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) 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, 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
Yuqi Yu, Arnau Rue Casamajo, William Finnigan, Christian Schnepel, Rhys Barker, Charlotte Morrill, Rachel S. Heath, Leonardo De Maria, Nicholas J. Turner, Nigel S. Scrutton
Summary: Biocatalysis plays a crucial role in the discovery, development, and manufacturing of pharmaceuticals. A structure-based computational workflow called IREDFisher has been developed to prioritize protein sequences based on predicted activities, reducing the need for resource-intensive laboratory-based screening. IREDFisher successfully identified highly active imine reductases for various reactions, significantly reducing the number of samples that need to be tested in vitro. With a user-friendly web interface, IREDFisher enables rapid discovery of biocatalysts with minimal time and resource expenditure.
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, 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, 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, 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.
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
Jinmei Zhu, Lu Yang, Jiequn Wu, Zixin Deng, Xudong Qu
Summary: By improving the specificity synthesis method for sterically hindered amines, researchers successfully synthesized the important 1-aryl-tetrahydro-beta-carboline framework, providing a new approach for its application in natural products and pharmaceuticals.
Article
Chemistry, Multidisciplinary
Mario Prejano, Xiang Sheng, Fahmi Himo
Summary: In this study, DFT calculations were used to investigate the reaction mechanism and enantioselectivity origin of IRED from Amycolatopsis orientalis. Results show that the calculated energies and transition states geometries are consistent with experimental observations, providing insights into the origins of enantioselectivity of this enzyme.
Article
Chemistry, Physical
Silvia Anselmi, Alexandra T. P. Carvalho, Angela Serrano-Sanchez, Jose L. Ortega-Roldan, Jill Caswell, Iman Omar, Gustavo Perez-Ortiz, Sarah M. Barry, Thomas S. Moody, Daniele Castagnolo
Summary: This study identifies selective and robust MsrA biocatalysts capable of efficiently catalyzing enantioselective reduction of various aromatic and aliphatic chiral sulfoxides at concentrations of 8-64 mM with high yields and excellent enantiomeric excess (up to 99%). Through rational mutagenesis design using in silico docking, molecular dynamics, and structural nuclear magnetic resonance (NMR) studies, a mutant enzyme MsrA33 was developed, which can catalyze the kinetic resolution of bulky sulfoxide substrates with non-methyl substituents on the sulfur atom with enantiomeric excess up to 99%, overcoming a significant limitation of current MsrA biocatalysts.
Article
Chemistry, Multidisciplinary
Davide Arnodo, Federica De Nardi, Stefano Parisotto, Eugenio De Nardo, Stefania Canana, Federica Salvatico, Elisa De Marchi, Dina Scarpi, Marco Blangetti, Ernesto G. Occhiato, Cristina Prandi
Summary: The enantioselective reduction of 2-substituted cyclic imines to corresponding amines using imine reductases in non-conventional solvents has been reported. The method achieved high conversions, moderate to good yields, and excellent enantioselectivities. A fed-batch protocol was developed for scale-up transformation, resulting in efficient production of enantiopure amines.
Article
Chemistry, Physical
Dominik Karrer, Martin Gand, Martin Ruhl
Summary: This study introduces a new type of ene/yne-reductase with a broad substrate scope that can efficiently reduce various aliphatic and aromatic alkenes and alkynes. The research found slightly different reduction pathways for alkenes and alkynes, and revealed regioselective reduction of double bonds at specific positions.
Article
Chemistry, Multidisciplinary
Haidong Peng, Yaya Wang, Kai Jiang, Xinru Chen, Wenlu Zhang, Yanan Zhang, Zixin Deng, Xudong Qu
Summary: This study identified a crucial biosynthetic pathway that efficiently converts phytosterols into 4-Androstenedione and progesterone, providing effective production routes for steroid drugs.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2021)
Article
Chemistry, Applied
Zhuotao Tan, Yaoying Han, Yaping Fu, Xiaowang Zhang, Mengjiao Xu, Qi Na, Wei Zhuang, Xudong Qu, Hanjie Ying, Chenjie Zhu
Summary: The study synthesized a series of C-5 methyl modified NCBs, finding that the hydrophobic interaction caused by the introduced methyl group contributed to the stabilization of binding conformation in enzyme active site, resulting in comparable catalytic activity with that of NADPH.
ADVANCED SYNTHESIS & CATALYSIS
(2022)
Article
Chemistry, Multidisciplinary
Xiaoli Yan, Jun Zhang, Hongqun Tan, Zhihao Liu, Kai Jiang, Wenya Tian, Mengmeng Zheng, Zhi Lin, Zixin Deng, Xudong Qu
Summary: This study reveals a novel polyketide synthase system involving two unique KAS IIIs in the synthesis of asukamycin. These KAS IIIs exhibit initiation and iterative elongation activity and functionally biased towards different steps. By cooperating with other enzymes, various polyenes can be efficiently synthesized.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2022)
Article
Plant Sciences
Kai Jiang, Xiaoli Yan, Zixin Deng, Chun Lei, Xudong Qu
Summary: This study develops new antibiotics through genome mining and biocatalytic modification of chemical structures. The newly obtained fasamycin derivatives show significant activity against Staphylococcus aureus and Bacillus subtilis, especially the C-29-methyl and C-2/C-22-halogen derivatives.
JOURNAL OF NATURAL PRODUCTS
(2022)
Article
Chemistry, Physical
Jinmei Zhu, Lu Yang, Jiequn Wu, Zixin Deng, Xudong Qu
Summary: By improving the specificity synthesis method for sterically hindered amines, researchers successfully synthesized the important 1-aryl-tetrahydro-beta-carboline framework, providing a new approach for its application in natural products and pharmaceuticals.
