Article
Chemistry, Multidisciplinary
Andrew J. J. Devine, Alice E. E. Parnell, Catherine R. R. Back, Nicholas R. R. Lees, Samuel T. T. Johns, Ainul Z. Z. Zulkepli, Rob Barringer, Katja Zorn, James E. M. Stach, Matthew P. P. Crump, Martin A. A. Hayes, Marc W. W. van der Kamp, Paul R. R. Race, Christine L. L. Willis
Summary: This study reveals the key epoxidation reaction in the synthesis of Abyssomicin C and the structure of the enzyme AbyV involved in this reaction. The combination of selective carbon-13 labeling with NMR spectroscopy proves to be an important tool in studying enzyme-catalyzed reactions in vitro.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
Article
Chemistry, Multidisciplinary
Li Zhang, Bo Zhang, Ao Zhu, Shuang He Liu, Rui Wu, Xuan Zhang, Zhengren Xu, Ren Xiang Tan, Hui Ming Ge
Summary: This study reveals the biosynthesis of phomactin natural products, which only requires two enzymes and involves rearrangement of the diterpene scaffold. The mechanism of phomactin biosynthesis was investigated through isotope labeling experiments and crystal complex analysis, providing insights into the efficient production of phomactins using synthetic biology approaches.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
Article
Chemistry, Multidisciplinary
Yu Meng Yang, Er Juan Zhao, Wanqing Wei, Zi Fei Xu, Jing Shi, Xuan Wu, Bo Zhang, Yasuhiro Igarashi, Rui Hua Jiao, Yong Liang, Ren Xiang Tan, Hui Ming Ge
Summary: In this study, a cytochrome P450 enzyme that can catalyze the formation of a benzene ring from an acyclic polyene substrate has been characterized. Through genome mining guided by this P450 enzyme, 12 homologous type I polyketide synthase gene clusters were obtained, among which two clusters were found to produce trialkyl-substituted aromatic polyketides. Quantum chemical calculations were performed to explore the possible mechanism for the P450-catalyzed benzene ring formation, expanding our knowledge of the catalytic diversity of cytochrome P450.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
Article
Chemistry, Multidisciplinary
Joon Soo An, Hyunbin Lee, Hyungyu Kim, Seungyeon Woo, Hyunsung Nam, Jayho Lee, Ji Yun Lee, Sang-Jip Nam, Sang Kook Lee, Ki-Bong Oh, Seokhee Kim, Dong-Chan Oh
Summary: Cihunamides A-D (1-4), novel antibacterial RiPPs, were isolated from volcanic-island-derived Streptomyces sp. The structures of 1-4 were elucidated by various analytical methods, and they contain a tetrapeptide core composed of WNIW, cyclized by a unique C-N linkage between two Trp units. Genome mining and heterologous co-expression experiments provided insights into the biosynthesis of cihunamides and their relationship with tryptorubins. A new RiPP family name, bitryptides, is proposed for cihunamides, tryptorubins, and similar compounds based on their Trp-Trp linkages.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
Article
Chemistry, Multidisciplinary
Jing Liu, Lauritz Harken, Yiling Yang, Xiulan Xie, Shu-Ming Li
Summary: This study reports two important gene clusters involved in the biosynthesis of mycocyclosin and guatyromycine. By reconstructing the biosynthetic pathways and conducting biochemical investigations, it was found that the enzymes encoded by these genes can catalyze both intramolecular oxidation and intermolecular nucleobase transfer reactions, leading to the synthesis of specific natural products.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2022)
Review
Biotechnology & Applied Microbiology
Lihong Jiang, Lei Huang, Jin Cai, Zhinan Xu, Jiazhang Lian
Summary: This article discusses the strategies for improving the expression and activity of eukaryotic P450s in yeast, followed by examples of P450s involved in biosynthetic pathway engineering.
