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2. Function-related replacement of bacterial siderophore pathways

Author

Bruns, Hilke, Crüsemann, Max, Letzel, Anne-Catrin, Alanjary, Mohammad, McInerney, James O, Jensen, Paul R, Schulz, Stefan, Moore, Bradley S, and Ziemert, Nadine

Subjects
Microbiology, Biological Sciences, Genetics, Algorithms, Bacterial Physiological Phenomena, Chromatography, High Pressure Liquid, Data Mining, Fourier Analysis, Gene Transfer Techniques, Genes, Bacterial, Genome, Bacterial, Iron, Magnetic Resonance Spectroscopy, Mass Spectrometry, Micromonosporaceae, Multigene Family, Phylogeny, Secondary Metabolism, Siderophores, Environmental Sciences, Technology, Biological sciences, Environmental sciences
Abstract

Bacterial genomes are rife with orphan biosynthetic gene clusters (BGCs) associated with secondary metabolism of unrealized natural product molecules. Often up to a tenth of the genome is predicted to code for the biosynthesis of diverse metabolites with mostly unknown structures and functions. This phenomenal diversity of BGCs coupled with their high rates of horizontal transfer raise questions about whether they are really active and beneficial, whether they are neutral and confer no advantage, or whether they are carried in genomes because they are parasitic or addictive. We previously reported that Salinispora bacteria broadly use the desferrioxamine family of siderophores for iron acquisition. Herein we describe a new and unrelated group of peptidic siderophores called salinichelins from a restricted number of Salinispora strains in which the desferrioxamine biosynthesis genes have been lost. We have reconstructed the evolutionary history of these two different siderophore families and show that the acquisition and retention of the new salinichelin siderophores co-occurs with the loss of the more ancient desferrioxamine pathway. This identical event occurred at least three times independently during the evolution of the genus. We surmise that certain BGCs may be extraneous because of their functional redundancy and demonstrate that the relative evolutionary pace of natural pathway replacement shows high selective pressure against retention of functionally superfluous gene clusters.

Published
2018

3. REASSIGNMENT OF THE STRUCTURE OF A TRYPTOPHAN‐CONTAINING CYCLIC TRIPEPTIDE PRODUCED BY THE BIARYLITIDE CROSSLINKING CYTOCHROME P450BLT

Author

Coe, Laura J., primary, Zhao, Yongwei, additional, Padva, Leo, additional, Keto, Angus, additional, Schittenhelm, Ralf, additional, Tailhades, Julien, additional, Pierens, Greg, additional, Krenske, Elizabeth H., additional, Crüsemann, Max, additional, De Voss, James, additional, and Cryle, Max J., additional

Published
2024
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4. Prioritizing Natural Product Diversity in a Collection of 146 Bacterial Strains Based on Growth and Extraction Protocols

Author

Crüsemann, Max, O’Neill, Ellis C, Larson, Charles B, Melnik, Alexey V, Floros, Dimitrios J, da Silva, Ricardo R, Jensen, Paul R, Dorrestein, Pieter C, and Moore, Bradley S

Subjects
Health Sciences, Traditional, Complementary and Integrative Medicine, Bacteria, Biological Products, Chromatography, High Pressure Liquid, Genetic Variation, Metabolomics, Molecular Structure, Salinity, Streptomyces, Chemical Sciences, Biological Sciences, Medical and Health Sciences, Medicinal & Biomolecular Chemistry, Traditional, complementary and integrative medicine
Abstract

In order to expedite the rapid and efficient discovery and isolation of novel specialized metabolites, while minimizing the waste of resources on rediscovery of known compounds, it is crucial to develop efficient approaches for strain prioritization, rapid dereplication, and the assessment of favored cultivation and extraction conditions. Herein we interrogated bacterial strains by systematically evaluating cultivation and extraction parameters with LC-MS/MS analysis and subsequent dereplication through the Global Natural Product Social Molecular Networking (GNPS) platform. The developed method is fast, requiring minimal time and sample material, and is compatible with high-throughput extract analysis, thereby streamlining strain prioritization and evaluation of culturing parameters. With this approach, we analyzed 146 marine Salinispora and Streptomyces strains that were grown and extracted using multiple different protocols. In total, 603 samples were analyzed, generating approximately 1.8 million mass spectra. We constructed a comprehensive molecular network and identified 15 molecular families of diverse natural products and their analogues. The size and breadth of this network shows statistically supported trends in molecular diversity when comparing growth and extraction conditions. The network provides an extensive survey of the biosynthetic capacity of the strain collection and a method to compare strains based on the variety and novelty of their metabolites. This approach allows us to quickly identify patterns in metabolite production that can be linked to taxonomy, culture conditions, and extraction methods, as well as informing the most valuable growth and extraction conditions.

