Article
Chemistry, Multidisciplinary
Anja Greule, Thierry Izore, Daniel Machell, Mathias H. Hansen, Melanie Schoppet, James J. De Voss, Louise K. Charkoudian, Ralf B. Schittenhelm, Jeffrey R. Harmer, Max J. Cryle
Summary: Cytochrome P450 enzymes are enzymes that can perform oxidative reactions using heme. However, some of these enzymes can be damaged by oxidation, leading to decreased enzyme activity. Research has shown that the heme orientation in the active site of certain cytochrome P450 enzymes may contribute to this oxidative damage.
FRONTIERS IN CHEMISTRY
(2022)
Article
Infectious Diseases
Andres Andreo-Vidal, Elisa Binda, Victor Fedorenko, Flavia Marinelli, Oleksandr Yushchuk
Summary: The global health security is challenged by the spread of antimicrobial resistance, affecting even glycopeptide antibiotics. Research has shown that GPA resistance determinants can be found not only in GPA producers, but also in non-producers, indicating a co-evolution of different vlgs.
Article
Chemistry, Medicinal
Vladimir Vimberg, Leona Zieglerova, Aninda Mazumdar, Zsolt Szucs, Aniko Borbas, Pal Herczegh, Gabriela Balikova Novotna
Summary: This paper compares the in vitro activities of two new semisynthetic glycopeptide antibiotics with two clinically used glycopeptide antibiotics, finding that the new antibiotics effectively kill various states of Staphylococcus aureus cells.
Article
Biochemistry & Molecular Biology
Katrina Browne, Rajesh Kuppusamy, William R. Walsh, David StC Black, Mark D. P. Willcox, Naresh Kumar, Renxun Chen
Summary: Antibiotic resistance is a global challenge, and combination therapies using antibiotics and antimicrobial peptidomimetics can mitigate the development of resistance in bacteria. This strategy demonstrates synergistic activity against both Gram-positive and Gram-negative bacteria and has significant potential in clinical applications.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Biochemistry & Molecular Biology
Peter D. Giang, Luke R. Churchman, Jeanette E. Stok, Rochelle M. Soo, James J. De Voss
Summary: A study found that Rhodococcus globerulus (R. globerulus) isolated from soil beneath Eucalyptus sp. can thrive on mono-terpenes such as 1,8-cineole, p-cymene and (R)- and (S)-limonene as its sole sources of carbon and energy. The research revealed a novel cytochrome P450 (CYP108N12) in R. globerulus which may be responsible for initiating the biodegradation of structurally similar monoterpene compounds. This finding suggests that CYP108N12 has potential as a biocatalyst with specific hydroxylation capabilities.
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
(2022)
Article
Engineering, Environmental
Yuhao Chu, Chaofan Zhang, Rupeng Wang, Xi Chen, Nanqi Ren, Shih-Hsin Ho
Summary: This study investigated the biotransformation of sulfamethoxazole by microalgae, particularly highlighting the role of CYP450 enzymes in the degradation process. The research elucidated the SMX biodegradation pathway involving CYP450 in microalgae, providing insights for using microalgae-mediated CYP450 to eliminate antibiotics.
Article
Engineering, Environmental
Yuhao Chu, Chaofan Zhang, Rupeng Wang, Xi Chen, Nanqi Ren, Shih-Hsin Ho
Summary: This study elucidated the SMX biodegradation pathway involving CYP450 in microalgae and revealed key details of the hydroxylamine group. It advances the development of using microalgae-mediated CYP450 to eliminate antibiotics.
Article
Chemistry, Organic
Xin Nie, Zihan Yan, Sergei Ivlev, Eric Meggers
Summary: Enantioselective C(sp(3))-H aminations provide an efficient access to nonracemic chiral amines. This work describes the catalytic asymmetric synthesis of chiral 1,2,5-thiadiazolidine-1,1-dioxides using a recently introduced simple chiral ruthenium bis(oxazoline) complex, achieving high yields and enantioselectivities. Mechanistic experiments confirmed a stepwise mechanism and demonstrated that the cyclic sulfamide products are suitable for the synthesis of chiral vicinal diamines.