BIOTECHNOLOGY AND BIOENGINEERING
(2021)
Review
Biotechnology & Applied Microbiology
Anup Adhikari, Sajan Shakya, Shreesti Shrestha, Dipa Aryal, Kavi Prasad Timalsina, Dipesh Dhakal, Yogan Khatri, Niranjan Parajuli
Summary: Cytochrome P450s are heme-binding monooxygenases that catalyze functionalization of various bonds, including heteroatom oxidation and C-C bond cleavage. Despite their biotechnological potential, P450s require redox partners for chemical transformations. This review focuses on the role of P450s in antibiotic biosynthesis, specifically macrolides, aminocoumarin antibiotics, NRPSs antibiotics, and RiPPs antibiotics.
BIOTECHNOLOGY AND BIOENGINEERING
(2023)
Article
Biochemistry & Molecular Biology
Guangchun Gao, Jiming Wu, Bai Li, Qi Jiang, Ping Wang, Jun Li
Summary: This study identified differentially expressed genes in saffron at different flowering stages and pinpointed cytochrome P450 genes potentially involved in crocin biosynthesis. The research sheds light on the molecular mechanisms underlying saffron quality and yield.
MOLECULAR BIOLOGY REPORTS
(2021)
Article
Pharmacology & Pharmacy
Line Skute Braten, Tore Haslemo, Marin M. Jukic, Maxim Ivanov, Magnus Ingelman-Sundberg, Espen Molden, Marianne Kristiansen Kringen
Summary: Escitalopram, a commonly used antidepressant drug, shows substantial interindividual variation in clinical response, which can be attributed to the polymorphic nature of the CYP2C19 gene. A novel CYP2C-haplotype associated with ultrarapid metabolism of escitalopram was identified in this study.
CLINICAL PHARMACOLOGY & THERAPEUTICS
(2021)
Article
Multidisciplinary Sciences
Yunjun Pan, Guobang Li, Ruxin Liu, Jiawei Guo, Yunjie Liu, Mingyu Liu, Xingwang Zhang, Luping Chi, Kangwei Xu, Ruibo Wu, Yuzhong Zhang, Yuezhong Li, Xiang Gao, Shengying Li
Summary: Cytochrome P450 enzymes play crucial roles in the biosynthesis of macrolide antibiotics. However, the 20 proteinogenic amino acids may not always meet the requirements of site-directed/random mutagenesis and rational protein design. In this study, the authors employed semi-rational non-canonical amino acid mutagenesis to improve the enzyme's activity and gain mechanistic insights.
NATURE COMMUNICATIONS
(2023)
Article
Biochemical Research Methods
Guang Chen, Mengqiu Wang, Xianpu Ni, Huanzhang Xia
Summary: Tetramycin is a tetraene antibiotic used in agriculture, consisting of two components tetramycin A and tetramycin B. By manipulating gene clusters and overexpressing enzymes, high-yield strains of tetramycin A and different ratios of tetramycin A and tetramycin B were successfully constructed.
JOURNAL OF BIOLOGICAL ENGINEERING
(2021)
Article
Chemistry, Multidisciplinary
Jie Chen, Sheng Dong, Wenhan Fang, Yiping Jiang, Zhifeng Chen, Xiangquan Qin, Cong Wang, Haifeng Zhou, Longyi Jin, Yingang Feng, Binju Wang, Zhiqi Cong
Summary: We report the selective hydroxylation of alkylbenzenes using an engineered P450 peroxygenase driven by a dual-functional small molecule (DFSM). By combining different P450BM3 variants with DFSMs, more than half of all possible hydroxylated products were obtained from each substrate with high regioselectivity (>99%), enantioselectivity (>99% ee), and high total turnover numbers (up to 80963). Synergistic effects between exogenous DFSMs and the protein environment controlled the regio- and enantioselectivity, as revealed by crystal structure analysis, molecular dynamic simulations, and theoretical calculations. This work has implications for exogenous-molecule-modulated enzymatic regiodivergent and enantioselective hydroxylation with potential applications in synthetic chemistry.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
Review
Biotechnology & Applied Microbiology
Baodong Hu, Xinrui Zhao, Endao Wang, Jingwen Zhou, Jianghua Li, Jian Chen, Guocheng Du
Summary: Natural products are structurally diverse molecules with a wide range of biological activities. Cytochrome P450 enzymes are involved in the biosynthesis of many natural products and recent research has provided new insights for their application in the biosynthesis of natural products.