Published
2017

5. A community resource for paired genomic and metabolomic data mining

Author

Schorn, Michelle A., Verhoeven, Stefan, Ridder, Lars, Huber, Florian, Acharya, Deepa D., Aksenov, Alexander A., Aleti, Gajender, Moghaddam, Jamshid Amiri, Aron, Allegra T., Aziz, Saefuddin, Bauermeister, Anelize, Bauman, Katherine D., Baunach, Martin, Beemelmanns, Christine, Beman, J. Michael, Berlanga-Clavero, María Victoria, Blacutt, Alex A., Bode, Helge B., Boullie, Anne, Brejnrod, Asker, Bugni, Tim S., Calteau, Alexandra, Cao, Liu, Carrión, Víctor J., Castelo-Branco, Raquel, Chanana, Shaurya, Chase, Alexander B., Chevrette, Marc G., Costa-Lotufo, Leticia V., Crawford, Jason M., Currie, Cameron R., Cuypers, Bart, Dang, Tam, de Rond, Tristan, Demko, Alyssa M., Dittmann, Elke, Du, Chao, Drozd, Christopher, Dujardin, Jean-Claude, Dutton, Rachel J., Edlund, Anna, Fewer, David P., Garg, Neha, Gauglitz, Julia M., Gentry, Emily C., Gerwick, Lena, Glukhov, Evgenia, Gross, Harald, Gugger, Muriel, Guillén Matus, Dulce G., Helfrich, Eric J. N., Hempel, Benjamin-Florian, Hur, Jae-Seoun, Iorio, Marianna, Jensen, Paul R., Kang, Kyo Bin, Kaysser, Leonard, Kelleher, Neil L., Kim, Chung Sub, Kim, Ki Hyun, Koester, Irina, König, Gabriele M., Leao, Tiago, Lee, Seoung Rak, Lee, Yi-Yuan, Li, Xuanji, Little, Jessica C., Maloney, Katherine N., Männle, Daniel, Martin H., Christian, McAvoy, Andrew C., Metcalf, Willam W., Mohimani, Hosein, Molina-Santiago, Carlos, Moore, Bradley S., Mullowney, Michael W., Muskat, Mitchell, Nothias, Louis-Félix, O’Neill, Ellis C., Parkinson, Elizabeth I., Petras, Daniel, Piel, Jörn, Pierce, Emily C., Pires, Karine, Reher, Raphael, Romero, Diego, Roper, M. Caroline, Rust, Michael, Saad, Hamada, Saenz, Carmen, Sanchez, Laura M., Sørensen, Søren Johannes, Sosio, Margherita, Süssmuth, Roderich D., Sweeney, Douglas, Tahlan, Kapil, Thomson, Regan J., Tobias, Nicholas J., Trindade-Silva, Amaro E., van Wezel, Gilles P., Wang, Mingxun, Weldon, Kelly C., Zhang, Fan, Ziemert, Nadine, Duncan, Katherine R., Crüsemann, Max, Rogers, Simon, Dorrestein, Pieter C., Medema, Marnix H., and van der Hooft, Justin J. J.

Published
2021
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6. Sharing and community curation of mass spectrometry data with Global Natural Products Social Molecular Networking

Author

Wang, Mingxun, Carver, Jeremy J, Phelan, Vanessa V, Sanchez, Laura M, Garg, Neha, Peng, Yao, Nguyen, Don Duy, Watrous, Jeramie, Kapono, Clifford A, Luzzatto-Knaan, Tal, Porto, Carla, Bouslimani, Amina, Melnik, Alexey V, Meehan, Michael J, Liu, Wei-Ting, Crüsemann, Max, Boudreau, Paul D, Esquenazi, Eduardo, Sandoval-Calderón, Mario, Kersten, Roland D, Pace, Laura A, Quinn, Robert A, Duncan, Katherine R, Hsu, Cheng-Chih, Floros, Dimitrios J, Gavilan, Ronnie G, Kleigrewe, Karin, Northen, Trent, Dutton, Rachel J, Parrot, Delphine, Carlson, Erin E, Aigle, Bertrand, Michelsen, Charlotte F, Jelsbak, Lars, Sohlenkamp, Christian, Pevzner, Pavel, Edlund, Anna, McLean, Jeffrey, Piel, Jörn, Murphy, Brian T, Gerwick, Lena, Liaw, Chih-Chuang, Yang, Yu-Liang, Humpf, Hans-Ulrich, Maansson, Maria, Keyzers, Robert A, Sims, Amy C, Johnson, Andrew R, Sidebottom, Ashley M, Sedio, Brian E, Klitgaard, Andreas, Larson, Charles B, Boya P, Cristopher A, Torres-Mendoza, Daniel, Gonzalez, David J, Silva, Denise B, Marques, Lucas M, Demarque, Daniel P, Pociute, Egle, O'Neill, Ellis C, Briand, Enora, Helfrich, Eric JN, Granatosky, Eve A, Glukhov, Evgenia, Ryffel, Florian, Houson, Hailey, Mohimani, Hosein, Kharbush, Jenan J, Zeng, Yi, Vorholt, Julia A, Kurita, Kenji L, Charusanti, Pep, McPhail, Kerry L, Nielsen, Kristian Fog, Vuong, Lisa, Elfeki, Maryam, Traxler, Matthew F, Engene, Niclas, Koyama, Nobuhiro, Vining, Oliver B, Baric, Ralph, Silva, Ricardo R, Mascuch, Samantha J, Tomasi, Sophie, Jenkins, Stefan, Macherla, Venkat, Hoffman, Thomas, Agarwal, Vinayak, Williams, Philip G, Dai, Jingqui, Neupane, Ram, Gurr, Joshua, Rodríguez, Andrés MC, Lamsa, Anne, Zhang, Chen, Dorrestein, Kathleen, Duggan, Brendan M, Almaliti, Jehad, Allard, Pierre-Marie, and Phapale, Prasad

