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":"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":"1962-1987"},"PeriodicalIF":12.5,"publicationDate":"2026-10-21","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}
Jan Luca Budde, Mehdi D Davari, Ahmed Hassanin, Mikail Karacam, Andreas Kirschning, Henry Struwe, Daghan Taser
{"title":"Terpene synthases are highly substrate tolerant - among them BcBOT2 is a \"jack of all trades\".","authors":"Jan Luca Budde, Mehdi D Davari, Ahmed Hassanin, Mikail Karacam, Andreas Kirschning, Henry Struwe, Daghan Taser","doi":"10.1039/d6np00040a","DOIUrl":"10.1039/d6np00040a","url":null,"abstract":"<p><p>Covering: up to 2026A traditional view regarding enzymes assigns them a markedly low substrate promiscuity. This is based, among other factors, on concepts concerning the evolution of metabolism, which, according to the \"patchwork model\", assumes that the first enzymes converted a variety of substrates more or less effectively into quite different products and that enzymes then differentiated through evolution and became more substrate selective. Starting from linear oligoprenyl diphosphate precursors, terpene synthases produce oligocyclic terpenes <i>via</i> complex carbocation cascades. It was found that these sometimes exhibit unusual substrate acceptance. Using the example of the fungal sesquiterpene synthase BcBOT2, it is shown that the \"terpenome\" can be expanded in an unprecedented way, whereby completely new terpene backbones can be generated that nature is usually unable to access, as of today.</p>","PeriodicalId":94,"journal":{"name":"Natural Product Reports","volume":" ","pages":"1940-1951"},"PeriodicalIF":12.5,"publicationDate":"2026-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148443596","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}
Tae-Young Gil, Ye-Seul Kim, Dong-Sung Lee, Hyo-Jin An
{"title":"Natural products for benign prostatic hyperplasia (BPH): structure-activity relationships and pathway mechanisms.","authors":"Tae-Young Gil, Ye-Seul Kim, Dong-Sung Lee, Hyo-Jin An","doi":"10.1039/d6np00001k","DOIUrl":"10.1039/d6np00001k","url":null,"abstract":"<p><p>Covering: 2012-2025Benign prostatic hyperplasia (BPH) is a prevalent age-related disorder characterized by non-malignant prostate enlargement and lower urinary tract symptoms, arising from the interplay of androgen dysregulation, chronic inflammation, oxidative stress, and stromal remodeling. Natural products and phyto-therapeutics have been extensively investigated as potential therapeutic agents for BPH. However, the literature remains dominated by compound-by-compound descriptions, limiting mechanistic generalization, and structure-guided prioritization. Here, we surveyed studies reported between 2012 and 2025 through a structure-guided, pathway-oriented framework to identify recurring links between chemical features and disease-relevant biological processes. Rather than cataloging individual agents, evidence is organized around major pathogenic axes (AR/5α-reductase-related growth control, inflammatory and redox networks such as NF-κB-Nrf2-NOX, and stroma-epithelium remodeling programs, including TGF-β/Smad and ECM dynamics) and interpreted using motif-level convergence across chemical classes. Across diverse scaffolds, polyphenolic hydroxyl arrays tend to align with inflammation and redox regulation, whereas nitrogen-containing and lipophilic polycyclic frameworks are more frequently associated with endocrine growth signaling and tissue-level remodeling. Importantly, many mechanistic claims rely on downstream biomarkers and are model-dependent, while direct target-engagement evidence remains limited, which constrains molecular-level structure-activity relationship interpretation. By explicitly mapping scaffold motifs to dominant pathogenic axes and highlighting translational gaps driven by pharmacokinetics, standardization, and experimental context, natural products are positioned as privileged starting scaffolds for pathway-directed optimization rather than empirically defined therapeutics.</p>","PeriodicalId":94,"journal":{"name":"Natural Product Reports","volume":" ","pages":"2125-2153"},"PeriodicalIF":12.5,"publicationDate":"2026-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148596687","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}
Sebastian Götze, Tanya Decker, Sven Balluff, Christine Beemelmanns
