Pub Date : 2025-07-01DOI: 10.1016/j.tibs.2025.03.011
Mayra A. Borrero-Landazabal , Vanessa Linke , Agnieszka Chacinska
Lipids are emerging as functional players in mitochondrial protein import beyond constituting membranes. Cryo–electron microscopy structures of protein translocases such as translocase of the outer membrane (TOM) and insertases such as translocase of the inner membrane (TIM22) link lipids to protein import by suggesting structural and functional roles for lipids in protein translocation and insertion, and for protein insertases in lipid scrambling.
{"title":"Lipids: emerging actors in mitochondrial protein import","authors":"Mayra A. Borrero-Landazabal , Vanessa Linke , Agnieszka Chacinska","doi":"10.1016/j.tibs.2025.03.011","DOIUrl":"10.1016/j.tibs.2025.03.011","url":null,"abstract":"<div><div>Lipids are emerging as functional players in mitochondrial protein import beyond constituting membranes. Cryo–electron microscopy structures of protein translocases such as translocase of the outer membrane (TOM) and insertases such as translocase of the inner membrane (TIM22) link lipids to protein import by suggesting structural and functional roles for lipids in protein translocation and insertion, and for protein insertases in lipid scrambling.</div></div>","PeriodicalId":440,"journal":{"name":"Trends in Biochemical Sciences","volume":"50 7","pages":"Pages 556-558"},"PeriodicalIF":11.6,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143957113","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 : 2025-07-01DOI: 10.1016/j.tibs.2025.04.005
Tania Martins-Marques , Maria Vasconcelos-Cardoso , Maria Isabel Geli , Trond Aasen , Brenda R. Kwak , Henrique Girao
Classically implicated in the transport of small molecules between neighboring cells or into the extracellular milieu, emerging evidence implicates connexins and pannexins in other noncanonical biological functions. Propelled by recent technological advances and genetic approaches, this review aims to provide a comprehensive and thought-provoking perspective on unconventional functions of connexins and pannexins that could be shared with other cell surface proteins. Although multiple studies have linked dysfunctional channel activity with human disorders, the contribution of non-junctional roles of connexins and pannexins during disease pathophysiology is now beginning to blossom. We highlight the potential regulatory signals and players involved in unfamiliar connexin and pannexin activities that can pave the way to design novel therapeutic tools.
{"title":"The ins and outs of connexins and pannexins beyond the cell surface","authors":"Tania Martins-Marques , Maria Vasconcelos-Cardoso , Maria Isabel Geli , Trond Aasen , Brenda R. Kwak , Henrique Girao","doi":"10.1016/j.tibs.2025.04.005","DOIUrl":"10.1016/j.tibs.2025.04.005","url":null,"abstract":"<div><div>Classically implicated in the transport of small molecules between neighboring cells or into the extracellular milieu, emerging evidence implicates connexins and pannexins in other noncanonical biological functions. Propelled by recent technological advances and genetic approaches, this review aims to provide a comprehensive and thought-provoking perspective on unconventional functions of connexins and pannexins that could be shared with other cell surface proteins. Although multiple studies have linked dysfunctional channel activity with human disorders, the contribution of non-junctional roles of connexins and pannexins during disease pathophysiology is now beginning to blossom. We highlight the potential regulatory signals and players involved in unfamiliar connexin and pannexin activities that can pave the way to design novel therapeutic tools.</div></div>","PeriodicalId":440,"journal":{"name":"Trends in Biochemical Sciences","volume":"50 7","pages":"Pages 622-635"},"PeriodicalIF":11.6,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144092015","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 : 2025-06-01DOI: 10.1016/j.tibs.2025.01.009
Caitlin L. Gare , Andrew M. White , Lara R. Malins
Peptides are a powerful drug modality with potential to access difficult targets. This recognition underlies their growth in the global pharmaceutical market, with peptides representing ~8% of drugs approved by the FDA over the past decade. Currently, the peptide therapeutic landscape is evolving, with high-throughput display technologies driving the identification of peptide leads with enhanced diversity. Yet, chemical modifications remain essential for improving the ‘drug-like’ properties of peptides and ultimately translating leads to market. In this review, we explore two recent therapeutic candidates (semaglutide, a peptide hormone analogue, and MK-0616, an mRNA display-derived candidate) as case studies that highlight general approaches to improving pharmacokinetics (PK) and potency. We also emphasize the critical link between advances in medicinal chemistry and the optimisation of highly efficacious peptide therapeutics.
