Pub Date : 2024-08-15DOI: 10.1016/j.chembiol.2024.07.016
Since the first award in 1901, the Nobel Prize has come to signify the pinnacle of scientific achievement. In this Voices piece in the August special issue of Cell Chemical Biology entitled “Bridging chemistry and biology,” we ask Nobel laureates to reflect on the impact the prize had on them. We learn how it affected their life or work, their outlook on science, the lessons learned, and their advice for the next generation of scientists.
{"title":"Reflections from Nobel laureates in chemistry","authors":"","doi":"10.1016/j.chembiol.2024.07.016","DOIUrl":"10.1016/j.chembiol.2024.07.016","url":null,"abstract":"<div><p>Since the first award in 1901, the Nobel Prize has come to signify the pinnacle of scientific achievement. In this Voices piece in the August special issue of <em>Cell Chemical Biology</em> entitled “Bridging chemistry and biology,” we ask Nobel laureates to reflect on the impact the prize had on them. We learn how it affected their life or work, their outlook on science, the lessons learned, and their advice for the next generation of scientists.</p></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":null,"pages":null},"PeriodicalIF":6.6,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141990569","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-15DOI: 10.1016/j.chembiol.2024.07.003
The septin cytoskeleton is primarily known for roles in cell division and host defense against bacterial infection. Despite recent insights, the full breadth of roles for septins in host defense is poorly understood. In macrophages, Shigella induces pyroptosis, a pro-inflammatory form of cell death dependent upon gasdermin D (GSDMD) pores at the plasma membrane and cell surface protein ninjurin-1 (NINJ1) for membrane rupture. Here, we discover that septins promote macrophage pyroptosis induced by lipopolysaccharide (LPS)/nigericin and Shigella infection, but do not affect cytokine expression or release. We observe that septin filaments assemble at the plasma membrane, and cleavage of GSDMD is impaired in septin-depleted cells. We found that septins regulate mitochondrial dynamics and the expression of NINJ1. Using a Shigella-zebrafish infection model, we show that septin-mediated pyroptosis is an in vivo mechanism of infection control. The discovery of septins as a mediator of pyroptosis may inspire innovative anti-bacterial and anti-inflammatory treatments.
{"title":"Septins promote macrophage pyroptosis by regulating gasdermin D cleavage and ninjurin-1-mediated plasma membrane rupture","authors":"","doi":"10.1016/j.chembiol.2024.07.003","DOIUrl":"10.1016/j.chembiol.2024.07.003","url":null,"abstract":"<div><p>The septin cytoskeleton is primarily known for roles in cell division and host defense against bacterial infection. Despite recent insights, the full breadth of roles for septins in host defense is poorly understood. In macrophages, <em>Shigella</em> induces pyroptosis, a pro-inflammatory form of cell death dependent upon gasdermin D (GSDMD) pores at the plasma membrane and cell surface protein ninjurin-1 (NINJ1) for membrane rupture. Here, we discover that septins promote macrophage pyroptosis induced by lipopolysaccharide (LPS)/nigericin and <em>Shigella</em> infection, but do not affect cytokine expression or release. We observe that septin filaments assemble at the plasma membrane, and cleavage of GSDMD is impaired in septin-depleted cells. We found that septins regulate mitochondrial dynamics and the expression of NINJ1. Using a <em>Shigella</em>-zebrafish infection model, we show that septin-mediated pyroptosis is an <em>in vivo</em> mechanism of infection control. The discovery of septins as a mediator of pyroptosis may inspire innovative anti-bacterial and anti-inflammatory treatments.</p></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":null,"pages":null},"PeriodicalIF":6.6,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2451945624003052/pdfft?md5=1fda9bdffaba472fc447836cdbe316e3&pid=1-s2.0-S2451945624003052-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141892170","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-15DOI: 10.1016/j.chembiol.2024.05.002
Aspartate is crucial for nucleotide synthesis, ammonia detoxification, and maintaining redox balance via the malate-aspartate-shuttle (MAS). To disentangle these multiple roles of aspartate metabolism, tools are required that measure aspartate concentrations in real time and in live cells. We introduce AspSnFR, a genetically encoded green fluorescent biosensor for intracellular aspartate, engineered through displaying and screening biosensor libraries on mammalian cells. In live cells, AspSnFR is able to precisely and quantitatively measure cytosolic aspartate concentrations and dissect its production from glutamine. Combining high-content imaging of AspSnFR with pharmacological perturbations exposes differences in metabolic vulnerabilities of aspartate levels based on nutrient availability. Further, AspSnFR facilitates tracking of aspartate export from mitochondria through SLC25A12, the MAS’ key transporter. We show that SLC25A12 is a rapidly responding and direct route to couple Ca2+ signaling with mitochondrial aspartate export. This establishes SLC25A12 as a crucial link between cellular signaling, mitochondrial respiration, and metabolism.
