{"title":"Inverse stable isotopic labeling for natural product characterization and discovery.","authors":"Jose Miguel D Robes, Aaron W Puri","doi":"10.1039/d6np00014b","DOIUrl":"10.1039/d6np00014b","url":null,"abstract":"<p><p>Covering: 2005 to 2026Stable isotopic labeling is a powerful tool in natural products research; however, the isotopically substituted precursors required for conventional labeling approaches are not always available. In such cases, inverse stable isotopic labeling (InverSIL) offers an effective alternative. In this approach, natural product producing organisms are grown on isotopically substituted media, which is then supplemented with precursors at their natural isotopic abundance. Incorporation of these unlabeled precursors can be readily detected due to their isotopic contrast, circumventing limitations associated with precursor availability. Here, we review applications of InverSIL in the characterization of natural product biosynthetic pathways and structures, as well as its use in genome mining to link biosynthetic genes to the natural products they produce. We also discuss contexts in which the InverSIL approach is particularly advantageous, as well as situations where its utility may be limited. Through this review, we aim to encourage broader adoption of InverSIL as a versatile strategy for advancing natural products research.</p>","PeriodicalId":94,"journal":{"name":"Natural Product Reports","volume":" ","pages":""},"PeriodicalIF":12.5,"publicationDate":"2026-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13232609/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148256313","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lin Qiu, Xianghui Chen, Zhan Luo, Min Jiang, Hu Chen, Biyu Hou, Haizheng Yu, Ning Li, Lei Zhang
{"title":"Synthetic biology as a game-changer for endangered medicinal orchids: biosynthesis, engineering and conservation.","authors":"Lin Qiu, Xianghui Chen, Zhan Luo, Min Jiang, Hu Chen, Biyu Hou, Haizheng Yu, Ning Li, Lei Zhang","doi":"10.1039/d6np00027d","DOIUrl":"https://doi.org/10.1039/d6np00027d","url":null,"abstract":"<p><p>Covering: 2012 to 2026Medicinal orchids constitute a rich yet vulnerable reservoir of high-value bioactive metabolites. However, their sustainable exploitation is severely hampered by resource depletion and the inefficiency of traditional extraction. Synthetic biology emerges as a transformative game-changer to resolve this impasse. This review delineates how synthetic biology drives a paradigm shift in endangered orchid conservation. Through modular design of biosynthetic pathways, heterologous reconstruction in microbial or plant chassis, directed evolution of key enzymes, metabolic engineering, and scalable production, it offers a disruptive solution, fundamentally redefining sustainable utilization by decoupling supply from ecological extraction. We highlight the successful heterologous biosynthesis of representative compounds like gastrodin and dendrobine. Facilitated by pathway optimization, chassis engineering and synthetic consortia design, these efforts have established cell factories that demonstrate the potential for sustainable and non-plant-based production, offering a viable alternative to wild harvest. Furthermore, the research encompasses recent breakthroughs in decoding orchid metabolic networks, including the elucidation of biosynthetic pathways, identification of core enzyme repertoires and discovery of regulatory switches involving transcription factors and miRNAs. Insights from evolutionary genomics and endophyte symbioses are also discussed as critical guides for pathway optimization. We explore the translational impact of these innovations, highlighting how the integration of multi-omics, artificial intelligence and gene editing accelerates the Design-Build-Test-Learn cycle. In summary, synthetic biology represents an essential paradigm shift, transitioning orchid resource management from a narrative of scarcity to one of predictable engineering creation and thereby securing a robust and sustainable supply chain for these prized medicinal plants.</p>","PeriodicalId":94,"journal":{"name":"Natural Product Reports","volume":" ","pages":""},"PeriodicalIF":10.6,"publicationDate":"2026-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148256425","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Byung Tae Lee , Byeongsub Lee , Joon Young Kwon , Tilmann Weber , Hyun Uk Kim
{"title":"AI and mechanistic modeling for characterizing biosynthetic pathways of natural products","authors":"Byung Tae Lee , Byeongsub Lee , Joon Young Kwon , Tilmann Weber , Hyun Uk Kim","doi":"10.1039/d5np00059a","DOIUrl":"10.1039/d5np00059a","url":null,"abstract":"<div><div>Covering: 2020 to 2025</div></div><div><div>Natural products are a major source of bioactive compounds, yet elucidating their biosynthetic pathways remains a major challenge due to complex genotype–phenotype relationships. Recent advances in computational approaches, particularly artificial intelligence (AI) and mechanistic modeling, are transforming this field. This highlight examines key databases that underpin computational studies, AI-driven methods for predicting biosynthetic pathways and enzyme–substrate interactions, and mechanistic simulations that provide energetic and structural insights. We also discuss current challenges and future opportunities for integrating these strategies to accelerate discovery, engineering, and application of natural products in drug discovery, biotechnology, and synthetic biology.</div></div>","PeriodicalId":94,"journal":{"name":"Natural Product Reports","volume":"43 5","pages":"Pages 787-802"},"PeriodicalIF":10.6,"publicationDate":"2026-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145456965","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Li Zhou , Xulei Shi , Hui Jiang , Yuanyuan Xia , Haiquan Yang , Wei Shen , Yu Cao , Xianzhong Chen