{"title":"From lead to market: chemical approaches to transform peptides into therapeutics","authors":"Caitlin L. Gare , Andrew M. White , Lara R. Malins","doi":"10.1016/j.tibs.2025.01.009","DOIUrl":"10.1016/j.tibs.2025.01.009","url":null,"abstract":"<div><div>Peptides are a powerful drug modality with potential to access difficult targets. This recognition underlies their growth in the global pharmaceutical market, with peptides representing ~8% of drugs approved by the FDA over the past decade. Currently, the peptide therapeutic landscape is evolving, with high-throughput display technologies driving the identification of peptide leads with enhanced diversity. Yet, chemical modifications remain essential for improving the ‘drug-like’ properties of peptides and ultimately translating leads to market. In this review, we explore two recent therapeutic candidates (semaglutide, a peptide hormone analogue, and MK-0616, an mRNA display-derived candidate) as case studies that highlight general approaches to improving pharmacokinetics (PK) and potency. We also emphasize the critical link between advances in medicinal chemistry and the optimisation of highly efficacious peptide therapeutics.</div></div>","PeriodicalId":440,"journal":{"name":"Trends in Biochemical Sciences","volume":"50 6","pages":"Pages 467-480"},"PeriodicalIF":11.6,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143514144","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 : 2025-06-01DOI: 10.1016/j.tibs.2025.03.012
Yoonjoo Seo , Na Wei
A recent study by Seo, Hong, Park, et al. maps the global fitness landscape of PET-degrading enzymes, identifying superior PETases for plastic depolymerization. The engineered high-performance variant surpasses benchmarks under industrial conditions. This study provides a powerful framework for enzyme discovery, advancing biocatalytic solutions for plastic waste recycling.
Seo、Hong、Park 等人最近的一项研究绘制了 PET 降解酶的全球适应性图谱，确定了用于塑料解聚的优质 PET 酶。工程化的高性能变体超越了工业条件下的基准。这项研究为酶的发现提供了一个强大的框架，推动了塑料废物回收的生物催化解决方案。
{"title":"Decoding PETase diversity through global landscape profiling: toward superior enzymes for plastic recycling","authors":"Yoonjoo Seo , Na Wei","doi":"10.1016/j.tibs.2025.03.012","DOIUrl":"10.1016/j.tibs.2025.03.012","url":null,"abstract":"<div><div>A recent study by <span><span>Seo, Hong, Park, <em>et al.</em></span><svg><path></path></svg></span> maps the global fitness landscape of PET-degrading enzymes, identifying superior PETases for plastic depolymerization. The engineered high-performance variant surpasses benchmarks under industrial conditions. This study provides a powerful framework for enzyme discovery, advancing biocatalytic solutions for plastic waste recycling.</div></div>","PeriodicalId":440,"journal":{"name":"Trends in Biochemical Sciences","volume":"50 6","pages":"Pages 464-466"},"PeriodicalIF":11.6,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143794291","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 : 2025-06-01DOI: 10.1016/S0968-0004(25)00116-1
{"title":"Subscription and Copyright Information","authors":"","doi":"10.1016/S0968-0004(25)00116-1","DOIUrl":"10.1016/S0968-0004(25)00116-1","url":null,"abstract":"","PeriodicalId":440,"journal":{"name":"Trends in Biochemical Sciences","volume":"50 6","pages":"Page e1"},"PeriodicalIF":11.6,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144212676","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 : 2025-06-01DOI: 10.1016/j.tibs.2025.03.006
Jordi Duran , Matthew S. Gentry
Joan J. Guinovart i Cirera, Emeritus Professor of Biochemistry and Molecular Biology, University of Barcelona (UB), and IRB Barcelona Emeritus Professor, passed away on January 1, 2025, at the age of 77 due to complications from pancreatic cancer. Dr Guinovart was a renowned biochemist celebrated for his pioneering research on glycogen metabolism and his influential leadership in science.