Subjects
Analytical Chemistry, Chemical Sciences, Generic health relevance, Biological Products, Data Curation, Database Management Systems, Databases, Chemical, Information Dissemination, Information Storage and Retrieval, Internationality, Mass Spectrometry
Abstract

The potential of the diverse chemistries present in natural products (NP) for biotechnology and medicine remains untapped because NP databases are not searchable with raw data and the NP community has no way to share data other than in published papers. Although mass spectrometry (MS) techniques are well-suited to high-throughput characterization of NP, there is a pressing need for an infrastructure to enable sharing and curation of data. We present Global Natural Products Social Molecular Networking (GNPS; http://gnps.ucsd.edu), an open-access knowledge base for community-wide organization and sharing of raw, processed or identified tandem mass (MS/MS) spectrometry data. In GNPS, crowdsourced curation of freely available community-wide reference MS libraries will underpin improved annotations. Data-driven social-networking should facilitate identification of spectra and foster collaborations. We also introduce the concept of 'living data' through continuous reanalysis of deposited data.

Published
2016

7. Molecular networking and pattern-based genome mining improves discovery of biosynthetic gene clusters and their products from Salinispora species.

Author

Duncan, Katherine R, Crüsemann, Max, Lechner, Anna, Sarkar, Anindita, Li, Jie, Ziemert, Nadine, Wang, Mingxun, Bandeira, Nuno, Moore, Bradley S, Dorrestein, Pieter C, and Jensen, Paul R

Subjects
Micromonosporaceae, Depsipeptides, Peptide Synthases, Chromatography, High Pressure Liquid, Genomics, Genome, Bacterial, Multigene Family, Tandem Mass Spectrometry, Metabolic Networks and Pathways, Metabolome, Chromatography, High Pressure Liquid, Genome, Bacterial, Genetics, Biotechnology, Human Genome, Infection, Organic Chemistry, Medicinal and Biomolecular Chemistry, Biochemistry and Cell Biology
Abstract

Genome sequencing has revealed that bacteria contain many more biosynthetic gene clusters than predicted based on the number of secondary metabolites discovered to date. While this biosynthetic reservoir has fostered interest in new tools for natural product discovery, there remains a gap between gene cluster detection and compound discovery. Here we apply molecular networking and the new concept of pattern-based genome mining to 35 Salinispora strains, including 30 for which draft genome sequences were either available or obtained for this study. The results provide a method to simultaneously compare large numbers of complex microbial extracts, which facilitated the identification of media components, known compounds and their derivatives, and new compounds that could be prioritized for structure elucidation. These efforts revealed considerable metabolite diversity and led to several molecular family-gene cluster pairings, of which the quinomycin-type depsipeptide retimycin A was characterized and linked to gene cluster NRPS40 using pattern-based bioinformatic approaches.

Published
2015

9. Structural Insights into a Side Chain Cross-Linking Biarylitide P450 from RiPP Biosynthesis

Author

Hansen, Mathias H., primary, Keto, Angus, additional, Treisman, Maxine, additional, Sasi, Vishnu Mini, additional, Coe, Laura, additional, Zhao, Yongwei, additional, Padva, Leo, additional, Hess, Caroline, additional, Leichthammer, Victor, additional, Machell, Daniel L., additional, Schittenhelm, Ralf B., additional, Jackson, Colin J., additional, Tailhades, Julien, additional, Crüsemann, Max, additional, De Voss, James J., additional, Krenske, Elizabeth H., additional, and Cryle, Max J., additional

Published
2024
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10. Reassignment of the Structure of a Tryptophan‐Containing Cyclic Tripeptide Produced by the Biarylitide Crosslinking Cytochrome P450blt.