JOURNAL OF ORGANIC CHEMISTRY
(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)
Article
Chemistry, Multidisciplinary
Kazuto Suzuki, Joshua Kyle Stanfield, Keita Omura, Yuma Shisaka, Shinya Ariyasu, Chie Kasai, Yuichiro Aiba, Hiroshi Sugimoto, Osami Shoji
Summary: Catching the structure of cytochrome P450 enzymes in flagrante is crucial for the development of P450 biocatalysts. We report the crystal structure of P450BM3 mimicking the state in the precise moment preceding epoxidation, which is in perfect agreement with the experimentally observed stereoselectivity. This method serves as a powerful tool for predicting and modelling the stereoselectivity of P450 reactions.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
Article
Chemistry, Multidisciplinary
Shuaiqi Meng, Yu Ji, Luo Liu, Mehdi D. Davari, Ulrich Schwaneberg
Summary: This study demonstrates that engineering the tunnels of cytochrome P450 can improve coupling efficiency by controlling water diffusion. The reduced water molecules around the active site lead to higher coupling efficiency. This research provides valuable insights for improving coupling efficiency through tunnel engineering.
Review
Biotechnology & Applied Microbiology
Li Tian, Shi Shi, Xiangmei Zhang, Fubo Han, Huijun Dong
Summary: Glycopeptide antibiotics (GPAs) are considered as the last resort for treating severe infections caused by multidrug-resistant Gram-positive pathogens. However, the increasing prevalence of Gram-positive resistant strain superbugs has posed a challenge, requiring further study and modification of GPAs.
WORLD JOURNAL OF MICROBIOLOGY & BIOTECHNOLOGY
(2023)
Article
Biotechnology & Applied Microbiology
Elisa Binda, Francesca Berini, Flavia Marinelli, Adriana Bava, Fabrizio Beltrametti
Summary: Exposing N. gerenzanensis wild-type population to sub-inhibitory concentrations of A40926 led to the isolation of differently resistant phenotypes, with the most resistant population (G) producing twice as much A40926 at bioreactor scale compared to the wild-type. This paves the way for rational strain improvement based on the selection of increasingly self-resistant colonies.
FERMENTATION-BASEL
(2021)
Review
Biochemistry & Molecular Biology
Yongwei Zhao, Y. T. Candace Ho, Julien Tailhades, Max Cryle
Summary: Researchers are intrigued by the complex biosynthesis of glycopeptide antibiotics, particularly the role of the X-domain in recruiting P450 enzymes. In vitro studies have provided insights into the tolerances and limitations of the GPA cyclisation cascade, paving the way for future reengineering of this important antibiotic class.
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
Biochemistry & Molecular Biology
Milda Kaniusaite, Julien Tailhades, Tiia Kittila, Christopher D. Fage, Robert J. A. Goode, Ralf B. Schittenhelm, Max J. Cryle
Summary: The biosynthesis of glycopeptide antibiotics demonstrates the exceptional ability of nonribosomal peptide synthesis to generate diverse and complex structures. An important study on the NRPS assembly lines involved in synthesizing GPAs revealed that they function as dynamic peptide assembly lines, allowing for flexible control over amino acid modifications and peptide formation, which is beneficial for the redesign of important biosynthetic systems.
Review
Biochemistry & Molecular Biology
Yongwei Zhao, Y. T. Candace Ho, Julien Tailhades, Max Cryle
Summary: Researchers are intrigued by the complex biosynthesis of glycopeptide antibiotics, particularly the role of the X-domain in recruiting P450 enzymes. In vitro studies have provided insights into the tolerances and limitations of the GPA cyclisation cascade, paving the way for future reengineering of this important antibiotic class.
Review
Pharmacology & Pharmacy
Xinyu Zhou, Fengzhi Suo, Kristina Haslinger, Wim J. Quax
Summary: This review provides an overview of the effect of artemisinin-type drugs on regulated cell death pathways. It also summarizes the recent advances in two different therapeutic approaches, combination therapy and the use of nanocarriers, to improve the efficacy of these drugs. Both approaches have shown promising findings in vitro and in vivo.
Letter
Biochemistry & Molecular Biology
Daniel L. Machell, Mathias H. Hansen, Max J. Cryle
Summary: Detection of pyrophosphate is crucial for quantifying enzyme activity, especially adenylation domain activity in non-ribosomal peptide synthesis. After screening, viable replacement enzymes with higher activity have been identified, allowing the continued use of the established online assay for pyrophosphate detection.