Joan J. Guinovart i Cirera，巴塞罗那大学（UB）生物化学和分子生物学名誉教授，巴塞罗那IRB名誉教授，因胰腺癌并发症于2025年1月1日去世，享年77岁。Guinovart博士是一位著名的生物化学家，因其在糖原代谢方面的开创性研究和他在科学领域的影响力而闻名。
{"title":"Joan J. Guinovart (1947–2025)","authors":"Jordi Duran , Matthew S. Gentry","doi":"10.1016/j.tibs.2025.03.006","DOIUrl":"10.1016/j.tibs.2025.03.006","url":null,"abstract":"<div><div>Joan J. Guinovart i Cirera, Emeritus Professor of Biochemistry and Molecular Biology, University of Barcelona (UB), and IRB Barcelona Emeritus Professor, passed away on January 1, 2025, at the age of 77 due to complications from pancreatic cancer. Dr Guinovart was a renowned biochemist celebrated for his pioneering research on glycogen metabolism and his influential leadership in science.</div></div>","PeriodicalId":440,"journal":{"name":"Trends in Biochemical Sciences","volume":"50 6","pages":"Pages 455-457"},"PeriodicalIF":11.6,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144212724","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 : 2025-06-01DOI: 10.1016/j.tibs.2025.03.004
Lin Cheng , Yanglu Wang , Jingyang Guan , Hongkui Deng
Pluripotent stem cells hold great promise as an unlimited resource for regenerative medicine due to their capacity to self-renew and differentiate into various cell types. Chemical reprogramming using small molecules precisely regulates cell signaling pathways and epigenetic states, providing a novel approach for generating human pluripotent stem cells. Since its successful establishment in 2022, human chemical reprogramming has rapidly achieved significant progress, demonstrating its significant potential in regenerative medicine. Mechanistic analyses have revealed distinct molecular pathways and regulatory mechanisms unique to chemical reprogramming, differing from traditional transcription-factor-driven methods. In this review we highlight recent advancements in our understanding of the mechanisms of human chemical reprogramming, with the goal of enhancing insights into the principles of cell fate control and advancing regenerative medicine.
{"title":"Decoding human chemical reprogramming: mechanisms and principles","authors":"Lin Cheng , Yanglu Wang , Jingyang Guan , Hongkui Deng","doi":"10.1016/j.tibs.2025.03.004","DOIUrl":"10.1016/j.tibs.2025.03.004","url":null,"abstract":"<div><div>Pluripotent stem cells hold great promise as an unlimited resource for regenerative medicine due to their capacity to self-renew and differentiate into various cell types. Chemical reprogramming using small molecules precisely regulates cell signaling pathways and epigenetic states, providing a novel approach for generating human pluripotent stem cells. Since its successful establishment in 2022, human chemical reprogramming has rapidly achieved significant progress, demonstrating its significant potential in regenerative medicine. Mechanistic analyses have revealed distinct molecular pathways and regulatory mechanisms unique to chemical reprogramming, differing from traditional transcription-factor-driven methods. In this review we highlight recent advancements in our understanding of the mechanisms of human chemical reprogramming, with the goal of enhancing insights into the principles of cell fate control and advancing regenerative medicine.</div></div>","PeriodicalId":440,"journal":{"name":"Trends in Biochemical Sciences","volume":"50 6","pages":"Pages 520-531"},"PeriodicalIF":11.6,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143762782","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 : 2025-06-01DOI: 10.1016/j.tibs.2025.03.015
Bradley J. Lukasak , Erica Korb
Replication-independent histone variants play an essential role in postmitotic neurons. Here, we review how the subtle sequence differences of histone variants compared to their canonical counterparts underly neuronal function. We focus on variants H3.3, H2A.Z, H2A.X, macroH2A, and H2BE; all of which contain divergent sequences that coordinate a diverse set of outcomes. In particular, we highlight their role in neuronal development, plasticity, and memory, with an emphasis on how single amino acid changes can mediate these complex functions. Lastly, we comment on an emerging field of study evaluating the link between histone variants and neurological disorders. Future studies of histone variants will be important to furthering our understanding of neuronal function.