Author

Coe, Laura J., Zhao, Yongwei, Padva, Leo, Keto, Angus, Schittenhelm, Ralf, Tailhades, Julien, Pierens, Greg, Krenske, Elizabeth H., Crüsemann, Max, De Voss, James J., and Cryle, Max J.

Subjects
PEPTIDES, AMINO acid sequence, RADIOLABELING, GENE clusters, ENZYMES, CROSSLINKED polymers, CYTOCHROME c
Abstract

The structure of the sidechain crosslinked Tyr‐Leu‐Trp peptide produced by the biarylitide crosslinking cytochrome P450Blt from Micromonospora sp. MW‐13 has been reanalysed by a series of NMR, computational and isotope labelling experiments and shown to contain a C−N rather than a C−O bond. Additional in vivo experiments using such a modified peptide show there is a general tolerance of biarylitide crosslinking P450 enzymes for histidine to tryptophan mutations within their minimal peptide substrate sequences despite the lack of such residues noted in natural biarylitide gene clusters. This work further highlights the impressive ability of P450s from biarylitide biosynthesis pathways to act as biocatalysts for the formation of a range of sidechain crosslinked tripeptides. [ABSTRACT FROM AUTHOR]

Published
2024
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14. Cofunctioning of bacterial exometabolites drives root microbiota establishment

Author

Getzke, Felix, primary, Hassani, M. Amine, additional, Crüsemann, Max, additional, Malisic, Milena, additional, Zhang, Pengfan, additional, Ishigaki, Yuji, additional, Böhringer, Nils, additional, Jiménez Fernández, Alicia, additional, Wang, Lei, additional, Ordon, Jana, additional, Ma, Ka-Wai, additional, Thiergart, Thorsten, additional, Harbort, Christopher J., additional, Wesseler, Hidde, additional, Miyauchi, Shingo, additional, Garrido-Oter, Ruben, additional, Shirasu, Ken, additional, Schäberle, Till F., additional, Hacquard, Stéphane, additional, and Schulze-Lefert, Paul, additional

Published
2023
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16. Structure-affinity and structure-residence time relationships of macrocyclic Gα(q) protein inhibitors

Author

Voss, Jan H., Crüsemann, Max, Bartling, Christian R.O., Kehraus, Stefan, Inoue, Asuka, König, Gabriele M., Strømgaard, Kristian, and Müller, Christa E.

Subjects
Pharmacology, Biological sciences, Multidisciplinary, Biochemistry, Article
Abstract

The macrocyclic depsipeptides YM-254890 (YM) and FR900359 (FR) are potent inhibitors of Gαq/11 proteins. They are important pharmacological tools and have potential as therapeutic drugs. The hydrogenated, tritium-labeled YM and FR derivatives display largely different residence times despite similar structures. In the present study we established a competition-association binding assay to determine the dissociation kinetics of unlabeled Gq protein inhibitors. Structure-affinity and structure-residence time relationships were analyzed. Small structural modifications had a large impact on residence time. YM and FR exhibited 4- to 10-fold higher residence times than their hydrogenated derivatives. While FR showed pseudo-irreversible binding, YM displayed much faster dissociation from its target. The isopropyl anchor present in FR and some derivatives was essential for slow dissociation. These data provide a basis for future drug design toward modulating residence times of macrocyclic Gq protein inhibitors, which has been recognized as a crucial determinant for therapeutic outcome.

Published
2023
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17. The Bacterial Gq Signal Transduction Inhibitor FR900359 Impairs Soil-Associated Nematodes.

Author

Hanke, Wiebke, Alenfelder, Judith, Liu, Jun, Gutbrod, Philipp, Kehraus, Stefan, Crüsemann, Max, Dörmann, Peter, Kostenis, Evi, Scholz, Monika, and König, Gabriele M.