{"title":"γ-Amino acid-containing natural products of bacterial origin: structure, biosynthesis, and bioactivity.","authors":"Sebastian Götze, Tanya Decker, Sven Balluff, Christine Beemelmanns","doi":"10.1039/d6np00072j","DOIUrl":"https://doi.org/10.1039/d6np00072j","url":null,"abstract":"<p><p>Covering: 1966 to 2026γ-Amino acids are structurally diverse non-proteinogenic building blocks that endow bacterial natural products with unique conformational, physicochemical, and biological properties. Although individual γ-amino acid-containing metabolites have been extensively investigated, their structural diversity, biosynthetic origins, and functional significance have rarely been considered from a unified perspective. Here, we review nearly six decades of research on bacterial γ-amino acid-containing natural products, covering from 1966 and the discovery of bleomycin to genome-guided discoveries in 2026. We discuss the major structural classes of γ-amino acids, including GABA-derived, β-keto, statine-type, vinylogous, fully reduced, and masked amino acid-derived motifs, and highlight how these building blocks are generated through primary metabolism, hybrid NRPS-PKS assembly lines, and specialized tailoring reactions. Particular emphasis is placed on the relationships between γ-amino acid structure, biosynthetic logic, and biological function, including their roles in protease inhibition, covalent target engagement, metallophore activity, and microbial ecology. Finally, we discuss emerging opportunities for genome mining and biosynthetic engineering that are expected to accelerate the discovery and exploitation of γ-amino acid-containing natural products.</p>","PeriodicalId":94,"journal":{"name":"Natural Product Reports","volume":" ","pages":""},"PeriodicalIF":12.5,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149177892","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}
Philipp Germer, Arne Hoffmann, Michael K F Mohr, Marius Schnutenhaus, Andrea Rentmeister, Stephan C Hammer, Jennifer N Andexer, Nicolas V Cornelissen
{"title":"Beyond methylation: (re)generation and application of SAM analogs.","authors":"Philipp Germer, Arne Hoffmann, Michael K F Mohr, Marius Schnutenhaus, Andrea Rentmeister, Stephan C Hammer, Jennifer N Andexer, Nicolas V Cornelissen","doi":"10.1039/d6np00073h","DOIUrl":"https://doi.org/10.1039/d6np00073h","url":null,"abstract":"<p><p>Covering: 2021 to 2026Methyltransferases (MTs) using <i>S</i>-adenosyl-L-methionine (SAM) and its analogs enable highly selective alkylation reactions. Until lately, broader application was limited by the inefficiency of SAM regeneration and laborious synthesis of SAM analogs. Recent advances in enzymatic <i>in situ</i> supply and regeneration overcome these barriers, facilitating progress toward <i>in vivo</i> alkylation, advanced MT-based labeling in cells as well as application in preparative synthesis. We summarize advances in one-step regeneration, biomimetic multi-enzyme pathways, and engineered whole-cell systems that (re)generate SAM analogs from methionine analogs, alkanethiols, haloalkanes and related alkylation reagents, covering the period from 2021 to 2026. Cofactor modifications include variations at the methyl unit, amino acid moiety, and nucleobase to expand scope, enhance stability and offer orthogonality in complex reaction mixtures. Together, these advances extend transferase chemistry beyond methylation, opening new avenues in biocatalysis, drug discovery, synthetic-method development, and synthetic biology.</p>","PeriodicalId":94,"journal":{"name":"Natural Product Reports","volume":" ","pages":""},"PeriodicalIF":12.5,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149134168","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}
Guan-Qiu Qin, Jie Wang, Wen-Cai Ye, Li-Jun Hu, Ying Wang
{"title":"Vinylogous Mannich reaction in total synthesis of alkaloids.","authors":"Guan-Qiu Qin, Jie Wang, Wen-Cai Ye, Li-Jun Hu, Ying Wang","doi":"10.1039/d6np00076b","DOIUrl":"https://doi.org/10.1039/d6np00076b","url":null,"abstract":"<p><p>Covering: up to July 2026The vinylogous Mannich reaction (VMR) enables γ-selective carbon-carbon bond formation between vinylogous nucleophiles and imines or iminium ions, yielding δ-aminocarbonyl frameworks. Compared with the classical Mannich reaction, VMR shows distinct advantages in remote functionalization and convergent bond formation, facilitating the rapid assembly of nitrogen-containing heterocycles, multiple stereogenic centers, and densely functionalized intermediates. As a result, this reaction has become an increasingly valuable strategy for generating complexity in the total