ACS Chemical Biology最新文献_第6页

Activation of the Trichodimerol Pathway through Deletion of mcrA in Marine Penicillium rubens YAP001. 海洋红青霉素YAP001中mcrA缺失激活Trichodimerol通路

IF 3.5 2区生物学

ACS Chemical Biology Pub Date : 2025-04-18 Epub Date: 2025-03-17 DOI: 10.1021/acschembio.4c00761

Jennifer Shyong, Quoc-Dung Tran Huynh, Stella Dziedzic, Emily Aguirre, Chris Rabot, Bo Yuan, Hugo Edward Herrero-MacKenzie, Jason E Stajich, Ching-Kuo Lee, Carly D Kenkel, Clay C C Wang

{"title":"Activation of the Trichodimerol Pathway through Deletion of mcrA in Marine Penicillium rubens YAP001.","authors":"Jennifer Shyong, Quoc-Dung Tran Huynh, Stella Dziedzic, Emily Aguirre, Chris Rabot, Bo Yuan, Hugo Edward Herrero-MacKenzie, Jason E Stajich, Ching-Kuo Lee, Carly D Kenkel, Clay C C Wang","doi":"10.1021/acschembio.4c00761","DOIUrl":"10.1021/acschembio.4c00761","url":null,"abstract":"Fungal secondary metabolites (SMs) are complex organic compounds comprising a variety of biological activities that are essential in medicine. These natural products can be found in various environments, with studies demonstrating the importance of studying marine-sourced fungi due to the increased potency of the compounds they produce. In this study, we sourced a Penicillium rubens YAP001 strain isolated from Exaiptasia diaphana and explored an avenue for the upregulation of its SMs by combining the one-strain-many-compounds (OSMAC) strategy with genetic manipulation of negative global regulator of secondary metabolism, mcrA. Here, we generated a mcrAΔ strain of marine P. rubens (YAP001), which led to the detection of sorbicillinoids, which is significant due to the prior discovery that these compounds illicit cytotoxic effects that have the potential as an anticancer agent. Specifically, we found that sorbicillin was not only upregulated but the mutant strain also produced the dimeric product, trichodimerol, which often exhibits stronger biological activities compared to sorbicillin. Furthermore, the reduced form of trichodimerol, dihydrotrichodimerol, was also detected in the mutant strain. This work suggests that genetic manipulation of global regulators in combination with the OSMAC method in filamentous fungi is a promising technique for upregulating pathways of interest for small-molecule drug discovery.","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":"823-829"},"PeriodicalIF":3.5,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143646406","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}

引用次数: 0

Noninvasive Bioluminescence Imaging of Serum Albumins in Living Mice. 活体小鼠血清白蛋白的无创生物发光成像。

IF 3.5 2区生物学

ACS Chemical Biology Pub Date : 2025-04-18 Epub Date: 2025-04-02 DOI: 10.1021/acschembio.4c00740

Sung-Bae Kim, Genta Kamiya, Tadaomi Furuta, Nobuo Kitada, Suresh Thangudu, Arutselvan Natarajan, Shojiro A Maki, Ramasamy Paulmurugan

{"title":"Noninvasive Bioluminescence Imaging of Serum Albumins in Living Mice.","authors":"Sung-Bae Kim, Genta Kamiya, Tadaomi Furuta, Nobuo Kitada, Suresh Thangudu, Arutselvan Natarajan, Shojiro A Maki, Ramasamy Paulmurugan","doi":"10.1021/acschembio.4c00740","DOIUrl":"10.1021/acschembio.4c00740","url":null,"abstract":"Bioluminescence (BL) is an emerging optical readout that has been extensively used in various bioassays and molecular imaging systems. In this study, we present the bioanalytical application of marine luciferins as an excellent optical indicator for noninvasive imaging of serum albumins. We synthesized 30 kinds of regioisomeric coelenterazine (CTZ) analogs and investigated their specificities for major serum proteins from various species. The results found that some of the CTZ analogs exhibited surprisingly specific optical signals upon binding with the serum albumins. These CTZ analogs showed diverse emission spectra ranging from 495 to 558 nm according to the albumin species used acting as pseudoluciferases. The selective albumin indicators, TS1 and TS2, exhibited long and linear dose-response curves and were sensitive enough to determine clinically normal and abnormal (microalbuminuria) ranges of albumins in saliva and urine. The sensitivity of this assay is superior to that of the conventional Bromocresol purple (BCP) method. We further demonstrated the advantages of the albumin indicators through noninvasive imaging of liver-albumin in vivo in living mice. The in vivo and ex vivo imaging results confirmed that the CTZ analog TS2 can sensitively image the liver-albumin in vivo with high signal-to-background ratio. This study paves a new way to make use of CTZ analogs for noninvasive albumin imaging and conceptualizes the pseudoluciferase-based imaging. The distinct in vivo imaging of serum albumins can potentially aid clinicians in providing insight into patients' liver function and other vital factors needed for whole-body homeostasis.","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":"802-814"},"PeriodicalIF":3.5,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143762587","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}