Subjects
CELLULAR signal transduction, SUGAR beet cyst nematode, NEMATODES, CAENORHABDITIS elegans, METABOLITES, SOUTHERN root-knot nematode, SOIL microbiology, PLANT nematodes, PLANT growth
Abstract

The cyclic depsipeptide FR900359 (FR) is derived from the soil bacterium Chromobacterium vaccinii and known to bind Gq proteins of mammals and insects, thereby abolishing the signal transduction of their Gq protein-coupled receptors, a process that leads to severe physiological consequences. Due to their highly conserved structure, Gq family of proteins are a superior ecological target for FR producing organisms, resulting in a defense towards a broad range of harmful organisms. Here, we focus on the question whether bacteria like C. vaccinii are important factors in soil in that their secondary metabolites impair, e.g., plant harming organisms like nematodes. We prove that the Gq inhibitor FR is produced under soil-like conditions. Furthermore, FR inhibits heterologously expressed Gαq proteins of the nematodes Caenorhabditis elegans and Heterodera schachtii in the micromolar range. Additionally, in vivo experiments with C. elegans and the plant parasitic cyst nematode H. schachtii demonstrated that FR reduces locomotion of C. elegans and H. schachtii. Finally, egg-laying of C. elegans and hatching of juvenile stage 2 of H. schachtii from its cysts is inhibited by FR, suggesting that FR might reduce nematode dispersion and proliferation. This study supports the idea that C. vaccinii and its excreted metabolome in the soil might contribute to an ecological equilibrium, maintaining and establishing the successful growth of plants. [ABSTRACT FROM AUTHOR]

Published
2023
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20. A Universal Language for Finding Mass Spectrometry Data Patterns

Author

Jarmusch, Alan K., primary, Aron, Allegra T., additional, Petras, Daniel, additional, Phelan, Vanessa V., additional, Bittremieux, Wout, additional, Acharya, Deepa D., additional, Ahmed, Mohammed M. A., additional, Bauermeister, Anelize, additional, Bertin, Matthew J., additional, Boudreau, Paul D., additional, Borges, Ricardo M., additional, Bowen, Benjamin P., additional, Brown, Christopher J., additional, Chagas, Fernanda O., additional, Clevenger, Kenneth D., additional, Correia, Mario S. P., additional, Crandall, William J., additional, Crüsemann, Max, additional, Damiani, Tito, additional, Fiehn, Oliver, additional, Garg, Neha, additional, Gerwick, William H, additional, Gilbert, Jeffrey R., additional, Globisch, Daniel, additional, Gomes, Paulo Wender P., additional, Heuckeroth, Steffen, additional, James, C. Andrew, additional, Jarmusch, Scott A., additional, Kakhkhorov, Sarvar A., additional, Kang, Kyo Bin, additional, Kersten, Roland D, additional, Kim, Hyunwoo, additional, Kirk, Riley D., additional, Kohlbacher, Oliver, additional, Kontou, Eftychia E., additional, Liu, Ken, additional, Lizama-Chamu, Itzel, additional, Luu, Gordon T., additional, Knaan, Tal Luzzatto, additional, Marty, Michael T., additional, McAvoy, Andrew C., additional, McCall, Laura-Isobel, additional, Mohamed, Osama G., additional, Nahor, Omri, additional, Niedermeyer, Timo H.J., additional, Northen, Trent R., additional, Overdahl, Kirsten E., additional, Pluskal, Tomáš, additional, Rainer, Johannes, additional, Reher, Raphael, additional, Rodriguez, Elys, additional, Sachsenberg, Timo T., additional, Sanchez, Laura M., additional, Schmid, Robin, additional, Stevens, Cole, additional, Tian, Zhenyu, additional, Tripathi, Ashootosh, additional, Tsugawa, Hiroshi, additional, Nishida, Kozo, additional, Matsuzawa, Yuki, additional, van der Hooft, Justin J.J., additional, Vicini, Andrea, additional, Walter, Axel, additional, Weber, Tilmann, additional, Xiong, Quanbo, additional, Xu, Tao, additional, Zhao, Haoqi Nina, additional, Dorrestein, Pieter C., additional, and Wang, Mingxun, additional

Published
2022
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21. Cytochrome P450Blt Enables Versatile Peptide Cyclisation to Generate Histidine‐ and Tyrosine‐Containing Crosslinked Tripeptide Building Blocks

Author

Zhao, Yongwei, primary, Marschall, Edward, additional, Treisman, Maxine, additional, McKay, Alasdair, additional, Padva, Leo, additional, Crüsemann, Max, additional, Nelson, David R., additional, Steer, David L., additional, Schittenhelm, Ralf B., additional, Tailhades, Julien, additional, and Cryle, Max J., additional

Published
2022
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22. Cytochrome P450 Blt Enables Versatile Peptide Cyclisation to Generate Histidine‐ and Tyrosine‐Containing Crosslinked Tripeptide Building Blocks

Author

Zhao, Yongwei, primary, Marschall, Edward, additional, Treisman, Maxine, additional, McKay, Alasdair, additional, Padva, Leo, additional, Crüsemann, Max, additional, Nelson, David R., additional, Steer, David L., additional, Schittenhelm, Ralf B., additional, Tailhades, Julien, additional, and Cryle, Max J., additional

Published
2022
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26. An environmental bacterial taxon with a large and distinct metabolic repertoire

