Covering: primarily from 2011 to 2026Terpenoids are an ancient and immensely diverse class of natural products. Since their emergence more than two billion years ago alongside early biological membranes, terpenoid metabolism has undergone a vast expansion in both structure and function, which directly contributed to the ecological success of terrestrial plants. Biosynthetically derived from two isomeric five-carbon isoprenoid precursors, plant terpenoids include hemi-, mono-, sesqui-, di-, sester-, tri-, tetra-, and poly-, and mero-terpenoids, that exhibit extensive variation in chain length, structural scaffolds, and functional decoration. This large chemical space is generated via dynamic metabolic networks, in which functionally versatile enzymes - most notably scaffold-forming terpene synthases and tailoring cytochrome P450 monooxygenases - are assembled into combinatorial pathway modules to yield complex bioactive terpenoid structures. Lineage-specific expansion of the underlying gene families, driven by recurrent genome and gene duplications followed by functional divergence, have facilitated the evolution of both conserved and specialized metabolic branches and natural products. Functionally, conserved terpenoids act as phytohormones, signaling molecules, and pigments governing plant growth and development, whereas typically species-specific specialized terpenoids mediate dynamic plant-environment interactions, including pest and pathogen defenses, allelopathy, pollinator attraction, root-microbiome communication, and abiotic stress tolerance. Advances in genomics, metabolomics, and synthetic biology continue to accelerate the discovery of terpenoid structures, pathways, and functions at an ever-increasing pace. Elucidating the mechanisms that generate this diversity, and the multifaceted roles that terpenoids play in plant ecology and physiology not only deepens our understanding of the evolutionary history of terrestrial plants, but also unlocks new opportunities for biotechnological innovation, spanning terpenoid-derived therapeutics, biofuels, fragrances, polymers, agrochemicals, and many other bioproducts.
Covering: up to 2026C-Methylation is a fundamental transformation in natural product biosynthesis. Although methyl groups are often regarded as simple functional groups that modulate physicochemical properties, they frequently play decisive roles in directing enzymatic reactivity and controlling biosynthetic pathway progression. Cobalamin (Cbl)-dependent radical S-adenosyl-L-methionine (SAM) C-methyltransferases catalyze the installation of C-methyl groups at sp3-hybridized carbon centers in biosynthetic intermediates. Recent studies have uncovered their remarkable catalytic capabilities, including precise control over regio- and stereoselectivity. Moreover, the installed methyl groups often influence downstream transformations and are essential for late-stage biosynthetic events. This highlight focuses on the functional roles of C-methylation mediated by Cbl-dependent radical SAM enzymes, emphasizing how these seemingly small modifications shape the biosynthesis of complex natural products.
Covering: 2005-2025Pyrrocidines and hirsutellones are a fascinating class of fungal natural products that possess an intricate chemical structure characterized by a distinctive macrocyclic ring fused to a decahydrofluorene core. Known for their complex architectures as PKS-NRPS hybrids, these metabolites are isolated from various fungi and have attracted significant attention due to their potent pharmacological properties, including antimicrobial, antifungal, and anticancer effects. This review article aims to shed light on the structural diversities of 52 fungal-derived pyrrocidines and hirsutellones reported over the period of 2005-2025, providing insights into their chemistry, biosynthetic origins, pharmacokinetic profiles, and structure-activity relationships (SARs). Furthermore, we critically evaluate their promising therapeutic potential, highlighting the opportunities they present for modern drug discovery and development.
Covering: up to 2025Alkaloids constitute an invaluable reservoir for pharmaceutical discovery. However, their therapeutic development has long been constrained by the inefficiencies of plant extraction, as well as the economic impracticality of total chemical synthesis. In recent years, biomanufacturing has emerged as a transformative paradigm, enabling sustainable and scalable access to these complex molecules. This review provides an overview of the pivotal advances in alkaloid biosynthesis, delineated across de novo biosynthesis in prokaryotic and eukaryotic systems, concise multi-enzyme cascades, and chemoenzymatic synthesis. By discussing these pioneering examples, analyzing the strategic lessons, inherent limitations, and corresponding solutions for these platforms, this review illuminates how synthetic biology and biocatalysis are collectively reshaping the landscape of alkaloid production and paving the way for their expanded pharmaceutical applications.
Covering: up to 2025Lipids are structurally diverse biomolecules that play a critical role in the homeostasis of organisms across all domains of life. While biogenesis of lipids varies by organism, the strategies employed to modify or functionalize inert lipid hydrocarbon chains often require the power of radical-based chemistry. Recently, an increasing number of lipid-modifying radical S-adenosylmethionine (RS) enzymes have been identified. RS enzymes are well known to mediate >100 reactions. In the context of lipids, these radical-mediated reactions proceed through Csp2 and Csp3 centers, affording C-C bond formations, methylations, cyclizations, and/or ring contractions. This review highlights our understanding of the function and mechanism of lipid-modifying RS enzymes. Mechanistic considerations of lipid modification by RS enzymes reveal the significance of cofactors (particularly B12) and auxiliary metal centers in substrate activation and intermediate stabilization. Understanding the function and mechanism strategies of these enzymes is crucial not only to advancing our understanding of RS enzymes but also to inform paleoenvironmental reconstructions and the emerging field of lipid-based drug delivery.
