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)
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
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
Sarah Bonhomme, Andrea Dessen, Pauline Macheboeuf
Summary: NRPSs are multienzymes that produce complex natural metabolites with applications in medicine and agriculture. They consist of multiple catalytic domains and non-catalytic carrier protein domains, allowing flexibility in catalyzing and transporting products. Recent studies providing structural views of multi-domain NRPSs have enhanced understanding of their catalytic cycle.
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)
Review
Pharmacology & Pharmacy
Shanmin Zheng, Jiawei Guo, Fangyuan Cheng, Zhengquan Gao, Lei Du, Chunxiao Meng, Shengying Li, Xingwang Zhang
Summary: This article comprehensively reviews the progress of P450 studies in algae from 2000 to 2021. It highlights the importance of algae as photosynthetic organisms and the role of P450 enzymes in natural product biosynthesis in algae. The article also emphasizes the advancing functional studies of algal P450 enzymes with the development of algae cultivation and genetic manipulation techniques, and the potential use of photoautotrophic algae as photo-bioreactors for high-value added pharmaceutical and chemical production.
ACTA PHARMACEUTICA SINICA B
(2022)
Article
Biotechnology & Applied Microbiology
Sebastian L. Wenski, Sirinthra Thiengmag, Eric J. N. Helfrich
Summary: Complex peptide natural products have diverse functions and properties, and can be biosynthesized through ribosomally synthesized and post-translationally modified peptide (RiPP) biosynthetic pathways and non-ribosomal peptide synthetases (NRPSs). Understanding these pathways has led to universal principles for targeted identification of peptide biosynthetic blueprints and rational engineering of biosynthetic pathways. This review contrasts the key principles of both routes and compares different strategies for peptide modifications.
SYNTHETIC AND SYSTEMS BIOTECHNOLOGY
(2022)
Article
Pharmacology & Pharmacy
Songya Zhang, Lin Zhang, Anja Greule, Julien Tailhades, Edward Marschall, Panward Prasongpholchai, Daniel J. Leng, Jingfan Zhang, Jing Zhu, Joe A. Kaczmarski, Ralf B. Schittenhelm, Oliver Einsle, Colin J. Jackson, Fabrizio Alberti, Andreas Bechthold, Youming Zhang, Manuela Tosin, Tong Si, Max J. Cryle
Summary: WS9326A is a peptide antibiotic synthesized by a non-ribosomal peptide synthetase (NRPS). The cytochrome P450 encoded by sas16 (P450Sas) is critical for the formation of an unusual amino acid residue in WS9326A. In this study, the researchers identified the substrate of P450Sas and elucidated its role in the biosynthetic pathway of WS9326A. The results suggest that P450Sas catalyzes the direct dehydrogenation of a dipeptide intermediate, expanding the range of P450 enzymes that can be used for the production of biologically active peptides.
ACTA PHARMACEUTICA SINICA B
(2023)
Article
Chemistry, Multidisciplinary
Min Xu, Wenliang Wang, Nicholas Waglechner, Elizabeth J. Culp, Allison K. Guitor, Gerard D. Wright
Summary: The rise and dissemination of glycopeptide antibiotic (GPA)-resistant pathogens in healthcare settings have driven efforts to discover new GPAs that can overcome resistance. In this study, a phylogeny-guided genome mining strategy and heterologous production using the GPAHex synthetic biology platform were used to characterize five newly discovered type V GPAs. These GPAs demonstrated potent activity against GPA-resistant clinical isolates and their mode of action was consistent with the inhibition of cell division by evading autolysin activity. This research expands the chemical diversity of GPAs, offers new drug development prospects, and showcases the potential of the GPAHex platform in mining GPA chemical dark matter.
ACS CENTRAL SCIENCE
(2022)
Article
Chemistry, Medicinal
Robert J. J. Stankey, Don Johnson, Brendan M. M. Duggan, David A. A. Mead, James J. J. La Clair
Summary: As one of the earliest marine natural products undergoing clinical trials, didemnin depsipeptides have played a significant role in inspiring the discovery of marine drugs. Originally developed for anticancer therapeutics, these compounds have recently been re-evaluated and advanced towards antiviral applications. While traditionally associated with colonial tunicates, their biosynthesis has now been found in the marine-derived bacteria Tistrella mobilis, although its low production and limited understanding hinder effective microbial or synthetic biological approaches. This study conducted a survey of Tistrella species and successfully developed conditions for the production of didemnin B at high titers.