Author

Wilson, Micheal C., Mori, Tetsushi, Rückert, Christian, Uria, Agustinus R., Helf, Maximilian J., Takada, Kentaro, Gernert, Christine, Steffens, Ursula A. E., Heycke, Nina, Schmitt, Susanne, Rinke, Christian, Helfrich, Eric J. N., Brachmann, Alexander O., Gurgui, Cristian, Wakimoto, Toshiyuki, Kracht, Matthias, Crüsemann, Max, Hentschel, Ute, Abe, Ikuro, Matsunaga, Shigeki, Kalinowski, Jörn, Takeyama, Haruko, and Piel, Jörn

Published
2014
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27. Feature-Based Molecular Networking for the Targeted Identification of Gq-Inhibiting FR900359 Derivatives

Author

Hanke, Wiebke, primary, Patt, Julian, additional, Alenfelder, Judith, additional, Voss, Jan H., additional, Zdouc, Mitja M., additional, Kehraus, Stefan, additional, Kim, Jung Bong, additional, Grujičić, Goran V., additional, Namasivayam, Vigneshwaran, additional, Reher, Raphael, additional, Müller, Christa E., additional, Kostenis, Evi, additional, Crüsemann, Max, additional, and König, Gabriele M., additional

Published
2021
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28. Cytochrome P450Blt Enables Versatile Peptide Cyclisation to Generate Histidine‐ and Tyrosine‐Containing Crosslinked Tripeptide Building Blocks.

Author

Zhao, Yongwei, Marschall, Edward, Treisman, Maxine, McKay, Alasdair, Padva, Leo, Crüsemann, Max, Nelson, David R., Steer, David L., Schittenhelm, Ralf B., Tailhades, Julien, and Cryle, Max J.

Subjects
PEPTIDES, AMINO acid residues, RING formation (Chemistry), TRIPEPTIDES, CYTOCHROME P-450, SYNTHETIC products
Abstract

We report our investigation of the utility of peptide crosslinking cytochrome P450 enzymes from biarylitide biosynthesis to generate a range of cyclic tripeptides from simple synthons. The crosslinked tripeptides produced by this P450 include both tyrosine‐histidine (A−N−B) and tyrosine‐tryptophan (A−O−B) crosslinked tripeptides, the latter a rare example of a phenolic crosslink to an indole moiety. Tripeptides are easily isolated following proteolytic removal of the leader peptide and can incorporate a wide range of amino acids in the residue inside the crosslinked tripeptide. Given the utility of peptide crosslinks in important natural products and the synthetic challenge that these can represent, P450 enzymes have the potential to play roles as important tools in the generation of high‐value cyclic tripeptides for incorporation in synthesis, which can be yet further diversified using selective chemical techniques through specific handles contained within these tripeptides. [ABSTRACT FROM AUTHOR]

Published
2022
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29. Biosynthesis and Mechanism of Action of the Cell Wall Targeting Antibiotic Hypeptin

Author

Wirtz, Daniel A., primary, Ludwig, Kevin C., additional, Arts, Melina, additional, Marx, Carina E., additional, Krannich, Sebastian, additional, Barac, Paul, additional, Kehraus, Stefan, additional, Josten, Michaele, additional, Henrichfreise, Beate, additional, Müller, Anna, additional, König, Gabriele M., additional, Peoples, Aaron J., additional, Nitti, Anthony, additional, Spoering, Amy L., additional, Ling, Losee L., additional, Lewis, Kim, additional, Crüsemann, Max, additional, and Schneider, Tanja, additional

Published
2021
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31. Effective approaches to discover new microbial metabolites in a large strain library

Author

Zdouc, Mitja M., Iorio, Marianna, Vind, Kristiina, Simone, Matteo, Serina, Stefania, Brunati, Cristina, Monciardini, Paolo, Tocchetti, Arianna, Zarazúa, Guadalupe S., Crüsemann, Max, Maffioli, Sonia I., Sosio, Margherita, Donadio, Stefano, Zdouc, Mitja M., Iorio, Marianna, Vind, Kristiina, Simone, Matteo, Serina, Stefania, Brunati, Cristina, Monciardini, Paolo, Tocchetti, Arianna, Zarazúa, Guadalupe S., Crüsemann, Max, Maffioli, Sonia I., Sosio, Margherita, and Donadio, Stefano

Abstract

Natural products have provided many molecules to treat and prevent illnesses in humans, animals and plants. While only a small fraction of the existing microbial diversity has been explored for bioactive metabolites, tens of thousands of molecules have been reported in the literature over the past 80 years. Thus, the main challenge in microbial metabolite screening is to avoid the re-discovery of known metabolites in a cost-effective manner. In this perspective, we report and discuss different approaches used in our laboratory over the past few years, ranging from bioactivity-based screening to looking for metabolic rarity in different datasets to deeply investigating a single Streptomyces strain. Our results show that it is possible to find novel chemistry through a limited screening effort, provided that appropriate selection criteria are in place.