CRITICAL REVIEWS IN BIOTECHNOLOGY
(2023)
Article
Plant Sciences
Simon Miranda, Jorge Lagreze, Anne-Sophie Knoll, Andrea Angeli, Richard Espley, Andrew P. Dare, Mickael Malnoy, Stefan Martens
Summary: In this study, researchers identified putative 3-hydroxylases in two wild Malus species that are capable of producing sieboldin, a specialised secondary metabolite of the dihydrochalcone group. They also discovered key residues mutations in the CYP98A protein of wild accessions that allow it to accept the substrate phloretin, leading to sieboldin accumulation. These findings provide important insights into the biosynthesis of sieboldin in Malus species.
FRONTIERS IN PLANT SCIENCE
(2022)
Article
Chemistry, Multidisciplinary
Gustavo Perez Ortiz, John D. Sidda, Emmanuel L. C. de los Santos, Catherine B. Hubert, Sarah M. Barry
Summary: The antimycobacterial peptides rufomycins exhibit antibiotic activity due to oxidative tailoring of the cyclic peptide. Cytochrome P450s RufS and RufM play roles in regioselective epoxidation and alkyl oxidation, creating a complex product profile dependent on redox partner availability. Additionally, in vitro one pot conversion of rufomycin B to rufomycin C has been successfully demonstrated.
CHEMICAL COMMUNICATIONS
(2021)
Article
Chemistry, Organic
Aireal D. Jenkins, Michael T. Robo, Paul M. Zimmerman, John Montgomery
JOURNAL OF ORGANIC CHEMISTRY
(2020)
Article
Chemistry, Multidisciplinary
Girish C. Sati, Joshua L. Martin, Yishu Xu, Tanmay Malakar, Paul M. Zimmerman, John Montgomery
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2020)
Article
Chemistry, Physical
Alexander W. Rand, Hongfei Yin, Liang Xu, Jessica Giacoboni, Raul Martin-Montero, Ciro Romano, John Montgomery, Ruben Martin
Article
Chemistry, Organic
Wesley L. Pein, Eric M. Wiensch, John Montgomery
Summary: This study describes the conversion of silyloxyarenes to boronic acid pinacol esters via nickel catalysis, showing competence in activating carbon-oxygen bonds of silyloxyarenes in isolated aromatic systems lacking a directing group. Additionally, catalytic functionalization of benzyl silyl ethers was achieved under these conditions, and sequential cross-coupling reactions were realized by leveraging the orthogonal reactivity of silyloxyarenes.
Article
Chemistry, Physical
Rosa Espinoza, Kersti Caddell Haatveit, S. Wald Grossman, Jin Yi Tan, Caylie A. McGlade, Yogan Khatri, Sean A. Newmister, Jennifer J. Schmidt, Marc Garcia-Borras, John Montgomery, K. N. Houk, David H. Sherman
Summary: Iterative P450 enzymes are powerful biocatalysts for selective late-stage C-H oxidation of complex natural product scaffolds. The study reports the structure of the multifunctional bacterial P450 TamI and the design of a toolbox of TamI biocatalysts, including a variant capable of catalyzing a four-step oxidative cascade without assistance. These tuned enzymes enable catalyst-controlled C-H functionalization and alkene epoxidation, leading to the synthesis of bioactive tirandamycin derivatives. Quantum mechanics calculations and MD simulations provide insights into the altered selectivity and enhanced oxidation mechanisms of the iterative P450 TamI.
Article
Chemistry, Multidisciplinary
Jichao Xiao, Zhenning Li, John Montgomery
Summary: This study demonstrates a method using nickel catalysis and BiOx ligand for the reductive coupling of redox-active esters with aliphatic aldehydes to obtain silyl-protected secondary alcohols. The protocol is simple, mild, and tolerates a variety of functional groups, with potential mechanistic insights pointing towards a radical chain pathway.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2021)
Article
Chemistry, Physical
Jichao Xiao, John Montgomery
Summary: A simple procedure for the nickel-catalyzed defluorinative alkylation of unactivated aliphatic aldehydes is reported. The protocol exhibits broad substrate scope, mild conditions, and a simple catalytic setup.