synthesis of alkaloids and has been successfully applied to a wide range of alkaloid families, including piperidine, pyrrolidine, indole, <i>Securinega</i>, <i>Stemona</i>, phthalideisoquinoline, steroidal, and <i>Daphniphyllum</i>. This review presents a structured and concept-oriented overview of VMR-based alkaloid synthesis. Representative applications are organized according to the nature of the vinylogous nucleophiles, including both acyclic and cyclic dienol equivalents. Particular emphasis is placed on reaction design, stereochemical control, complexity generation, and the integration of VMR into asymmetric, collective, and biomimetic synthetic strategies. Overall, this review highlights the evolution of VMR from a methodological variant of the classical Mannich reaction into a broadly applicable approach for the efficient synthesis of structurally diverse alkaloids. It also provides perspectives on its future development in alkaloid synthesis.</p>","PeriodicalId":94,"journal":{"name":"Natural Product Reports","volume":" ","pages":""},"PeriodicalIF":12.5,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149101176","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}
Xinyun Jian, Mathias H Hansen, Lauren A M Murray, Max J Cryle
{"title":"NRPS megasynthases - the A to X of assembling peptide antibiotics.","authors":"Xinyun Jian, Mathias H Hansen, Lauren A M Murray, Max J Cryle","doi":"10.1039/d6np00070c","DOIUrl":"https://doi.org/10.1039/d6np00070c","url":null,"abstract":"<p><p>Focuses on the period 2020-2025Antibiotics remain a cornerstone of modern medicine, with natural products representing many of the molecules used in the clinic or in agriculture. Nonribosomal peptides represent a significant class within our antibiotic arsenal, with the tantalising prospects for engineering the megaenzyme machineries that produce these molecules continuing to captivate the fields of enzymology, biocatalysis and discovery. Recent studies have demonstrated that there is significant diversity yet to be elucidated within both the types of molecules produced by these assembly lines and the enzymatic machineries that produce them, and thus the field of antibiotics produced by NRPS biosynthesis will continue to grow. This review seeks to highlight the impressive nature of recent discoveries made by the field over the period from 2020-2025, including the identification of novel antimicrobial peptides produced by NRPS assembly lines, exemplars of novel substrates and transformations within the assembly of these peptides, the role of chemistry in supporting both the discovery and engineering of these pathways, and key discoveries that challenge established paradigms within the field in terms of how nature can assemble bioactive antimicrobial peptides.</p>","PeriodicalId":94,"journal":{"name":"Natural Product Reports","volume":" ","pages":""},"PeriodicalIF":12.5,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149072950","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":"Expanding bile acid diversity <i>via</i> host and microbial conjugation pathways.","authors":"Tae Hyung Won, Frank C Schroeder","doi":"10.1039/d6np00058d","DOIUrl":"10.1039/d6np00058d","url":null,"abstract":"<p><p>Covering: 2019 to April 2026Bile acids, originally identified as digestive emulsifiers, are now recognized as signaling molecules at the nexus of metabolism and immunity. Recent advances in metabolomics have revealed unexpected chemical diversity of BAs, derived from previously unrecognized conjugation pathways involving both the gut microbiota and the host. This includes microbial conjugation of the bile acid carboxy terminus with diverse amino acids and other biogenic amines as well as host-derived conjugation with cysteamine derivatives. In addition, microbial acylation of the steroid core has been shown to introduce succinyl, acetyl, and other chemical modifications, including expansion of the canonical bile acid carbon skeleton. This review synthesizes recent discoveries (2019-2026) in bile acid conjugation chemistry and highlights how the expanded bile acid diversity regulates host physiology through activation of different nuclear receptors and G-protein coupled receptors, including therapeutic implications for metabolic and immune disorders such as non-alcoholic steatohepatitis, inflammatory bowel disease, and cardiometabolic diseases. The emerging picture reveals that bile acid pools result from an intricate network of host-microbe metabolic pathways, and that considering both host and microbial contributions is essential for understanding bile acid biology in health and disease.</p>","PeriodicalId":94,"journal":{"name":"Natural Product Reports","volume":" ","pages":""},"PeriodicalIF":12.5,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13602198/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149035580","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}