{"title":"AspSnFR: A genetically encoded biosensor for real-time monitoring of aspartate in live cells","authors":"","doi":"10.1016/j.chembiol.2024.05.002","DOIUrl":"10.1016/j.chembiol.2024.05.002","url":null,"abstract":"<div><p>Aspartate is crucial for nucleotide synthesis, ammonia detoxification, and maintaining redox balance via the malate-aspartate-shuttle (MAS). To disentangle these multiple roles of aspartate metabolism, tools are required that measure aspartate concentrations in real time and in live cells. We introduce AspSnFR, a genetically encoded green fluorescent biosensor for intracellular aspartate, engineered through displaying and screening biosensor libraries on mammalian cells. In live cells, AspSnFR is able to precisely and quantitatively measure cytosolic aspartate concentrations and dissect its production from glutamine. Combining high-content imaging of AspSnFR with pharmacological perturbations exposes differences in metabolic vulnerabilities of aspartate levels based on nutrient availability. Further, AspSnFR facilitates tracking of aspartate export from mitochondria through SLC25A12, the MAS’ key transporter. We show that SLC25A12 is a rapidly responding and direct route to couple Ca<sup>2+</sup> signaling with mitochondrial aspartate export. This establishes SLC25A12 as a crucial link between cellular signaling, mitochondrial respiration, and metabolism.</p></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":null,"pages":null},"PeriodicalIF":6.6,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S245194562400179X/pdfft?md5=3b3153c35af18753feadccb80f236687&pid=1-s2.0-S245194562400179X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141156564","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-15DOI: 10.1016/j.chembiol.2024.07.005
We describe a protein proximity inducing therapeutic modality called Regulated Induced Proximity Targeting Chimeras or RIPTACs: heterobifunctional small molecules that elicit a stable ternary complex between a target protein (TP) selectively expressed in tumor cells and a pan-expressed protein essential for cell survival. The resulting co-operative protein-protein interaction (PPI) abrogates the function of the essential protein, thus leading to death selectively in cells expressing the TP. This approach leverages differentially expressed intracellular proteins as novel cancer targets, with the advantage of not requiring the target to be a disease driver. In this chemical biology study, we design RIPTACs that incorporate a ligand against a model TP connected via a linker to effector ligands such as JQ1 (BRD4) or BI2536 (PLK1) or CDK inhibitors such as TMX3013 or dinaciclib. RIPTACs accumulate selectively in cells expressing the HaloTag-FKBP target, form co-operative intracellular ternary complexes, and induce an anti-proliferative response in target-expressing cells.