{"title":"Histone variants: expanding the epigenetic potential of neurons one amino acid at a time","authors":"Bradley J. Lukasak , Erica Korb","doi":"10.1016/j.tibs.2025.03.015","DOIUrl":"10.1016/j.tibs.2025.03.015","url":null,"abstract":"<div><div>Replication-independent histone variants play an essential role in postmitotic neurons. Here, we review how the subtle sequence differences of histone variants compared to their canonical counterparts underly neuronal function. We focus on variants H3.3, H2A.Z, H2A.X, macroH2A, and H2BE; all of which contain divergent sequences that coordinate a diverse set of outcomes. In particular, we highlight their role in neuronal development, plasticity, and memory, with an emphasis on how single amino acid changes can mediate these complex functions. Lastly, we comment on an emerging field of study evaluating the link between histone variants and neurological disorders. Future studies of histone variants will be important to furthering our understanding of neuronal function.</div></div>","PeriodicalId":440,"journal":{"name":"Trends in Biochemical Sciences","volume":"50 6","pages":"Pages 532-543"},"PeriodicalIF":11.6,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143955091","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 : 2025-06-01DOI: 10.1016/j.tibs.2025.03.003
Zi-Liang Hu , Hong Wei , Linfeng Sun , Eugenia Russinova
Brassinosteroids (BRs) are essential plant steroidal hormones that regulate growth and development. The recent discoveries of ATP-binding cassette subfamily B (ABCB) members, ABCB19 and ABCB1, as BR transporters highlight the significance of active export to the apoplast in maintaining BR homeostasis and enabling effective signaling. This review focuses on the latest progress in understanding ABCB-mediated BR transport, with particular attention to the structural and functional characterization of arabidopsis ABCB19 and ABCB1. These findings reveal both conserved and distinct features in substrate recognition and transport mechanisms, providing valuable insights into their roles in hormonal regulation. Additionally, the evolutionary conservation of ABC transporters in mediating steroid-based signaling across biological kingdoms underscores their fundamental biological significance.
{"title":"Plant steroids on the move: mechanisms of brassinosteroid export","authors":"Zi-Liang Hu , Hong Wei , Linfeng Sun , Eugenia Russinova","doi":"10.1016/j.tibs.2025.03.003","DOIUrl":"10.1016/j.tibs.2025.03.003","url":null,"abstract":"<div><div>Brassinosteroids (BRs) are essential plant steroidal hormones that regulate growth and development. The recent discoveries of ATP-binding cassette subfamily B (ABCB) members, ABCB19 and ABCB1, as BR transporters highlight the significance of active export to the apoplast in maintaining BR homeostasis and enabling effective signaling. This review focuses on the latest progress in understanding ABCB-mediated BR transport, with particular attention to the structural and functional characterization of arabidopsis ABCB19 and ABCB1. These findings reveal both conserved and distinct features in substrate recognition and transport mechanisms, providing valuable insights into their roles in hormonal regulation. Additionally, the evolutionary conservation of ABC transporters in mediating steroid-based signaling across biological kingdoms underscores their fundamental biological significance.</div></div>","PeriodicalId":440,"journal":{"name":"Trends in Biochemical Sciences","volume":"50 6","pages":"Pages 508-519"},"PeriodicalIF":11.6,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143956848","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 : 2025-06-01DOI: 10.1016/j.tibs.2025.04.001
Ayoola B. Smith , Renee C. Ejindu , Jonathan R. Chekan
Historically, natural products have been essential sources of therapeutic agents, many of which are currently used to manage various diseases. In recent years, ribosomally synthesized and post-translationally modified peptides (RiPPs) have garnered considerable interest in drug discovery and development due to their biosynthetic plasticity and their ability to generate diverse bioactive structural scaffolds. Unfortunately, many RiPPs have suboptimal bioavailability and proteolytic stability, significantly limiting their clinical potential. Moreover, the complexity of RiPP structures makes total synthesis extremely difficult. These drawbacks necessitate pathway engineering to create derivatives with potentially optimized physicochemical properties. Herein, we review recent efforts to surmount pathway engineering challenges and to rationally modify components of RiPP pathways for new functions to derive new bioactive analogs.
{"title":"Engineering RiPP pathways: strategies for generating complex bioactive peptides","authors":"Ayoola B. Smith , Renee C. Ejindu , Jonathan R. Chekan","doi":"10.1016/j.tibs.2025.04.001","DOIUrl":"10.1016/j.tibs.2025.04.001","url":null,"abstract":"<div><div>Historically, natural products have been essential sources of therapeutic agents, many of which are currently used to manage various diseases. In recent years, ribosomally synthesized and post-translationally modified peptides (RiPPs) have garnered considerable interest in drug discovery and development due to their biosynthetic plasticity and their ability to generate diverse bioactive structural scaffolds. Unfortunately, many RiPPs have suboptimal bioavailability and proteolytic stability, significantly limiting their clinical potential. Moreover, the complexity of RiPP structures makes total synthesis extremely difficult. These drawbacks necessitate pathway engineering to create derivatives with potentially optimized physicochemical properties. Herein, we review recent efforts to surmount pathway engineering challenges and to rationally modify components of RiPP pathways for new functions to derive new bioactive analogs.</div></div>","PeriodicalId":440,"journal":{"name":"Trends in Biochemical Sciences","volume":"50 6","pages":"Pages 495-507"},"PeriodicalIF":11.6,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143960087","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}
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