Review
Biochemistry & Molecular Biology
Riccardo Iacovelli, Nika Sokolova, Kristina Haslinger
Summary: The discovery of new antimicrobials is crucial in combating the advance of multidrug-resistant pathogens. Screening for antimicrobial agents naturally produced by living organisms is a promising approach. Genetically tractable microbes can be used as alternative hosts to aid the discovery process, facilitate product diversification through genetic engineering, and enable environmentally friendly production.
BIOCHEMICAL SOCIETY TRANSACTIONS
(2022)
Article
Biochemistry & Molecular Biology
Y. T. Candace Ho, Ralf B. Schittenhelm, Dumitrita Iftime, Evi Stegmann, Julien Tailhades, Max J. Cryle
Summary: Glycopeptide antibiotics inhibit bacterial cell-wall biosynthesis by sequestration of precursor lipid II. The oxidative crosslinking of the core peptide during GPA biosynthesis is essential and challenging. Understanding the activity and selectivity of Oxy enzymes is important for future engineering of this compound class.
Article
Chemistry, Multidisciplinary
Rania A. A. Hashad, Edwina Jap, Joanne L. L. Casey, Y. T. Candace Ho, Alexander Wright, Claudia Thalmann, Mark Sleeman, David W. W. Lupton, Christoph E. E. Hagemeyer, Max J. J. Cryle, Remy Robert, Karen Alt
Summary: A highly effective 2-step system using engineered methionine residues was used for site-specific antibody modification and conjugation. This system offers a novel way to fundamentally change the process of antibody bioconjugation. The versatility of this system was demonstrated by incorporating a fluorescent dye and can be applied to a wide variety of conjugation partners.
CHEMISTRY-A EUROPEAN JOURNAL
(2023)
Review
Biochemistry & Molecular Biology
Songya Zhang, Yunliang Chen, Jing Zhu, Qiujie Lu, Max J. Cryle, Youming Zhang, Fu Yan
Summary: Streptomyces bacteria are widely distributed in terrestrial and marine environments and are a rich source of active natural products due to their metabolic diversity. This review highlights the importance of nonribosomal lipopeptides as important natural products with diverse biological activities that play crucial roles in the lifestyle of Streptomyces. Recent advances in the biosynthesis of lipopeptide antibiotics produced by Streptomyces have greatly contributed to our understanding of their structures, properties, biosynthetic mechanisms, chemical and chemoenzymatic synthesis, and biological functions. The use of genome mining techniques has led to the discovery of many novel lipopeptides, further demonstrating their potential for future development in modern medicine.
NATURAL PRODUCT REPORTS
(2023)
Article
Biochemistry & Molecular Biology
Barbara R. Terlouw, Kai Blin, Jorge C. Navarro-Munoz, Nicole E. Avalon, Marc G. Chevrette, Susan Egbert, Sanghoon Lee, David Meijer, Michael J. J. Recchia, Zachary L. Reitz, Jeffrey A. van Santen, Nelly Selem-Mojica, Thomas Torring, Liana Zaroubi, Mohammad Alanjary, Gajender Aleti, Cesar Aguilar, Suhad A. A. Al-Salihi, Hannah E. Augustijn, J. Abraham Avelar-Rivas, Luis A. Avitia-Dominguez, Francisco Barona-Gomez, Jordan Bernaldo-Aguero, Vincent A. Bielinski, Friederike Biermann, Thomas J. Booth, Victor J. Carrion Bravo, Raquel Castelo-Branco, Fernanda O. Chagas, Pablo Cruz-Morales, Chao Du, Katherine R. Duncan, Athina Gavriilidou, Damien Gayrard, Karina Gutierrez-Garcia, Kristina Haslinger, Eric J. N. Helfrich, Justin J. J. van der Hooft, Afif P. Jati, Edward Kalkreuter, Nikolaos Kalyvas, Kyo B. Kang, Satria Kautsar, Wonyong Kim, Aditya M. Kunjapur, Yong-Xin Li, Geng-Min Lin, Catarina Loureiro, Joris J. R. Louwen, Nico L. L. Louwen, George Lund, Jonathan Parra, Benjamin Philmus, Bita Pourmohsenin, Lotte J. U. Pronk, Adriana Rego, Devasahayam Arokia Balaya Rex, Serina Robinson, L. Rodrigo Rosas-Becerra, Eve T. Roxborough, Michelle A. Schorn, Darren J. Scobie, Kumar Saurabh Singh, Nika Sokolova, Xiaoyu Tang, Daniel Udwary, Aruna Vigneshwari, Kristiina Vind, Sophie P. J. M. Vromans, Valentin Waschulin, Sam E. Williams, Jaclyn M. Winter, Thomas E. Witte, Huali Xie, Dong Yang, Jingwei Yu, Mitja Zdouc, Zheng Zhong, Jerome Collemare, Roger G. Linington, Tilmann Weber, Marnix H. Medema
Summary: With the increasing amount of genomic data, (meta)genome mining plays a critical role in discovering pharmaceutical drugs and other materials. MIBiG is a standardized data format and online database for describing and characterizing biosynthetic gene clusters. MIBiG 3.0 is an update of the database that includes validation, re-annotation, and new entries.