Published
2021

33. Effective approaches to discover new microbial metabolites in a large strain library

Author

Zdouc, Mitja M, primary, Iorio, Marianna, additional, Vind, Kristiina, additional, Simone, Matteo, additional, Serina, Stefania, additional, Brunati, Cristina, additional, Monciardini, Paolo, additional, Tocchetti, Arianna, additional, Zarazúa, Guadalupe S, additional, Crüsemann, Max, additional, Maffioli, Sonia I, additional, Sosio, Margherita, additional, and Donadio, Stefano, additional

Published
2021
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36. An experimental strategy to probe Gq contribution to signal transduction in living cells

Author

Patt, Julian, primary, Alenfelder, Judith, additional, Pfeil, Eva Marie, additional, Voss, Jan Hendrik, additional, Merten, Nicole, additional, Eryilmaz, Funda, additional, Heycke, Nina, additional, Rick, Uli, additional, Inoue, Asuka, additional, Kehraus, Stefan, additional, Deupi, Xavier, additional, Müller, Christa E., additional, König, Gabriele M., additional, Crüsemann, Max, additional, and Kostenis, Evi, additional

Published
2021
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41. Rational design of a heterotrimeric G protein α subunit with artificial inhibitor sensitivity

Author

Malfacini, Davide, primary, Patt, Julian, additional, Annala, Suvi, additional, Harpsøe, Kasper, additional, Eryilmaz, Funda, additional, Reher, Raphael, additional, Crüsemann, Max, additional, Hanke, Wiebke, additional, Zhang, Hang, additional, Tietze, Daniel, additional, Gloriam, David E., additional, Bräuner-Osborne, Hans, additional, Strømgaard, Kristian, additional, König, Gabriele M., additional, Inoue, Asuka, additional, Gomeza, Jesus, additional, and Kostenis, Evi, additional

Published
2019
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42. Rational design of a heterotrimeric G protein α subunit with artificial inhibitor sensitivity

Author

Malfacini, Davide, Patt, Julian, Annala, Suvi, Harpsøe, Kasper, Eryilmaz, Funda, Reher, Raphael, Crüsemann, Max, Hanke, Wiebke, Zhang, Hang, Tietze, Daniel, Gloriam, David E, Bräuner-Osborne, Hans, Strømgaard, Kristian, König, Gabriele M, Inoue, Asuka, Gomeza, Jesus, Kostenis, Evi, Malfacini, Davide, Patt, Julian, Annala, Suvi, Harpsøe, Kasper, Eryilmaz, Funda, Reher, Raphael, Crüsemann, Max, Hanke, Wiebke, Zhang, Hang, Tietze, Daniel, Gloriam, David E, Bräuner-Osborne, Hans, Strømgaard, Kristian, König, Gabriele M, Inoue, Asuka, Gomeza, Jesus, and Kostenis, Evi

Abstract

Transmembrane signals initiated by a range of extracellular stimuli converge on members of the Gq family of heterotrimeric G proteins, which relay these signals in target cells. Gq family G proteins comprise Gq, G11, G14, and G16, which upon activation mediate their cellular effects via inositol lipid-dependent and -independent signaling to control fundamental processes in mammalian physiology. To date, highly specific inhibition of Gq/11/14 signaling can be achieved only with FR900359 (FR) and YM-254890 (YM), two naturally occurring cyclic depsipeptides. To further development of FR or YM mimics for other Gα subunits, we here set out to rationally design Gα16 proteins with artificial FR/YM sensitivity by introducing an engineered depsipeptide binding site. Thereby we permit control of G16 function through ligands that are inactive on the wild type protein. Using CRISPR/Cas9-generated Gαq/Gα11-null cells and loss- and gain-of-function mutagenesis along with label-free whole-cell biosensing, we determined the molecular coordinates for FR/YM inhibition of Gq and transplanted these to FR/YM-insensitive G16. Intriguingly, despite having close structural similarity, FR and YM yielded biologically distinct activities: it was more difficult to perturb Gq inhibition by FR and easier to install FR inhibition onto G16 than perturb or install inhibition with YM. A unique hydrophobic network utilized by FR accounted for these unexpected discrepancies. Our results suggest that non-Gq/11/14 proteins should be amenable to inhibition by FR scaffold-based inhibitors, provided that these inhibitors mimic the interaction of FR with Gα proteins harboring engineered FR-binding sites.