Article
Chemistry, Organic
Joshua L. Martin, Girish C. Sati, Tanmay Malakar, Jessica Hatt, Paul M. Zimmerman, John Montgomery
Summary: A novel mode of reactivity involving a dioxolenium ion as a key intermediate that promotes both glycosylation and glycosyl exchange pathways has been discovered through experimental and computational mechanistic studies. By modifying the catalyst structure, it is possible to selectively favor one pathway, leading to improved multicomponent iterative couplings and glycosyl exchange processes.
JOURNAL OF ORGANIC CHEMISTRY
(2022)
Article
Chemistry, Physical
Rosa Espinoza, Mark A. Maskeri, Aneta Turlik, Anjanay Nangia, Yogan Khatri, John Montgomery, K. N. Houk, David H. Sherman
Summary: This study reports the ability of bacterial P450 TamI L295A to switch between different oxidizing species in the synthesis of new tirandamycin antibiotics. By providing experimental evidence and theoretical calculations, new insights into the active oxidant species used by P450 TamI are revealed, providing new understanding of the oxidative decorations of tirandamycin.
Article
Chemistry, Inorganic & Nuclear
Michael T. Robo, Amie R. Frank, Ellen Butler, Alex J. Nett, Santiago Canellas, Paul M. Zimmerman, John Montgomery
Summary: This study delves into the activation mechanism of an IMes-nickel(0) catalyst, stabilized by covalent modification of the stabilizing ligand, revealing an unexpected catalyst activation pathway when ligand exchange is thermodynamically unfavorable.
Article
Chemistry, Physical
Mo Chen, John Montgomery
Summary: Regio- and enantioselective functionalization of heteroarene C-H bonds in the absence of directing groups has been a long-standing challenge. In this study, we developed a new approach for intermolecular enantioselective C-H alkylation of heteroarenes using nickel catalysts. The reaction can be carried out under mild conditions without the need for Lewis acid co-catalysts. Synthesis of NHC nickel complexes stabilized with 1,5-hexadiene improved the functional group tolerance and heteroarene scope. Mechanistic investigations revealed a ligand-to-ligand hydrogen transfer pathway.
Article
Chemistry, Multidisciplinary
Mo Chen, Austin M. Ventura, Soumik Das, Ammar F. Ibrahim, Paul M. Zimmerman, John Montgomery
Summary: Current methodologies for metal-catalyzed cross-couplings require the installation of reactive functional groups on both reaction partners in advance. In contrast, C-H functionalization approaches show potential in simplifying the substrates required; however, challenges such as low reactivity and similar reactivity of different C-H bonds add complexity. This study describes an oxidative cross dehydrogenative coupling of α-amino C(sp(3))-H bonds and aldehydes to produce ketone derivatives using an unusual reaction medium that simultaneously utilizes di-tert-butyl peroxide as an oxidant and zinc metal as a reductant. The method has a broad substrate scope and offers an attractive approach for accessing α-amino ketones through the formal acylation of C-H bonds adjacent to nitrogen in N-heterocycles. Experimental investigation and computational modeling provide evidence for a mechanistic pathway involving cross-selective nickel-mediated cross-coupling of α-amino radicals and acyl radicals.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2023)
Article
Chemistry, Multidisciplinary
Cole L. Cruz, John Montgomery
Summary: A mild and convenient coupling reaction between aliphatic aldehydes and unactivated alkyl bromides has been developed using a common Ni(II) precatalyst and a readily available bioxazoline ligand, affording silyl-protected secondary alcohols. The reaction is operationally simple, utilizes Mn as a stoichiometric reductant, and tolerates a wide range of functional groups. The presence of 1,5-hexadiene as an additive plays a crucial role in optimizing yields.
Article
Chemistry, Organic
Annabel Q. Ansel, John Montgomery
Article
Chemistry, Multidisciplinary
Alexander W. Rand, John Montgomery