引用次数: 0

Reconstitution and Characterization of Biosynthetic Machinery for Parageocin I, a Novel Thiazole-Rich Peptide from the Thermophilic Bacterium Parageobacillus caldoxylosilyticus. 从嗜热细菌中提取的一种新型富含噻唑的肽- Parageocin I的生物合成机制的重构和表征。

IF 3.5 2区生物学

ACS Chemical Biology Pub Date : 2025-04-18 Epub Date: 2025-04-02 DOI: 10.1021/acschembio.4c00758

Ayane Yano, Hiroya Tomita, Kentaro Miyazaki, Kohsuke Honda

{"title":"Reconstitution and Characterization of Biosynthetic Machinery for Parageocin I, a Novel Thiazole-Rich Peptide from the Thermophilic Bacterium Parageobacillus caldoxylosilyticus.","authors":"Ayane Yano, Hiroya Tomita, Kentaro Miyazaki, Kohsuke Honda","doi":"10.1021/acschembio.4c00758","DOIUrl":"10.1021/acschembio.4c00758","url":null,"abstract":"Ribosomally synthesized and post-translationally modified peptides (RiPPs) are the representative microbial peptidyl secondary metabolites including the class of linear azol(in)e-containing peptides (LAPs). A substantial proportion of LAPs have been identified in mesophilic microorganisms, including actinomycetes. In this study, we report the biosynthetic reconstitution and characterization of parageocin I, a novel thiazole-rich LAP derived from the thermophilic bacterium Parageobacillus caldoxylosilyticus KH1-5 which exhibits optimal growth around 60 °C. The biosynthetic gene cluster (pgc) consists of four genes: pgcA, pgcB, pgcC, and pgcD, encoding the precursor peptide, dehydrogenase, YcaO family cyclodehydratase, and biosynthetic scaffold protein, respectively. The precursor peptide PgcA possesses 13 Cys and 2 Ser residues, with regularly repeated sequences interspaced between Cys residues. We first reconstituted the biosynthesis heterologously in Escherichia coli. Mass spectrometry analysis of the synthesized peptide, coupled with mutational analyses of the modified PgcA, revealed that the final product, designated as parageocin I, harbors 13 thiazole rings derived from the cyclization of Cys residues, while Ser residues remain intact. Furthermore, mutational studies of PgcA revealed three key principles governing heterocyclization by PgcC: (i) Cys is acceptable, but Ser and Thr are not; (ii) the presence of an acidic amino acid preceding Cys is not permissible; and (iii) a minimum of two amino acids must separate Cys residues. In addition, we successfully reconstituted the biosynthesis in vitro using the purified recombinant enzymes. This is the first report of LAP biosynthesis in thermophilic Bacillaceae, thereby expanding our understanding of not only LAPs but also secondary metabolism in thermophiles.","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":"815-822"},"PeriodicalIF":3.5,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143770724","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}

引用次数: 0

Targeted Protein Degradation: From Basic Science to Therapeutic Applications 靶向蛋白降解：从基础科学到治疗应用

IF 3.5 2区生物学

ACS Chemical Biology Pub Date : 2025-04-18 DOI: 10.1021/acschembio.5c0006710.1021/acschembio.5c00067

Rongfeng Zhu*, Xiaoyu Tang* and Heng Zhang*,

引用次数: 0

Structural and Biochemical Insights into Lignin-Oxidizing Activity of Bacterial Peroxidases against Soluble Substrates and Kraft Lignin. 细菌过氧化物酶对可溶性底物和硫酸盐木质素氧化活性的结构和生化研究。

IF 3.5 2区生物学

ACS Chemical Biology Pub Date : 2025-04-18 Epub Date: 2025-03-27 DOI: 10.1021/acschembio.4c00788

Zahra Choolaei, Anna N Khusnutdinova, Tatiana Skarina, Peter Stogios, Patrick Diep, Sofia Lemak, Elizabeth A Edwards, Alexei Savchenko, Alexander F Yakunin

