Fabien C. Lecomte, Jeremiah S. Joseph, Jacek Stalewski, Qingliang Shen, Eric Arnoult, Vandana Sridhar, Mengjie Liu, Yingxia Hu, Jovylyn Gatchalian Gasendo, Hagit Ben Arie, Nurit Keinan, Liraz Keidar, Israel Aviv, Emil Ruvinov, Julia Grandjean, Paulo Roberto Dores-Silva, Annie Mak, Buyung Santoso, Suzie Kim, Vikram Shende, Walter J. Wever, Tara Mirzadegan, Zhaoning Zhu, Bryan Fuchs, Philippe Pinton* and Rose Szabady,
{"title":"","authors":"Fabien C. Lecomte, Jeremiah S. Joseph, Jacek Stalewski, Qingliang Shen, Eric Arnoult, Vandana Sridhar, Mengjie Liu, Yingxia Hu, Jovylyn Gatchalian Gasendo, Hagit Ben Arie, Nurit Keinan, Liraz Keidar, Israel Aviv, Emil Ruvinov, Julia Grandjean, Paulo Roberto Dores-Silva, Annie Mak, Buyung Santoso, Suzie Kim, Vikram Shende, Walter J. Wever, Tara Mirzadegan, Zhaoning Zhu, Bryan Fuchs, Philippe Pinton* and Rose Szabady, ","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":"20 7","pages":"XXX-XXX XXX-XXX"},"PeriodicalIF":3.5,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acschembio.5c00181","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144646173","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Stephen B. Ruiz, Daniel E. Tylawsky, Janki Shah, Michelle Saoi, Brandon Cuevas, Shanay Desai, Boglarka Racz, Ana Marie Perea, Arianna R. Izawa-Ishiguro, Justin Cross and Daniel A. Heller*,
{"title":"","authors":"Stephen B. Ruiz, Daniel E. Tylawsky, Janki Shah, Michelle Saoi, Brandon Cuevas, Shanay Desai, Boglarka Racz, Ana Marie Perea, Arianna R. Izawa-Ishiguro, Justin Cross and Daniel A. Heller*, ","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":"20 7","pages":"XXX-XXX XXX-XXX"},"PeriodicalIF":3.5,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acschembio.5c00273","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144646184","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Qinheng Zheng, Tianfang Shen, Julius Pampel and Kevan M. Shokat*,
{"title":"","authors":"Qinheng Zheng, Tianfang Shen, Julius Pampel and Kevan M. Shokat*, ","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":"20 7","pages":"XXX-XXX XXX-XXX"},"PeriodicalIF":3.5,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acschembio.5c00249","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144646162","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Maria J. Ortiz-Ruiz, Olajumoke Popoola, Konstantinos Mitsopoulos, Robert Te-Poele, Rahul S. Samant, Gary Box, Will Court, Alexis De Haven Brandon, Sharon Gowan, Aurelie Mallinger, Toby Roe, Kate Swabey, Melanie Valenti, Bissan Al-Lazikani, Julian Blagg, Christina Esdar, Kai Schiemann, Dirk Wienke, Suzanne A. Eccles, Paul Workman and Paul A. Clarke*,
{"title":"","authors":"Maria J. Ortiz-Ruiz, Olajumoke Popoola, Konstantinos Mitsopoulos, Robert Te-Poele, Rahul S. Samant, Gary Box, Will Court, Alexis De Haven Brandon, Sharon Gowan, Aurelie Mallinger, Toby Roe, Kate Swabey, Melanie Valenti, Bissan Al-Lazikani, Julian Blagg, Christina Esdar, Kai Schiemann, Dirk Wienke, Suzanne A. Eccles, Paul Workman and Paul A. Clarke*, ","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":"20 7","pages":"XXX-XXX XXX-XXX"},"PeriodicalIF":3.5,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acschembio.5c00338","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144646180","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lisa M. Boatner, Jerome Eberhardt, Flowreen Shikwana, Matthew Holcomb, Peiyuan Lee, Kendall N. Houk, Stefano Forli* and Keriann M. Backus*,
{"title":"","authors":"Lisa M. Boatner, Jerome Eberhardt, Flowreen Shikwana, Matthew Holcomb, Peiyuan Lee, Kendall N. Houk, Stefano Forli* and Keriann M. Backus*, ","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":"20 7","pages":"XXX-XXX XXX-XXX"},"PeriodicalIF":3.5,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acschembio.5c00225","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144646188","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