NUCLEIC ACIDS RESEARCH
(2023)
Article
Biochemistry & Molecular Biology
Nika Sokolova, Lili Zhang, Sadaf Deravi, Rick Oerlemans, Matthew R. Groves, Kristina Haslinger
Summary: Oxygen-directed methylation is a common tailoring reaction in natural product pathways catalyzed by O-methyltransferases (OMTs). Two bacterial OMTs from Desulforomonas acetoxidans and Streptomyces avermitilis were characterized for their enzymatic properties and substrate scope, and their crystal structures were determined. Both OMTs methylated a wide range of catechol-like substrates, including flavonoids, coumarins, hydroxybenzoic acids, and their respective aldehydes, an anthraquinone and an indole. This study expands knowledge on the substrate preference and structural diversity of bacterial catechol OMTs and opens up possibilities for their use in (combinatorial) pathway engineering.
Review
Biochemistry & Molecular Biology
Nika Sokolova, Bo Peng, Kristina Haslinger
Summary: This article summarizes the progress made in the past five years in the engineering of microbial biotransformation processes, including the use of enzymes and (micro)organisms to catalyze renewable resources. By redesigning existing pathways, directed evolution of enzymes, and designing new pathways, novel routes for the synthesis of target chemicals can be unlocked. Microbial production of commodity and specialty chemicals has the potential to reduce reliance on fossil fuels and decrease environmental impacts.
Article
Multidisciplinary Sciences
Ursula Vide, Dzenita Kasapovic, Maximilian Fuchs, Martin P. Heimboeck, Massimo G. Totaro, Elfriede Zenzmaier, Andreas Winkler
Summary: Regulatory proteins, such as the LOV-activated diguanylate cyclase (LadC), can provide precise control over enzymatic activity with high dynamic range. LadC exhibits switch-like characteristics by inhibiting its effector domains in the dark and activating them upon illumination through coiled-coil formation. This system can be utilized to develop optogenetic tools with tight regulation.
Article
Microbiology
Ting He, Xiao Li, Riccardo Iacovelli, Thomas Hackl, Kristina Haslinger
Summary: In this study, an endophytic fungus Fusarium sp. VM-40 isolated from Vinca minor was characterized, and its genome sequence, biosynthetic potential, and metabolome were investigated. The whole genome of Fusarium sp. VM-40 was 40 Mb in size with 13,546 protein-coding genes, including 691 carbohydrate-active enzyme-encoding genes. In addition, the fungus was found to produce structurally diverse secondary metabolites with potential pharmacological relevance.
Article
Chemistry, Multidisciplinary
Y. T. Candace Ho, Joe A. Kaczmarski, Julien Tailhades, Thierry Izore, David L. Steer, Ralf B. Schittenhelm, Manuela Tosin, Colin J. Jackson, Max J. Cryle
Summary: Nonribosomal peptide synthetases play a significant role in producing essential peptide natural products, with carrier proteins as their core component. By replacing the CP substrate thioesters with stabilized ester analogues, active condensation domain complexes are formed, while amide stabilization leads to non-functional complexes.