{"title":"Biosynthetic crosstalk in bacteria: routes to chimeric natural products.","authors":"Wen-Chao Yu, Zhiyuan Peng, Yan-Song Ye, Qihao Wu","doi":"10.1039/d6np00048g","DOIUrl":"10.1039/d6np00048g","url":null,"abstract":"<p><p>Covering: up to the end of April 2026Chimeric natural products are formed when biosynthetic inputs from distinct pathways, gene clusters, or metabolic branches are integrated into a single scaffold. In bacteria, such crosstalk-driven assembly can generate structurally diverse metabolites with distinct biological activities. However, these metabolites remain underexplored because most discovery pipelines are optimized to connect one metabolite family to one co-localized biosynthetic gene cluster (BGC). As a result, metabolites produced through inter-pathway collaboration, recruitment of primary-metabolic intermediates, or non-enzymatic coupling of products from separate pathways are often deprioritized as genome-metabolome mismatches. Here, we describe chimeric natural products as an important yet overlooked class of bacterial metabolites and present a discovery framework that prioritizes candidate hybrid scaffolds from LC-MS-based metabolomics. We suggest that public-repository spectral searching, multi-class MS/MS annotation, retrospective genome-to-metabolite linkage, and isotope-guided validation can improve discovery of these overlooked scaffolds. Prioritizing such metabolites can expand natural product discovery beyond canonical frameworks, uncover new biosynthetic design principles, and inform future efforts to engineer hybrid molecules.</p>","PeriodicalId":94,"journal":{"name":"Natural Product Reports","volume":" ","pages":"1755-1764"},"PeriodicalIF":12.5,"publicationDate":"2026-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148336979","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}
Yeo Jin Lee, Hyeon-Jeong Hwang, Jungro Lee, Hyeon Seung Park, Juwan Son, Mohammad Seyedsayamdost, Munhyung Bae, Seoung Rak Lee, Yun Kwon
{"title":"Natural products with atypical atoms: unveiling structures, biosynthetic pathways, and bioactivities.","authors":"Yeo Jin Lee, Hyeon-Jeong Hwang, Jungro Lee, Hyeon Seung Park, Juwan Son, Mohammad Seyedsayamdost, Munhyung Bae, Seoung Rak Lee, Yun Kwon","doi":"10.1039/d5np00083a","DOIUrl":"10.1039/d5np00083a","url":null,"abstract":"<p><p>Covering: 1944-2025Nature's biosynthetic repertoire extends far beyond conventional CHON(S) chemistry and encompasses a rare but diverse array of natural products that incorporate atypical elements such as arsenic, selenium, fluorine, iodine, boron, and vanadium. These metabolites reveal how living systems have evolved to harness atypical atoms through both enzyme-mediated and spontaneous chemical strategies. Biological C-F and Se-C bond formation, SAM-dependent arsenic methylation, and non-enzymatic boron complexation exemplify nature's ingenuity in overcoming extreme energetic or coordination constraints. Despite their scarcity, these compounds play critical ecological and physiological roles in detoxification and redox regulation (As, Se), defense, and signaling (F, I, B), and in some cases, sustain global biogeochemical cycles (Mo, V). Structurally, they exhibit exceptional chemical stability, redox versatility, and metal-ligand diversity. Functionally, these findings expand our understanding of enzyme evolution, chemical defense strategies, and symbiotic metabolism in both marine and terrestrial ecosystems. Recent genomic and biochemical advances have uncovered new families of atypical natural products and the specialized enzymes responsible for their formation. Taken together, these discoveries define the limits of biogenic chemistry and highlight promising avenues for sustainable biocatalysis and drug discovery, particularly in the fluorination, selenation, and boronation pathways that bridge biological and synthetic chemistry.</p>","PeriodicalId":94,"journal":{"name":"Natural Product Reports","volume":" ","pages":"1817-1841"},"PeriodicalIF":12.5,"publicationDate":"2026-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148256414","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}