ACS Chemical BiologyPub Date : 2025-07-18Epub Date: 2025-04-18DOI: 10.1021/acschembio.5c00081
Taku Tsukidate, Ansuman Sahoo, Geetanjali Pendyala, Rong-Sheng Yang, Jonathan Welch, Sri Madabhushi, Xuanwen Li
{"title":"Discovery of Chemical Tools for Polysorbate-Degradative Enzyme Control in the Biopharmaceutical Upstream Process via Multi-Omic Profiling of Host Cell Clones.","authors":"Taku Tsukidate, Ansuman Sahoo, Geetanjali Pendyala, Rong-Sheng Yang, Jonathan Welch, Sri Madabhushi, Xuanwen Li","doi":"10.1021/acschembio.5c00081","DOIUrl":"10.1021/acschembio.5c00081","url":null,"abstract":"<p><p>Host cell proteins are process-related impurities in biotherapeutics and can potentially pose risks to patient safety and product quality. Specifically, certain host cell-derived enzymes, including lipases, can degrade the formulation excipient polysorbate (PS) in biopharmaceutical formulations, affecting drug product stability in liquid formulations. We leveraged multiomics approaches, including transcriptomics, proteomics, and activity-based protein profiling (ABPP), to identify mechanisms that regulate PS-degradative enzyme (PSDE) abundance and to develop strategies for their control. Comparative multiomics analysis of two monoclonal antibody (mAb)-producing host cell clones revealed differential lipase profiles at the mRNA, protein, and enzyme activity levels and associated increased lipase activity with upregulated lipid catabolic pathways such as the fatty acid beta oxidation pathway. Further, for the first time in the literature, we identified peroxisome proliferator-activated receptor γ (PPARγ) as a key regulator of PSDEs in manufacturing Chinese Hamster Ovary (CHO) cells. Downregulation of the PPARγ pathway with its antagonists resulted in a selective reduction of PSDE levels and improved PS stability without compromising mAb productivity or quality. This study highlights the potential of PPARγ modulators as chemical tools for PSDE control at the gene regulation level, offering significant implications for biopharmaceutical process development and control.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":"1505-1515"},"PeriodicalIF":3.5,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143952936","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
ACS Chemical BiologyPub Date : 2025-07-18Epub Date: 2025-06-15DOI: 10.1021/acschembio.5c00280
Zhanzhao Cui, Xiaozheng Wang, Lixin Yin, Lu Chen, Kai Liu, Yemin Wang, Shuangjun Lin, Zixin Deng, Min Xu, Meifeng Tao
{"title":"Characterization of the Postaglycone Modifications in Ristomycin Biosynthesis.","authors":"Zhanzhao Cui, Xiaozheng Wang, Lixin Yin, Lu Chen, Kai Liu, Yemin Wang, Shuangjun Lin, Zixin Deng, Min Xu, Meifeng Tao","doi":"10.1021/acschembio.5c00280","DOIUrl":"10.1021/acschembio.5c00280","url":null,"abstract":"<p><p><i>Amycolatopsis</i> sp. TNS106 produces ristomycin (ristocetin), a type III glycopeptide antibiotic (GPA) featuring extensive glycosyl modifications and potent antimicrobial activity against Gram-positive pathogens. Unlike the well-documented nonribosomal peptide synthetase-assembled peptide scaffold, the timing and specificity of its postassembly tailoring steps remain poorly understood. In this study, we generated a series of <i>A.</i> sp. TNS106 mutants and characterized accumulated derivatives to delineate the postaglycone tailoring steps for ristomycin maturation. <i>In vitro</i> biochemical reactions confirmed the function and timing of the RgtfB and RgtfC glycosyltransferases and MtfA carboxyl methyltransferase. By integrating our findings with prior studies, we propose a comprehensive model for the sequential glycosylation and C-terminal methylation processes governing ristomycin biosynthesis. Notably, we identified multiple ristomycin glycoforms that demonstrate improved antimicrobial activity compared to the parent molecule. Strikingly, removal of the ristosamine on β-hydroxytyrosine 6 (βht6) or the presence of rhamnose on 4-hydroxyphenylglycine 4 (Hpg4) markedly impaired its antibacterial activity, particularly against vancomycin-resistant <i>Enterococcus</i>. The engineered strains constructed here provide a versatile platform for generating novel ristomycin analogs through combinatorial biosynthesis or chemical synthesis, advancing the development of new-to-nature GPAs with improved potency.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":"1764-1774"},"PeriodicalIF":3.5,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144300534","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