{"title":"Charting the path for l-tyrosine derivatives: from engineering strategies to microbial cell factories","authors":"Li Zhou , Xulei Shi , Hui Jiang , Yuanyuan Xia , Haiquan Yang , Wei Shen , Yu Cao , Xianzhong Chen","doi":"10.1039/d5np00091b","DOIUrl":"10.1039/d5np00091b","url":null,"abstract":"<div><div>Covering: primarily from 2021 to the end of 2025</div></div><div><div> <span>l</span>-Tyrosine (<span>l</span>-Tyr) and its derivatives are high-value aromatic compounds with broad applications in food, pharmaceutical, and chemical industries. The traditional methods for producing these natural products through natural extraction and chemical synthesis are often limited by sustainability, efficiency, and environmental concerns. Advances in synthetic biology have enabled the construction of microbial cell factories for green and scalable production, with <em>Escherichia coli</em> and yeast emerging as the preferred chassis organisms due to their well-characterized genetics and extensive toolkits. This review systematically summarizes the engineering strategies applied for the biosynthesis of <span>l</span>-Tyr and its derivatives in these hosts at the enzymatic, metabolic, and cellular levels. Focusing on tyrosol, <em>p</em>-coumaric acid, and <span>l</span>-3,4-dihydroxyphenylalanine (<span>l</span>-DOPA) as the key nodes, it highlights the cutting-edge advances primarily within the last five years. Finally, the review critically assesses the persistent challenges and future opportunities, offering a strategic roadmap to accelerate the biomanufacturing of <span>l</span>-Tyr-derived natural products.</div></div>","PeriodicalId":94,"journal":{"name":"Natural Product Reports","volume":"43 5","pages":"Pages 1026-1062"},"PeriodicalIF":10.6,"publicationDate":"2026-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147502558","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Natural product inspired antibiotics approved for human use – 1943 to 2025","authors":"Mark S. Butler , Robert J. Capon","doi":"10.1039/d5np00067j","DOIUrl":"10.1039/d5np00067j","url":null,"abstract":"<div><div>Covering literature to September 2025</div></div><div><div>This review provides a comprehensive account of the 217 natural product inspired antibiotics that have been approved for human use from 1943 through to September 2025, inclusive of 52 (24%) that are natural products (NPs) and 165 (76%) that are semi-synthetic or synthetic derivatives of natural products (NP-Ds). These are organized into sixteen categories defined by shared structural motifs and, in many cases, common mechanisms of action. Each antibiotic is classified as either a NP or NP-D, annotated by a molecular structure that, where relevant, highlights the relationships between NPs and NP-Ds. Market details are also provided, including the company that brought each antibiotic to market, the year and country of first approval, the spectrum of usage across pathogen classes, routes of administration, current status, and selected commentary on mechanisms of action. The assembled dataset is further analysed through a series of charts that illustrate insightful trends that document the remarkable history and lasting impact of NP inspired antibiotics. The review concludes with observations on the historic impact and future prospects of natural products as a source of inspiration for the development of new generations of antibiotics.</div></div>","PeriodicalId":94,"journal":{"name":"Natural Product Reports","volume":"43 5","pages":"Pages 813-896"},"PeriodicalIF":10.6,"publicationDate":"2026-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145720181","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Qiaoqiao Dai , Jiaqi Xu , Jing Wu , Xiaomin Li , Cong Gao , Guipeng Hu , Liming Liu
{"title":"Microbial production of C7–C9 aromatic building blocks for the production of natural products","authors":"Qiaoqiao Dai , Jiaqi Xu , Jing Wu , Xiaomin Li , Cong Gao , Guipeng Hu , Liming Liu","doi":"10.1039/d5np00068h","DOIUrl":"10.1039/d5np00068h","url":null,"abstract":"<div><div>Covering: up to 2025</div></div><div><div>Aromatic compounds have been widely applied in the production of plastics, pharmaceuticals, dyes, fragrances and cosmetics. Since conventional chemical synthesis of aromatic compounds relies on non-renewable fossil-based feedstocks and involves complex processes, microbial biosynthesis has emerged as a sustainable and efficient alternative. However, the complexity of the metabolic pathways of aromatic compounds, limited precursor supply, and the cytotoxicity of certain products severely constrain the efficient production of target compounds. To address these bottlenecks, various metabolic engineering strategies have been developed, which include modular pathway design to enhance metabolic flux coordination and flexibility, the introduction of novel biosynthetic pathways to expand the substrate spectrum, and evolutionary engineering approaches to improve host strain tolerance to product-induced toxicity. In this review, we systematically introduce the application potential of representative C<sub>7</sub>–C<sub>9</sub> aromatic compounds, elucidate their biosynthetic pathways, analyze the specific challenges inherent to each compound, and summarize the recent progress in metabolic engineering strategies. We further discuss emerging strategies in light of the current state-of-the-art developments in microbial aromatic biosynthesis, incorporating comparisons between microbial and petrochemical production in industrial applications to outline future directions for aromatic compound biosynthesis.</div></div>","PeriodicalId":94,"journal":{"name":"Natural Product Reports","volume":"43 5","pages":"Pages 897-931"},"PeriodicalIF":10.6,"publicationDate":"2026-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147275280","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Manuel J. Verganista , Iago C. Vogel , Nuno R. Candeias