{"title":"Structural and Biochemical Insights into Lignin-Oxidizing Activity of Bacterial Peroxidases against Soluble Substrates and Kraft Lignin.","authors":"Zahra Choolaei, Anna N Khusnutdinova, Tatiana Skarina, Peter Stogios, Patrick Diep, Sofia Lemak, Elizabeth A Edwards, Alexei Savchenko, Alexander F Yakunin","doi":"10.1021/acschembio.4c00788","DOIUrl":"10.1021/acschembio.4c00788","url":null,"abstract":"Great interest has recently been drawn to the production of value-added products from lignin; however, its recalcitrance and high chemical complexity have made this challenging. Dye-decolorizing peroxidases and catalase-peroxidases are among the enzymes that are recognized to play important roles in environmental lignin oxidation. However, bacterial lignin-oxidizing enzymes remain less characterized compared to related proteins from fungi. In this study, screening of 18 purified bacterial peroxidases against the general chromogenic substrate 2,2'-azinobis(3-ethylbenzthiazoline-6-sulfonate) (ABTS) revealed the presence of peroxidase activity in all proteins. Agarose plate-based screens with kraft lignin identified detectable and high lignin oxidation activity in 15 purified proteins. Crystal structures were determined for the DyP-type peroxidases FC2591 from Frankia casuarinae, PF3257 from Pseudomonas fluorescens, and PR9465 from Pseudomonas rhizosphaerae. The structures revealed the presence of hemes with bound oxygens coordinated by conserved His, Arg, and Asp residues as well as three molecular tunnels connecting the heme with the protein surface. Structure-based site-directed mutagenesis of FC2591 identified at least five active site residues as essential for oxidase activity against both ABTS and lignin, whereas the S370A mutant protein showed a three- to 4-fold activity increase with both substrates. HPLC analysis of reaction products of the wild-type FC2591 and S370A mutant proteins with the model lignin dimer guaiacylglycerol-β-guaiacyl ether and kraft lignin revealed the formation of products consistent with the radical coupling of the reaction intermediates. Thus, this study identified novel bacterial heme peroxidases with lignin oxidation activity and provided further insights into our understanding of these enzymes.","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":"830-844"},"PeriodicalIF":3.5,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143717570","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}

引用次数: 0

Chemically Induced Nuclear Pore Complex Protein Degradation via TRIM21 通过TRIM21化学诱导核孔复合物蛋白降解

IF 3.5 2区生物学

ACS Chemical Biology Pub Date : 2025-04-18 DOI: 10.1021/acschembio.4c0083310.1021/acschembio.4c00833

Xiaomei Li, Qingyang Wang, Anping Guo, Yaping Qiu, Qiuxia Chen, You Li, Lanjun Zhang, Yaxin Guo, Xiaoyun Meng, Shiqian Li, Guizhi Liu, Liyun Zhang, Jian Liu, Xianyang Li, Longying Cai, Xuemin Cheng, Chuan Liu, Xiaotao Wang, Andrew Wood, James Murray, Guansai Liu, Jin Li, Xiaodong Huang* and Dengfeng Dou*,

{"title":"Chemically Induced Nuclear Pore Complex Protein Degradation via TRIM21","authors":"Xiaomei Li, Qingyang Wang, Anping Guo, Yaping Qiu, Qiuxia Chen, You Li, Lanjun Zhang, Yaxin Guo, Xiaoyun Meng, Shiqian Li, Guizhi Liu, Liyun Zhang, Jian Liu, Xianyang Li, Longying Cai, Xuemin Cheng, Chuan Liu, Xiaotao Wang, Andrew Wood, James Murray, Guansai Liu, Jin Li, Xiaodong Huang* and Dengfeng Dou*, ","doi":"10.1021/acschembio.4c0083310.1021/acschembio.4c00833","DOIUrl":"https://doi.org/10.1021/acschembio.4c00833https://doi.org/10.1021/acschembio.4c00833","url":null,"abstract":"Despite the exciting progress of bifunctional degrader molecules, also known as proteolysis-targeting chimeras (PROTACs), the rapidly expanding field is still significantly hampered by the lack of available E3 ligase ligands. Our research bridges this gap by uncovering a series of small-molecule ligands to the E3 ligase TRIM21 through DNA-Encoded Library (DEL) technology. We confirmed their interaction with TRIM21 using crystallography and demonstrated their antiproliferative effects across various cancer cell types. Furthermore, proteomic studies identified that the mRNA Export Factor GLE1 and the Nuclear Pore Complex Protein NUP155 were significantly downregulated on TRIM21 ligand treatment. This degradation required TRIM21 and was ubiquitin-proteasome-dependent. More specifically, NUP155 was the primary target for the TRIM21 ligands, while GLE1 was considered a passenger target on initial degradation of NUP155. Using immunofluorescence techniques, we further demonstrated that the degradation of GLE1 and NUP155 proteins impaired the integrity of the nuclear envelope, leading to cell death. Highlighted by this research, a novel mode of action has been discovered for the TRIM21 E3 ligase ligand, acting as a monovalent degrader that triggers de novo interaction with functional complex proteins and induces their degradation.","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":"20 5","pages":"1020–1028 1020–1028"},"PeriodicalIF":3.5,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144067744","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}