ACS Chemical BiologyPub Date : 2025-07-18Epub Date: 2025-06-29DOI: 10.1021/acschembio.5c00078
Rashmi S Bhosale, Arnab Chakraborty, Tsung-Yun Wong, Dattatraya P Masal, Rahul Choudhury, Sonali Srivastava, D Srinivasa Reddy, Courtney C Aldrich, Siddhesh S Kamat, Debasisa Mohanty, Rajesh S Gokhale
{"title":"Enzymatic Pathway for Kupyaphore Degradation in <i>Mycobacterium tuberculosis</i>: Mechanism of Metal Homeostasis and Turnover.","authors":"Rashmi S Bhosale, Arnab Chakraborty, Tsung-Yun Wong, Dattatraya P Masal, Rahul Choudhury, Sonali Srivastava, D Srinivasa Reddy, Courtney C Aldrich, Siddhesh S Kamat, Debasisa Mohanty, Rajesh S Gokhale","doi":"10.1021/acschembio.5c00078","DOIUrl":"10.1021/acschembio.5c00078","url":null,"abstract":"<p><p>Metallophores are essential for metal homeostasis, regulating availability, and mediating host-pathogen interactions. Kupyaphores are specialized metallophores produced by <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>) that primarily chelate zinc to support bacterial survival. Elevated kupyaphore levels early in infection highlight their importance, while their rapid decline, despite increasing bacterial loads, indicates tightly regulated mechanisms of production, consumption, and degradation. However, the processes driving kupyaphore catabolism and their role in preventing zinc toxicity in <i>Mtb</i> remain unclear. Here, we show that covalent modification of the isonitrile moiety in kupyaphores releases zinc, triggering degradation through a sequential three-step enzymatic pathway encoded by <i>Mtb</i>. Isonitrile hydratase converts isonitrile groups into formamides, which are subsequently processed into amines by <i>N</i>-substituted formamide deformylase and ultimately oxidized to β-ketoesters by amine oxidases. The biological significance of this pathway is underscored by the upregulation of these genes under metal-depleted and biofilm-forming conditions. Mutant <i>Mtb</i> strains lacking these genes exhibit impaired growth in metal-limiting environments and reduced levels of biofilm formation. Catalytic intermediates detected in <i>Mtb</i> cultures and infected mouse lung tissues confirm the pathway's in vivo activity. Further, genome mining reveals that similar enzymes are conserved across organisms producing isonitrile-containing metabolites, emphasizing the broader importance of this pathway. Understanding these processes could pave the way for novel therapeutic strategies targeting kupyaphore catabolism.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":"1492-1504"},"PeriodicalIF":3.5,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144525305","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Peiyuan Zhang, Amirhossein Taghavi, Masahito Abe, Haruo Aikawa, Yoshihiro Akahori, Jonathan L. Chen, Yuquan Tong, Jared T. Baisden, Michael D. Cameron, Jessica L. Childs-Disney and Matthew D. Disney*,
{"title":"","authors":"Peiyuan Zhang, Amirhossein Taghavi, Masahito Abe, Haruo Aikawa, Yoshihiro Akahori, Jonathan L. Chen, Yuquan Tong, Jared T. Baisden, Michael D. Cameron, Jessica L. Childs-Disney and Matthew D. Disney*, ","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":"20 7","pages":"XXX-XXX XXX-XXX"},"PeriodicalIF":3.5,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acschembio.5c00260","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144646161","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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