Published
2019

45. Front Cover: Deciphering Specificity Determinants for FR900359-Derived Gq α Inhibitors Based on Computational and Structure-Activity Studies (ChemMedChem 16/2018)

Author

Reher, Raphael, primary, Kühl, Toni, additional, Annala, Suvi, additional, Benkel, Tobias, additional, Kaufmann, Desireé, additional, Nubbemeyer, Britta, additional, Odhiambo, Justin Patrick, additional, Heimer, Pascal, additional, Bäuml, Charlotte Anneke, additional, Kehraus, Stefan, additional, Crüsemann, Max, additional, Kostenis, Evi, additional, Tietze, Daniel, additional, König, Gabriele M., additional, and Imhof, Diana, additional

Published
2018
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47. Deciphering Specificity Determinants for FR900359-Derived Gqα Inhibitors Based on Computational and Structure-Activity Studies

Author

Reher, Raphael, primary, Kühl, Toni, additional, Annala, Suvi, additional, Benkel, Tobias, additional, Kaufmann, Desireé, additional, Nubbemeyer, Britta, additional, Odhiambo, Justin Patrick, additional, Heimer, Pascal, additional, Bäuml, Charlotte Anneke, additional, Kehraus, Stefan, additional, Crüsemann, Max, additional, Kostenis, Evi, additional, Tietze, Daniel, additional, König, Gabriele M., additional, and Imhof, Diana, additional

Published
2018
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49. Heterologous Expression, Biosynthetic Studies, and Ecological Function of the Selective Gq-Signaling Inhibitor FR900359

Author

Crüsemann, Max, Reher, Raphael, Schamari, Isabella, Brachmann, Alexander O, Ohbayashi, Tsubasa, Kuschak, Markus, Malfacini, Davide, Seidinger, Alexander, Pinto-Carbó, Marta, Richarz, René, Reuter, Tatjana, Kehraus, Stefan, Hallab, Asis, Attwood, Misty M., Schiöth, Helgi B., Mergaert, Peter, Kikuchi, Yoshitomo, Schäberle, Till F, Kostenis, Evi, Wenzel, Daniela, Müller, Christa E, Piel, Jörn, Carlier, Aurélien, Eberl, Leo, König, Gabriele M, Crüsemann, Max, Reher, Raphael, Schamari, Isabella, Brachmann, Alexander O, Ohbayashi, Tsubasa, Kuschak, Markus, Malfacini, Davide, Seidinger, Alexander, Pinto-Carbó, Marta, Richarz, René, Reuter, Tatjana, Kehraus, Stefan, Hallab, Asis, Attwood, Misty M., Schiöth, Helgi B., Mergaert, Peter, Kikuchi, Yoshitomo, Schäberle, Till F, Kostenis, Evi, Wenzel, Daniela, Müller, Christa E, Piel, Jörn, Carlier, Aurélien, Eberl, Leo, and König, Gabriele M

Abstract

The cyclic depsipeptide FR900359 (FR), isolated from the tropical plant Ardisia crenata, is a strong and selective inhibitor of Gq proteins, making it an indispensable pharmacological tool to study Gq-related processes, as well as a promising drug candidate. Gq inhibition is a novel mode of action for defense chemicals and crucial for the ecological function of FR, as shown by in vivo experiments in mice, its affinity to insect Gq proteins, and insect toxicity studies. The uncultured endosymbiont of A. crenata was sequenced, revealing the FR nonribosomal peptide synthetase (frs) gene cluster. We here provide a detailed model of FR biosynthesis, supported by in vitro enzymatic and bioinformatic studies, and the novel analogue AC-1, which demonstrates the flexibility of the FR starter condensation domains. Finally, expression of the frs genes in E. coli led to heterologous FR production in a cultivable, bacterial host for the first time.

Published
2018
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50. Heterologe Expression, Biosynthese und ökologische Funktion des selektiven Gq‐Signaltransduktionsinhibitors FR900359

Author

Crüsemann, Max, primary, Reher, Raphael, additional, Schamari, Isabella, additional, Brachmann, Alexander O., additional, Ohbayashi, Tsubasa, additional, Kuschak, Markus, additional, Malfacini, Davide, additional, Seidinger, Alexander, additional, Pinto‐Carbó, Marta, additional, Richarz, René, additional, Reuter, Tatjana, additional, Kehraus, Stefan, additional, Hallab, Asis, additional, Attwood, Misty, additional, Schiöth, Helgi B., additional, Mergaert, Peter, additional, Kikuchi, Yoshitomo, additional, Schäberle, Till F., additional, Kostenis, Evi, additional, Wenzel, Daniela, additional, Müller, Christa E., additional, Piel, Jörn, additional, Carlier, Aurélien, additional, Eberl, Leo, additional, and König, Gabriele M., additional

Published
2017
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