{"title":"Quinic acid as a chiron in total synthesis†","authors":"Manuel J. Verganista , Iago C. Vogel , Nuno R. Candeias","doi":"10.1039/d5np00087d","DOIUrl":"10.1039/d5np00087d","url":null,"abstract":"<div><div>Covering: 1980 up to 2025.</div></div><div><div>Quinic acid became a versatile, accessible chiral building block for asymmetric synthesis, offering a functionalized, stereochemically rich scaffold that enables the creation of many natural products and bioactive compounds. This review covers synthetic strategies from the 1980s to 2025, highlighting quinic acid's ongoing importance in organic synthesis. It discusses its role in synthesizing carbocyclic frameworks, vitamin D analogues, carbasugars, cyclitols, aminocyclitols, lactones, alkaloids, and macrocyclic fragments. The review summarizes four decades of progress and emerging trends that reinforce quinic acid's status as a key chiral building block for complex molecule synthesis.</div></div>","PeriodicalId":94,"journal":{"name":"Natural Product Reports","volume":"43 5","pages":"Pages 932-960"},"PeriodicalIF":10.6,"publicationDate":"2026-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147343010","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Decision making by modular polyketide synthases and implications for genetic engineering","authors":"Kira J. Weissman","doi":"10.1039/d6np00010j","DOIUrl":"10.1039/d6np00010j","url":null,"abstract":"<div><div>Covering: up to 2025</div></div><div><div>Modular polyketide synthases (PKSs) are often described as molecular-scale assembly lines – a moniker that implies a high-degree of coordinated and regulated activity. Belying this characterization, all of these systems must navigate a number of critical biosynthetic ‘choices’ in order to faithfully produce one or a limited number of products. Such alternative options occur at all stages of the assembly process, including building block selection, chain extension, intersubunit transfer, modification by in-<em>trans</em> acting enzymes, and chain termination. Here we discuss research over many decades that has shed substantial light on the detailed and often stunningly complex molecular mechanisms that underpin PKS biosynthetic fidelity. These insights have inspired increasingly effective efforts to intervene at these decision points by genetic engineering to redirect the pathways towards alternative outcomes and their associated novel products.</div></div>","PeriodicalId":94,"journal":{"name":"Natural Product Reports","volume":"43 5","pages":"Pages 961-1007"},"PeriodicalIF":10.6,"publicationDate":"2026-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147442055","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Highlights of cyanobacterial metabolites reported between 2021–2024","authors":"Simon Sieber , Elisabeth M.-L. Janssen","doi":"10.1039/d5np00076a","DOIUrl":"10.1039/d5np00076a","url":null,"abstract":"<div><div>Covering: 2021 to 2024</div></div><div><div>This review highlights cyanobacteria secondary metabolites reported between 2021 and 2024. Those compounds are categorised into major classes, including peptides, alkaloids, lipids, polyketides, terpenes/terpenoids, and natural products from other classes. For selected compounds, the review provides details of advanced methodologies employed in their discovery, isolation and structure elucidation. Particular attention is placed on techniques for determining the relative and absolute configurations of stereocentres, including computational approaches, chemical derivatisation, and total synthesis. Furthermore, the review outlines the biosynthetic pathway of several newly identified cyanobacterial natural products.</div></div>","PeriodicalId":94,"journal":{"name":"Natural Product Reports","volume":"43 5","pages":"Pages 1008-1025"},"PeriodicalIF":10.6,"publicationDate":"2026-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147466183","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Isolation and synthesis of bisabosquals, fungal triprenyl phenol meroterpenoids with a densely functionalised bisabolane core","authors":"James P. Shephard , David W. Lupton","doi":"10.1039/d5np00085h","DOIUrl":"10.1039/d5np00085h","url":null,"abstract":"<div><div>Covering: up to 2026</div></div><div><div>The <em>Stachybotrys</em> fungi have proven to be rich sources of triprenyl meroterpenoids. In addition to natural products typified by the relatively well known K76, stachybotrin, kampanol and stachyflin are the bisabosquals. The first four bisabosquals were discovered in 2001 and found to have a unique molecular structure displaying an all <em>cis</em> benzopyran-fused benzofuran core. Over the past two decades, this family has been extended, while their novel structure has stimulated efforts focused on their chemical synthesis. Herein, we provide a highlight, covering the isolation, biosynthesis and bioactivities of the bisabosquals and <em>seco</em>-bisabosquals along with studies focused on their total syntheses.</div></div>","PeriodicalId":94,"journal":{"name":"Natural Product Reports","volume":"43 5","pages":"Pages 803-812"},"PeriodicalIF":10.6,"publicationDate":"2026-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146103078","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}