for regioselective N-methylation of unsaturated heterocycles. By using two methyltransferases and simple reagents, important molecules with biological activities can be synthesized efficiently.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2022)
Article
Chemistry, Multidisciplinary
Jordi Soler, Sebastian Gergel, Cindy Klaus, Stephan C. Hammer, Marc Garcia-Borras
Summary: A new enzyme called aMOx has been evolved in the laboratory, which can efficiently and selectively oxidize styrenes to their corresponding aldehydes. This study combines computational modeling and mechanistic experiments to reveal the molecular basis behind the selectivity achieved by aMOx. The results show that the enzyme controls the accessible conformations of the covalent radical intermediate, disfavoring epoxidation and promoting the formation of a carbocation intermediate that generates the desired aldehyde product.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2022)
Article
Chemistry, Multidisciplinary
Matus Gajdos, Jendrik Wagner, Felipe Ospina, Antonia Koehler, Martin K. M. Engqvist, Stephan C. Hammer
Summary: In this study, a fatty acid hydratase from Marinitoga hydrogenitolerans was identified and evolved for the highly enantioselective hydration of styrenes, resulting in chiral 1-arylethanols. The evolved enzyme exhibited remarkable asymmetric styrene hydration activity in the absence of small molecule activators. This engineered styrene hydratase enables the synthesis of chiral alcohols from simple alkenes and water with high enantioselectivity (>99 : 1 e.r.) and can be used on a preparative scale.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
Article
Chemistry, Multidisciplinary
Benjamin Aberle, Daniel Kowalczyk, Simon Massini, Alexander-N. Egler-Kemmerer, Sebastian Gergel, Stephan C. C. Hammer, Bernhard Hauer
Summary: In this study, (S)-adenosyl-l-methionine-dependent sterol methyltransferases were identified and engineered for selective C-methylation of linear terpenoids. The method allows for the modification of carbon scaffold of alkenes and terpenoids by selective methylation.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
Article
Chemistry, Physical
Bernd A. Nebel, Michael Breuer, Andreas Schneider, Benjamin Aberle, Stephan C. Hammer, Per-Olof Syren, Martin J. Weissenborn, Bettina M. Nestl
Summary: This article reflects on Professor Bernhard Hauer's distinguished career in biocatalysis and highlights his contributions to the application and development of enzymes.
Article
Chemistry, Physical
Sebastian Gergel, Jordi Soler, Alina Klein, Kai H. Schuelke, Bernhard Hauer, Marc Garcia-Borras, Stephan C. Hammer
Summary: Researchers have developed an engineered enzyme that can catalyze the direct synthesis of ketones from internal alkenes with high turnover rates and selectivity. This discovery provides a new method for synthesis and opens up possibilities for various functionalization reactions of alkenes.
Article
Chemistry, Multidisciplinary
Arne Hoffmann, Kai H. Schuelke, Stephan C. Hammer, Andrea Rentmeister, Nicolas V. Cornelissen
Summary: Methyltransferases show excellent specificity in late-stage alkylation of biomolecules. SAM analogues are necessary for efficient access to SAM for biocatalytic applications, and both halide methyltransferase (HMT) and methionine adenosyltransferase (MAT) provide SAM analogues for alkylation reactions. The HMT cascade efficiently provides SAM for methylation, while the MAT cascade also supplies high levels of SAM analogues for alkylation reactions.
CHEMICAL COMMUNICATIONS
(2023)
Article
Multidisciplinary Sciences
Wendy Escobedo-Hinojosa, Stephan C. Hammer, Julian L. Wissner, Bernhard Hauer
Summary: The researchers established a customized method for the production of isobutyl-monophosphate (ammonium salt), which is fast, easy and affordable.
Article
Chemistry, Multidisciplinary
Ammar Al-Shameri, Niels Borlinghaus, Leonie Weinmann, Philipp N. Scheller, Bettina M. Nestl, Lars Lauterbach