{"title":"Regulated induced proximity targeting chimeras—RIPTACs—A heterobifunctional small molecule strategy for cancer selective therapies","authors":"","doi":"10.1016/j.chembiol.2024.07.005","DOIUrl":"10.1016/j.chembiol.2024.07.005","url":null,"abstract":"<div><p>We describe a protein proximity inducing therapeutic modality called Regulated Induced Proximity Targeting Chimeras or RIPTACs: heterobifunctional small molecules that elicit a stable ternary complex between a target protein (TP) selectively expressed in tumor cells and a pan-expressed protein essential for cell survival. The resulting co-operative protein-protein interaction (PPI) abrogates the function of the essential protein, thus leading to death selectively in cells expressing the TP. This approach leverages differentially expressed intracellular proteins as novel cancer targets, with the advantage of not requiring the target to be a disease driver. In this chemical biology study, we design RIPTACs that incorporate a ligand against a model TP connected via a linker to effector ligands such as JQ1 (BRD4) or BI2536 (PLK1) or CDK inhibitors such as TMX3013 or dinaciclib. RIPTACs accumulate selectively in cells expressing the HaloTag-FKBP target, form co-operative intracellular ternary complexes, and induce an anti-proliferative response in target-expressing cells.</p></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":null,"pages":null},"PeriodicalIF":6.6,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141899985","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-15DOI: 10.1016/j.chembiol.2024.07.010
Electrical signaling is essential for all fast processes in biology, but its molecular mechanisms have been uncertain. This review article focuses on studies of bacterial sodium channels in order to home in on the essential molecular and chemical mechanisms underlying transmembrane ion conductance and voltage-dependent gating without the overlay of complex protein interactions and regulatory mechanisms in mammalian sodium channels. This minimalist approach has yielded a nearly complete picture of sodium channel function at the atomic level that are mostly conserved in mammalian sodium channels, including sodium selectivity and conductance, voltage sensing and activation, electromechanical coupling to pore opening and closing, slow inactivation, and pathogenic dysfunction in a debilitating channelopathy. Future studies of nature’s simplest sodium channels may continue to yield key insights into the fundamental molecular and chemical principles of their function and further elucidate the chemical basis of electrical signaling.
{"title":"The chemistry of electrical signaling in sodium channels from bacteria and beyond","authors":"","doi":"10.1016/j.chembiol.2024.07.010","DOIUrl":"10.1016/j.chembiol.2024.07.010","url":null,"abstract":"<div><p>Electrical signaling is essential for all fast processes in biology, but its molecular mechanisms have been uncertain. This review article focuses on studies of bacterial sodium channels in order to home in on the essential molecular and chemical mechanisms underlying transmembrane ion conductance and voltage-dependent gating without the overlay of complex protein interactions and regulatory mechanisms in mammalian sodium channels. This minimalist approach has yielded a nearly complete picture of sodium channel function at the atomic level that are mostly conserved in mammalian sodium channels, including sodium selectivity and conductance, voltage sensing and activation, electromechanical coupling to pore opening and closing, slow inactivation, and pathogenic dysfunction in a debilitating channelopathy. Future studies of nature’s simplest sodium channels may continue to yield key insights into the fundamental molecular and chemical principles of their function and further elucidate the chemical basis of electrical signaling.</p></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":null,"pages":null},"PeriodicalIF":6.6,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S245194562400312X/pdfft?md5=0c34706ac158a70d52d3dd2d116ee049&pid=1-s2.0-S245194562400312X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141990568","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-15DOI: 10.1016/j.chembiol.2024.07.009
In an interview with Dr. Samantha Nelson, a scientific editor of Cell Chemical Biology, the authors of the perspective entitled “A versatile residue numbering scheme for Nav and Cav channels” share their thoughts on life as scientists.