CHEMICAL COMMUNICATIONS
(2023)
Article
Biochemistry & Molecular Biology
Cornelia Boehm, Geoffrey Gourinchas, Sophie Zweytick, Elvira Hujdur, Martina Reiter, Sara Trstenjak, Christoph Wilhelm Sensen, Andreas Winkler
Summary: Understanding the relationship between protein sequence, structure, and function is a fundamental challenge in biochemistry. This study investigates a subfamily of bacterial light sensors and reveals the important role of a coiled-coil linker element in signal integration. The length and composition of this linker determine the sensor-effector function, and the linker is under evolutionary pressure. The study also shows the influence of linker length on effector activation and even light-induced enzyme inhibition.
PHOTOCHEMICAL & PHOTOBIOLOGICAL SCIENCES
(2022)
Article
Chemistry, Organic
Faiza Diaba, Gisela Trenchs
Summary: The first violet light-mediated synthesis of gamma- and delta-lactams from N-alkenyl trichloroacetamides is reported in this paper. The reactions are conducted in tetrahydrofuran or 2-methyltetrahydrofuran as the sole solvent without catalysts or additives, under non-anhydrous conditions in an air atmosphere where the solvent serves as the radical initiator.
ORGANIC & BIOMOLECULAR CHEMISTRY
(2024)
Article
Chemistry, Organic
Feroze Hussain, Sajjad Ahmed, Ashiq Hussain Padder, Qazi Naveed Ahmed
Summary: This study reports a novel and efficient one-pot synthesis method for mixed phosphorotrithioates, which does not require supplementary additives and shows broad applicability.
ORGANIC & BIOMOLECULAR CHEMISTRY
(2024)
Article
Chemistry, Organic
Hyunjin Oh, Ikyon Kim
Summary: A new 1,2,4-triazole-pyrrolo[1,2-a]pyrazine hybrid system, 6-acylpyrrolo[1,2-a][1,2,4]triazolo[5,1-c]pyrazine, was synthesized using a catalyst-free method. This method involved sequential exposure of pyrrole-2-carbonitrile-derived substrates to DMF-DMA and acyl hydrazide, resulting in the formation of acylated pyrazine and 1,2,4-triazole rings, enabling the installation of various substituents at specific positions on the core skeleton.
ORGANIC & BIOMOLECULAR CHEMISTRY
(2024)
Article
Chemistry, Organic
Ming Yan, Si-fan Wang, Yong-po Zhang, Jin-zhong Zhao, Zhuo Tang, Guang-xun Li
Summary: Here we developed an efficient photocatalytic approach for the convenient preparation of sulfinamides. The reaction allows for the gram-scale preparation of sulfinamides and the one-pot synthesis of various sulfonyl amides.
ORGANIC & BIOMOLECULAR CHEMISTRY
(2024)
Article
Chemistry, Organic
Farzaneh Bandehali-Naeini, Zahra Tanbakouchian, Noushin Farajinia-Lehi, Nicolas Mayer, Morteza Shiri, Martin Breugst
Summary: Two tandem catalytic systems were developed for the synthesis of novel 3,4-disubstituted maleimides using the same Ugi adducts. Different maleimide structures can be synthesized using either Pd or Cu catalysis.
ORGANIC & BIOMOLECULAR CHEMISTRY
(2024)
Article
Chemistry, Organic
Tanya Raghava, Anjan Chattopadhyay, Subhadeep Banerjee, Nivedita Sarkar
Summary: Amine substitution of two ortho fluorine atoms of tetrafluoroterephthalonitrile through SNAr chemistry is easily achievable. But further fluorine substitution is only possible under forcing conditions, yielding valuable fluorophores for bioimaging.
ORGANIC & BIOMOLECULAR CHEMISTRY
(2024)
Review
Chemistry, Organic
Anju Chadha, Santosh Kumar Padhi, Selvaraj Stella, Sowmyalakshmi Venkataraman, Thangavelu Saravanan
Summary: Alcohol dehydrogenases are enzymes that use cofactors for oxidation or reduction reactions of alcohols or carbonyl compounds. They are utilized in green chemistry and have applications in the production of pharmaceuticals. Recombinant enzymes have solved the challenge of producing purified enzymes in large quantities. Engineered alcohol dehydrogenases have been used in asymmetric synthesis in industry. Various methods have been established for regenerating expensive cofactors to make the enzymatic process more efficient and economically viable.
ORGANIC & BIOMOLECULAR CHEMISTRY
(2024)