引用次数: 0

Introducing Our Authors. 介绍作者。

IF 3.5 2区生物学

ACS Chemical Biology Pub Date : 2025-04-18 DOI: 10.1021/acschembio.5c00191

Jen Wagner

引用次数: 0

TRIM21-NUP98 Interface Accommodates Structurally Diverse Molecular Glue Degraders. TRIM21-NUP98接口适应结构多样的分子胶水降解剂。

IF 3.5 2区生物学

ACS Chemical Biology Pub Date : 2025-04-18 Epub Date: 2025-04-09 DOI: 10.1021/acschembio.5c00036

Yalong Cheng, Longzhi Cao, Panrui Lu, Lei Xue, Xiaomei Li, Qingyang Wang, Dengfeng Dou, Jin Li, Ting Han

{"title":"TRIM21-NUP98 Interface Accommodates Structurally Diverse Molecular Glue Degraders.","authors":"Yalong Cheng, Longzhi Cao, Panrui Lu, Lei Xue, Xiaomei Li, Qingyang Wang, Dengfeng Dou, Jin Li, Ting Han","doi":"10.1021/acschembio.5c00036","DOIUrl":"https://doi.org/10.1021/acschembio.5c00036","url":null,"abstract":"Molecular glue degraders enable targeted protein degradation by bridging interactions between target proteins and E3 ubiquitin ligases. Whereas some target-E3 interfaces exhibit the capacity to accommodate structurally diverse degraders, the extent of this adaptability across molecular glue targets remains unclear. We recently identified (S)-ACE-OH as a molecular glue degrader that recruits the E3 ubiquitin ligase TRIM21 to the nuclear pore complex by recognizing NUP98, thereby inducing the degradation of nuclear pore proteins. Here, we analyzed public compound toxicity data across a large collection of cell lines and identified two additional molecular glue degraders, PRLX 93936 and BMS-214662, which engage the TRIM21-NUP98 interface to induce selective degradation of nuclear pore proteins. Additionally, we confirmed that HGC652, another TRIM21-dependent molecular glue degrader, also binds at this interface. Together with our previously characterized degrader (S)-ACE-OH, these findings demonstrate that the TRIM21-NUP98 interface can accommodate structurally diverse molecular glue degraders.","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":"20 4","pages":"953-959"},"PeriodicalIF":3.5,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143951023","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}

引用次数: 0

The Hunt for the Putative Epoxyeicosatrienoic Acid Receptor. 寻找假定的环氧二碳三烯酸受体。

IF 3.5 2区生物学

ACS Chemical Biology Pub Date : 2025-04-18 Epub Date: 2025-03-24 DOI: 10.1021/acschembio.5c00047

William R Arnold, Sona Jain, Vidya Sinha, Aditi Das

{"title":"The Hunt for the Putative Epoxyeicosatrienoic Acid Receptor.","authors":"William R Arnold, Sona Jain, Vidya Sinha, Aditi Das","doi":"10.1021/acschembio.5c00047","DOIUrl":"10.1021/acschembio.5c00047","url":null,"abstract":"Epoxyeicosatrienoic acids, or EETs, are signaling molecules formed by the metabolism of arachidonic acid by cytochrome P450 enzymes. They are well-known for their anti-inflammatory effects, their ability to lower blood pressure, and benefits to cardiovascular outcomes. Despite the wealth of data demonstrating their physiological benefits, the putative high-affinity receptor that mediates these effects is yet to be identified. The recent report that the sphingosine-1-phosphate receptor 1 (S1PR1) is a high-affinity receptor for a related epoxy lipid prompted us to ask, \"Why has the putative EET receptor not been discovered yet? What information about the discoveries of lipid epoxide receptors can help us identify the putative EET receptor?\" In this review, we summarize the evidence supporting that the putative EET receptor exists. We then review the data showing EETs binding to other, low-affinity receptors and the discovery of receptors for similar lipid metabolites that can serve as a model for identifying the putative EET receptor. We hope this review will revitalize the search for this important receptor, which can facilitate the development of anti-inflammatory and cardiovascular therapeutics.","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":"762-777"},"PeriodicalIF":3.5,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12012780/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143699060","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}

引用次数: 0

Small-Molecule FICD Inhibitors Suppress Endogenous and Pathologic FICD-Mediated Protein AMPylation. 小分子FICD抑制剂抑制内源性和病理性FICD介导的蛋白amppyation。

IF 3.5 2区生物学

ACS Chemical Biology Pub Date : 2025-04-18 Epub Date: 2025-03-04 DOI: 10.1021/acschembio.4c00847

Bhaskar K Chatterjee, Maroof Alam, Arghya Chakravorty, Shannon M Lacy, William Giblin, Jason Rech, Charles L Brooks, Peter Arvan, Matthias C Truttmann

引用次数: 0