在接受《细胞化学生物学》(Cell Chemical Biology)科学编辑萨曼莎-尼尔森博士(Samantha Nelson)的采访时,题为《Nav 和 Cav 通道的通用残基编号方案》的作者分享了他们对科学家生活的看法。
{"title":"Meet the authors: Xueqin Jin, Jian Huang, Huan Wang, Kan Wang, and Nieng Yan","authors":"","doi":"10.1016/j.chembiol.2024.07.009","DOIUrl":"10.1016/j.chembiol.2024.07.009","url":null,"abstract":"<div><p>In an interview with Dr. Samantha Nelson, a scientific editor of <em>Cell Chemical Biology</em>, the authors of the perspective entitled “A versatile residue numbering scheme for Na<sub>v</sub> and Ca<sub>v</sub> channels” share their thoughts on life as scientists.</p></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":null,"pages":null},"PeriodicalIF":6.6,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2451945624003118/pdfft?md5=f053f546661ed81fd5923d1d16882438&pid=1-s2.0-S2451945624003118-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141990629","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-15DOI: 10.1016/j.chembiol.2024.05.018
Directed evolution focuses on optimizing single genetic components for predefined engineering goals by artificial mutagenesis and selection. In contrast, experimental evolution studies the adaptation of entire genomes in serially propagated cell populations, to provide an experimental basis for evolutionary theory. There is a relatively unexplored gap at the middle ground between these two techniques, to evolve in vivo entire synthetic gene circuits with nontrivial dynamic function instead of single parts or whole genomes. We discuss the requirements for such mid-scale evolution, with hypothetical examples for evolving synthetic gene circuits by appropriate selection and targeted shuffling of a seed set of genetic components in vivo. Implementing similar methods should aid the rapid generation, functionalization, and optimization of synthetic gene circuits in various organisms and environments, accelerating both the development of biomedical and technological applications and the understanding of principles guiding regulatory network evolution.
{"title":"Synthetic gene circuit evolution: Insights and opportunities at the mid-scale","authors":"","doi":"10.1016/j.chembiol.2024.05.018","DOIUrl":"10.1016/j.chembiol.2024.05.018","url":null,"abstract":"<div><p>Directed evolution focuses on optimizing single genetic components for predefined engineering goals by artificial mutagenesis and selection. In contrast, experimental evolution studies the adaptation of entire genomes in serially propagated cell populations, to provide an experimental basis for evolutionary theory. There is a relatively unexplored gap at the middle ground between these two techniques, to evolve <em>in vivo</em> entire synthetic gene circuits with nontrivial dynamic function instead of single parts or whole genomes. We discuss the requirements for such mid-scale evolution, with hypothetical examples for evolving synthetic gene circuits by appropriate selection and targeted shuffling of a seed set of genetic components <em>in vivo</em>. Implementing similar methods should aid the rapid generation, functionalization, and optimization of synthetic gene circuits in various organisms and environments, accelerating both the development of biomedical and technological applications and the understanding of principles guiding regulatory network evolution.</p></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":null,"pages":null},"PeriodicalIF":6.6,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2451945624002198/pdfft?md5=ab725988d0ab4ed2c1198c5281ace930&pid=1-s2.0-S2451945624002198-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141448798","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-15DOI: 10.1016/j.chembiol.2024.07.004
The growing clinical success of bispecific antibodies (bsAbs) has led to rapid interest in leveraging dual targeting in order to generate novel modes of therapeutic action beyond mono-targeting approaches. While bsAbs that bind targets on two different cells (trans-targeting) are showing promise in the clinic, the co-targeting of two proteins on the same cell surface through cis-targeting bsAbs (cis-bsAbs) is an emerging strategy to elicit new functionalities. This includes the ability to induce proximity, enhance binding to a target, increase target/cell selectivity, and/or co-modulate function on the cell surface with the goal of altering, reversing, or eradicating abnormal cellular activity that contributes to disease. In this review, we focus on the impact of cis-bsAbs in the clinic, their emerging applications, and untangle the intricacies of improving bsAb discovery and development.