Review
Plant Sciences
Anqi Zhou, Kang Zhou, Yanran Li
Summary: This review highlights the potential of microbial bioproduction as an alternative sourcing to plant natural products, focusing on strategies to enhance the activity of plant CYPs in Escherichia coli and Saccharomyces cerevisiae. In-depth investigations on the native microenvironment of plant CYPs are essential for further improving the efficiency of functional reconstitution of plant CYPs in microbial systems.
CURRENT OPINION IN PLANT BIOLOGY
(2021)
Article
Ecology
Sharel Pamela Diaz-Perez, Christian Said Solis, Jesus Salvador Lopez-Bucio, Juan J. Valdez Alarcon, Javier Villegas, Homero Reyes-De la Cruz, Jesus Campos-Garcia
Summary: This study investigated the impact of pvd genes on bacterial pathogenesis in Pseudomonas aeruginosa. The results showed that mutations in pvdL and pvdI increased the production of virulence factors, biofilm formation, and altered biofilm structure. Mutations in pvdI, pvdJ, and pvdL also enhanced the survival of nematodes exposed to bacterial cultures. These findings demonstrate the contribution of siderophores to the establishment and pathogenicity of Pseudomonas aeruginosa.
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
Biochemical Research Methods
Levi Kramer, Ankur Sarkar, Tom Foderaro, Andrew L. Markley, Jessica Lee, Hannah Edstrom, Shajesh Sharma, Eden Gill, Matthew J. Traylor, Jerome M. Fox
Summary: This study develops a general approach for detecting microbially synthesized protease inhibitors and uses it to screen terpenoid pathways for inhibitory compounds. The detection scheme relies on a bacterial two-hybrid (B2H) system that links protease inactivation to the transcription of a swappable reporter gene. This study provides a detailed experimental framework for using microbes to screen libraries of biosynthetic pathways for targeted protease inhibitors.
ACS SYNTHETIC BIOLOGY
(2023)
Article
Biotechnology & Applied Microbiology
Qing Fang, Linrui Wu, Caroline Urwald, Morgane Mugat, Shan Wang, Kwaku Kyeremeh, Carol Philips, Samantha Law, Yongjun Zhou, Hai Deng
Summary: Non-ribosomal peptides are structurally diverse natural products with important therapeutic and agrochemical applications. Bacterial pyrrolizidine alkaloids (PAs) are rare in natural product inventory, but the biosynthetic gene clusters responsible for similar metabolites are widely distributed in bacterial genomes, providing insights into the biosynthetic pathways of these bioactive compounds.
SYNTHETIC AND SYSTEMS BIOTECHNOLOGY
(2021)
Letter
Microbiology
Roderich D. Sussmuth, Alexandra Lensch, Stefan Pelzer
Summary: A recent study claims that a newly isolated Bacillus velezensis strain RP137 from the Persian Gulf can produce an aminoglycoside compound called S-137-R. However, the provided data does not prove its structure and purity, and lacks proper comparison with other aminoglycosides. Therefore, it is scientifically unjustified to confirm the production of aminoglycosides by this strain, and it should not be regarded as a probiotic.
CURRENT MICROBIOLOGY
(2022)
Article
Microbiology
Nicole Hugouvieux-Cotte-Pattat, Monique Royer, Erwan Gueguen, Paul Le Guen, Roderich D. Suessmuth, Sylvie Reverchon, Stephane Cociancich
Summary: The Vfm quorum sensing system is important for the virulence of Dickeya bacteria, with a strain-specific polymorphism in the biosynthesis genes vfmO and vfmP potentially leading to the production of different analogues of the QS signal.
ENVIRONMENTAL MICROBIOLOGY
(2022)
Article
Chemistry, Multidisciplinary
Timur Bulatov, Sebastian Gensel, Andi Mainz, Tam Dang, Timm O. Koller, Kerstin Voigt, Julia Ebeling, Daniel N. Wilson, Elke Genersch, Roderich D. Suessmuth
Summary: The study reports the total synthesis and structural revision of paenilamicin B2, highlighting the N-terminal fragment as an important pharmacophore, and conducts biological activity evaluation and competition experiments with bacterial competitors in the ecological niche. It also presents data classifying paenilamicins as potential ribosome inhibitors, contributing to a better understanding of the pathogenicity of P. larvae and paving the way for future structure-activity relationship and mode-of-action studies.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2022)
Article
Biotechnology & Applied Microbiology
Joana C. Barbosa, Itala C. Silva, Tania Caetano, Eva Mosker, Maria Seidel, Joana Lourenco, Roderich D. Suessmuth, Nuno C. Santos, Sonia Goncalves, Sonia Mendo
Summary: Lichenicidin is a promising natural antimicrobial peptide with strong bactericidal activity and no cytotoxicity towards human cells.