Article
Chemistry, Multidisciplinary
Mengmeng Zheng, Jun Zhang, Wan Zhang, Lu Yang, Xiaoli Yan, Wenya Tian, Zhihao Liu, Zhi Lin, Zixin Deng, Xudong Qu
Summary: In this study, an ACS enzyme was improved through protein engineering, leading to enhanced activity in synthesizing acyl-CoAs. By combining it with carboxylases, several novel antimycin analogues were successfully produced through a modified biosynthetic pathway. This study expands the catalytic mode of ACSs and provides an important tool for the biosynthesis of acyl-CoA-derived natural products.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2022)
Article
Chemistry, Organic
Zhi Lin, Xudong Qu
Summary: This article reviews three recently reported polyketide synthases (PKSs) that demonstrate novel and representative biosynthetic pathways, providing new insights into the mechanistic and structural diversity of PKSs.
TETRAHEDRON LETTERS
(2022)
Article
Biotechnology & Applied Microbiology
Lan Jiang, Kangjie Lv, Guoliang Zhu, Zhi Lin, Xue Zhang, Cuiping Xing, Huanting Yang, Weiyan Zhang, Zhixin Wang, Chengwei Liu, Xudong Qu, Tom Hsiang, Lixin Zhang, Xueting Liu
Summary: The research on BFTS from plant endophytic fungi has led to the discovery of new terpenoids with different biological activities, demonstrating the potential of the two-enzyme biosynthetic system to produce structurally unique terpenoids.
SYNTHETIC AND SYSTEMS BIOTECHNOLOGY
(2022)
Article
Chemistry, Multidisciplinary
Zhijun Tang, Bo Pang, Chang Liu, Shengjie Guo, Xudong Qu, Wen Liu
Summary: SFA is a spirolactam-conjugated, 22-membered macrolide with remarkable immunosuppressive and antiviral activities. The formation and loading of the starter unit in the SFA assembly line involve two unusual enzymatic reactions that occur on a discrete acyl carrier protein, SfaO.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
Article
Chemistry, Multidisciplinary
Chenghai Sun, Bao-Di Ma, Guangjun Li, Wenya Tian, Lu Yang, Haidong Peng, Zhi Lin, Zixin Deng, Xu-Dong Kong, Xudong Qu
Summary: Through genome mining and study of the sequence-product relationship, we identified three key residues (F387, F388, and E73) that play pivotal roles in selecting different diketopiperazine (DKP) substrates. Engineering these residues in Nas(F5053) greatly expanded its substrate specificity, enabling the biosynthesis of 12 self-dimerized and at least 81 cross-dimerized HTDKPs. Structural and molecular dynamics analysis of F387G and E73S revealed that they control substrate specificity by reducing steric hindrance and regulating substrate tunnels.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
Article
Chemistry, Organic
Wenya Tian, Xinru Chen, Jun Zhang, Mengmeng Zheng, Guangzheng Wei, Zixin Deng, Xudong Qu
Summary: A cryptic tetronate biosynthetic pathway was discovered in Kitasatospora niigatensis DSM 44781 through heterologous expression. Unlike the known pathways, this system utilizes a partially functional nonribosomal peptide synthetase and a broadly selective polyketide synthase to assemble and lactonize the tetronate scaffold. By using a permissive crotonyl-CoA reductase/carboxylase to provide different extender units, seven new tetronates (kitaniitetronins A-G) were obtained via precursor-directed biosynthesis.
Article
Multidisciplinary Sciences
Zhi Lin, Zhiwei Hu, Linjun Zhou, Benben Liu, Xiaowei Huang, Zixin Deng, Xudong Qu
Summary: Small-molecule carboxyl methyltransferases (CbMTs) have important physiological functions and are mostly found in plants as members of the SABATH family. This study identified a distinct type of CbMT (OPCMT) in Mycobacteria, which has a different catalytic mechanism. The OPCMT_like MTs can accept diverse carboxylic acids and are widely distributed in microorganisms, including well-known pathogens.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Chemistry, Multidisciplinary
Wengui Wang, Yingyue Song, Shuya Xing, Jinfeng Li, Wei Feng, Xudong Qu, Shoufeng Wang
Summary: In this study, a silver-catalyzed Minisci-type reaction is reported for the alkylation of electron-deficient N-heteroarenes in aqueous solution. The reaction proceeds through decarboxylative cross-coupling of aliphatic acids without the need for external Bronsted acid, and is conducted in open air. Selectfluor is used as a mild oxidant. The reaction shows tolerance towards different substituents on heteroarenes and acids, allowing efficient introduction of primary and secondary alkyl groups into the heteroarenes.
Review
Chemistry, Multidisciplinary
Fengqiao Zhu, Wengui Wang, Xudong Qu, Shoufeng Wang
Summary: Thiopetheride antibiotics are a class of ribosomal peptides produced by microbial secondary metabolism. They have important biological activities, but their poor water solubility and low bioavailability limit their clinical application. Researchers have achieved rapid progress in improving the physicochemical properties of thiopetheride antibiotics through chemical semi-synthetic modification.
ACTA CHIMICA SINICA
(2022)
Review
Biochemistry & Molecular Biology
Chenghai Sun, Wenya Tian, Zhi Lin, Xudong Qu
Summary: This article reviews the progress made in the past few decades regarding the different substitutions on the C3 position of Pyrroloindoline-containing natural products (PiNPs), especially the various key enzymatic mechanisms involved in the biosynthesis of different types of PiNPs.
NATURAL PRODUCT REPORTS
(2022)