{"title":"Therapeutic potential of cis-targeting bispecific antibodies","authors":"","doi":"10.1016/j.chembiol.2024.07.004","DOIUrl":"10.1016/j.chembiol.2024.07.004","url":null,"abstract":"<div><p>The growing clinical success of bispecific antibodies (bsAbs) has led to rapid interest in leveraging dual targeting in order to generate novel modes of therapeutic action beyond mono-targeting approaches. While bsAbs that bind targets on two different cells (<em>trans</em>-targeting) are showing promise in the clinic, the co-targeting of two proteins on the same cell surface through <em>cis</em>-targeting bsAbs (<em>cis</em>-bsAbs) is an emerging strategy to elicit new functionalities. This includes the ability to induce proximity, enhance binding to a target, increase target/cell selectivity, and/or co-modulate function on the cell surface with the goal of altering, reversing, or eradicating abnormal cellular activity that contributes to disease. In this review, we focus on the impact of <em>cis</em>-bsAbs in the clinic, their emerging applications, and untangle the intricacies of improving bsAb discovery and development.</p></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":null,"pages":null},"PeriodicalIF":6.6,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141895917","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-15DOI: 10.1016/j.chembiol.2024.07.015
{"title":"Carolyn Bertozzi: Building new bonds between molecules, fields, and communities","authors":"","doi":"10.1016/j.chembiol.2024.07.015","DOIUrl":"10.1016/j.chembiol.2024.07.015","url":null,"abstract":"","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":null,"pages":null},"PeriodicalIF":6.6,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2451945624003179/pdfft?md5=4bf455a57cb56e81d734c6d2248d8ca7&pid=1-s2.0-S2451945624003179-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141990628","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-09DOI: 10.1016/j.chembiol.2024.07.011
Natavan Dudkina, Hyun Bong Park, Deguang Song, Abhishek Jain, Sajid A Khan, Richard A Flavell, Caroline H Johnson, Noah W Palm, Jason M Crawford
Altered human aldo-keto reductase family 1 member C3 (AKR1C3) expression has been associated with poor prognosis in diverse cancers, ferroptosis resistance, and metabolic diseases. Despite its clinical significance, the endogenous biochemical roles of AKR1C3 remain incompletely defined. Using untargeted metabolomics, we identified a major transformation mediated by AKR1C3, in which a spermine oxidation product "sperminal" is reduced to "sperminol." Sperminal causes DNA damage and activates the DNA double-strand break response, whereas sperminol induces autophagy in vitro. AKR1C3 also pulls down acyl-pyrones and pyrone-211 inhibits AKR1C3 activity. Through G protein-coupled receptor ligand screening, we determined that pyrone-211 is also a potent agonist of the semi-orphan receptor GPR84. Strikingly, mammalian fatty acid synthase produces acyl-pyrones in vitro, and this production is modulated by NADPH. Taken together, our studies support a regulatory role of AKR1C3 in an expanded polyamine pathway and a model linking fatty acid synthesis and NADPH levels to GPR84 signaling.
{"title":"Human AKR1C3 binds agonists of GPR84 and participates in an expanded polyamine pathway.","authors":"Natavan Dudkina, Hyun Bong Park, Deguang Song, Abhishek Jain, Sajid A Khan, Richard A Flavell, Caroline H Johnson, Noah W Palm, Jason M Crawford","doi":"10.1016/j.chembiol.2024.07.011","DOIUrl":"10.1016/j.chembiol.2024.07.011","url":null,"abstract":"<p><p>Altered human aldo-keto reductase family 1 member C3 (AKR1C3) expression has been associated with poor prognosis in diverse cancers, ferroptosis resistance, and metabolic diseases. Despite its clinical significance, the endogenous biochemical roles of AKR1C3 remain incompletely defined. Using untargeted metabolomics, we identified a major transformation mediated by AKR1C3, in which a spermine oxidation product \"sperminal\" is reduced to \"sperminol.\" Sperminal causes DNA damage and activates the DNA double-strand break response, whereas sperminol induces autophagy in vitro. AKR1C3 also pulls down acyl-pyrones and pyrone-211 inhibits AKR1C3 activity. Through G protein-coupled receptor ligand screening, we determined that pyrone-211 is also a potent agonist of the semi-orphan receptor GPR84. Strikingly, mammalian fatty acid synthase produces acyl-pyrones in vitro, and this production is modulated by NADPH. Taken together, our studies support a regulatory role of AKR1C3 in an expanded polyamine pathway and a model linking fatty acid synthesis and NADPH levels to GPR84 signaling.</p>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":null,"pages":null},"PeriodicalIF":6.6,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142007975","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}