WORLD JOURNAL OF MICROBIOLOGY & BIOTECHNOLOGY
(2022)
Article
Chemistry, Multidisciplinary
Romina Schnegotzki, Jeroen Koopman, Stefan Grimme, Roderich D. Suessmuth
Summary: In organic mass spectrometry, quantum chemical calculations can be used to predict ion fragment structures, particularly for large molecules, and discover previously unknown fragmentation pathways.
CHEMISTRY-A EUROPEAN JOURNAL
(2022)
Article
Chemistry, Organic
Romina Schnegotzki, Vincent Wiebach, Marina Sanchez-Hidalgo, Marcel Tietzmann, Andreas B. zur Bonsen, Olga Genilloud, Roderich D. Suessmuth
Summary: Phenylglycines are crucial components in the synthesis of non-ribosomally synthesized peptides. The cyclodepsipeptide cochinmicin I, which contains dihydroxyphenylglycine, acts as an endothelin receptor antagonist. In this study, we accomplished the total synthesis of cochinmicin I and its non-natural derivative cochinmicin VI. Additionally, we identified and assigned the gene cluster responsible for cochinmicin biosynthesis, which encodes a non-ribosomal peptide synthetase.
Article
Chemistry, Multidisciplinary
Christian E. Stieger, Yerin Park, Mark A. R. de Geus, Dongju Kim, Christiane Huhn, J. Sophia Slenczka, Philipp Ochtrop, Judith M. Muechler, Roderich D. Suessmuth, Johannes Broichhagen, Mu-Hyun Baik, Christian P. R. Hackenberger
Summary: We have discovered ethynyl-triazolyl-phosphinates (ETPs) as a new class of electrophilic warheads with cysteine selectivity for bioconjugation. Through Cu-I-catalyzed azide alkyne cycloaddition (CuAAC), various functional electrophilic building blocks, including proteins, were obtained from diethynyl-phosphinate. ETP-reagents were used to create fluorescent peptide-conjugates for receptor labeling on live cells and stable and biologically active antibody-drug conjugates. The excellent cysteine selectivity of ETP-electrophiles was demonstrated in mass spectrometry-based, proteome-wide cysteine profiling, highlighting their potential for homogeneous bioconjugation strategies to connect complex biomolecules.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2022)
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.
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
Sylvester Hoffmann, Maik Damm, Leonard Roth, Roderich D. Suessmuth
Summary: This study investigates the activation mechanism of hydroxy acid substrates in non-ribosomal peptide synthetases (NRPSs). By homology modelling and molecular docking, it was found that the selection of hydroxy acid is determined by its interaction with the backbone carbonyls rather than a specific side chain. These findings contribute to the understanding of non-amino acid substrate activation and have implications for the engineering of depsipeptide synthetases.
Article
Food Science & Technology
Ignazio Avella, Maik Damm, Ines Freitas, Wolfgang Wuster, Nahla Lucchini, Oscar Zuazo, Roderich D. Suessmuth, Fernando Martinez-Freiria
Summary: This study analyzed the venom of Vipera seoanei snakes from different locations and found that there is little variation in venom composition, which may be due to recent population expansion or other factors.
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)
Review
Multidisciplinary Sciences
Roland Hellinger, Arnar Sigurdsson, Wenxin Wu, Elena V. Romanova, Lingjun Li, Jonathan V. Sweedler, Roderich D. Suessmuth, Christian W. Gruber
Summary: Peptidomics combines genomics, modern proteomics, analytical chemistry, and computational biology techniques for peptide discovery and characterization. Peptides are biopolymers composed of 2-50 amino acids, often produced by cellular machinery or enzymes. They play important physiological roles as signaling molecules and toxins, and have emerging applications in biomarker discovery and therapeutics. Peptidomics involves qualitative and quantitative analysis of peptides in biological samples using a specialized set of tools and workflows.
NATURE REVIEWS METHODS PRIMERS
(2023)