Covering: 2013 up to 2026The rapid escalation of antimicrobial resistance has outpaced the discovery of natural product (NP)-derived antibiotics, underscoring the need for new strategies to identify and characterize antibacterial agents. NPs have historically dominated antibiotic development due to their structural and mechanistic diversity, yet their chemical complexity, low abundance, laborious dereplication, and challenging mode of action (MoA) identification continue to limit discovery efficiency. Bacterial Cytological Profiling (BCP), an image-based phenotypic screening, has emerged as a powerful approach capable of capturing rich, single-cell-resolved responses, making it particularly well suited for investigating complex NP-derived antibiotic discovery. This review focuses on how BCP, a prokaryotic image-based strategy central to antibiotic MoA elucidation, addresses key challenges in NP-derived antibacterial discovery, including dereplication, deconvolution of multiple MoAs, and identification of novel mechanisms. We also discuss current biological and methodological limitations of the approach and provide practical perspectives for NP researchers seeking to implement BCP in discovery programs. Finally, we examine how lessons from the widely adopted eukaryotic image-based profiling method, the Cell Painting Assay, could inform future BCP development and propose a "BCP v1.0" framework to facilitate broader adoption and ultimately accelerate NP-derived antibiotic discovery.
Covering: 1992 to 2025Natural products contribute to roughly half of FDA-approved small-molecule drugs, yet their discovery has remained surprisingly resistant to the automation that has reshaped synthetic medicinal chemistry. In this review, we examine why. We propose that natural product workflows encounter a "complexity cliff", a threshold beyond which automation success rates fall sharply rather than degrading gradually. We define the complexity cliff in operational terms as a discontinuity in the performance of standardized, scaled pipelines, which is triggered when chemical, biological or ecological complexity exceeds the assumptions encoded in the workflow. The cliff manifests across three coupled axes: a chemical axis, where unprecedented scaffolds and stereochemistry overwhelm pattern-based dereplication and structure elucidation; a biological axis, where unculturable organisms, silent biosynthetic gene clusters and context-dependent metabolite production frustrate standardized cultivation; and an operational axis, where matrix-specific extraction, scale-up and sustainable sourcing resist consistency-driven design. We distinguish challenges that are intrinsic to natural product research from those that are unique to automation, and we argue that several often-cited "automation barriers" (such as scale-dependent yields) are, in fact, universal pre-automation problems for which automation may help rather than hinder. Emerging technologies, including AI- and machine-learning-guided genome mining, CRISPR-enabled pathway engineering and ecosystem-scale digital twins, address parts of the cliff but not its serendipitous core. We close by arguing that the most productive path forward is not full autonomy but a collaborative intelligence framework: machine throughput and pattern recognition coupled with human curiosity, biological intuition, and willingness to follow anomalies. This framing reframes the central question from "how do we automate natural product discovery?" to "how do we partition natural product discovery between humans and machines so that each side does what it does best?"
Covering: 1995 up to the end of 2025Homocyclic aromatic compounds (HAC) represent the second most abundant class of natural and anthropogenic products. Their biodegradation is central to the global carbon cycle and the bioremediation of aromatic pollutants. A key step in this process is enzymatic dearomatization, historically attributed exclusively to oxygen-dependent mono- or dioxygenases. However, over the past three decades, a growing diversity of oxygen-independent dearomatizing reductases has been identified. These enzymes act either on partially activated di- or trihydroxybenzenes and trihydroxynaphthalenes with meta-oriented hydroxyl groups, or on coenzyme A (CoA) thioesters of carboxylated HAC, converting aromatic substrates into cyclic dienes. Class I and II benzoyl-CoA reductases catalyze Birch-like reductions via radical intermediates at metal cofactors, with low-potential electrons supplied either through ATP-dependent electron transfer (class I) or flavin-based electron bifurcation (class II), whereas 2-naphthoyl-CoA reductase appears independent of an electron-activation system. An alternative, non-redox dearomatization mechanism has been identified in S-adenosyl-L-methionine-dependent methyltransferases involved in the anaerobic bacterial estrogen-to-androgen conversion, as well as in polyketide tailoring. Together, these findings reveal a broad enzymatic repertoire for overcoming arene resonance stabilization under anoxic conditions. Beyond their ecological significance, these pathways provide mechanistically diverse routes and opportunities for biocatalysis and the sustainable synthesis of valuable chemical building blocks.
Covering: up to 2026Volatile organic compounds (VOCs) are key mediators of long-distance communication in biological systems. While their roles in plant-insect interactions are well established, emerging evidence highlights their importance in plant-microbe interactions. In this highlight, we discuss the biosynthesis and ecological functions of plant VOCs (pVOCs) and their impact on microbiome assembly and function. We examine how constitutive and stress-induced pVOCs shape microbial community composition and how microbial VOCs (mVOCs) influence plant growth and defense by modulating hormonal and metabolic pathways. We further address the bidirectional nature of volatile-mediated interactions and the challenges associated with studying complex VOC blends in natural environments. Understanding these dynamic volatile dialogues provides new opportunities for microbiome engineering and sustainable crop production.
Using elansolids as a case study, it is demonstrated how nature tames the highly reactive p -quinone methide by controlling its reactivity and conformation in a very efficient manner.
Latest development of radical-mediated enzymes catalyze various cross-linkings between one aromatic side chain and one aliphatic amino acid (monoaryl cyclophane) or between two aromatic side chains (biaryl cyclophane) on the precursor peptides.
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 via 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.
The cofactor S-adenosylmethionine (SAM, AdoMet) is generally considered to be only its canonical (SS,SCα)-SAM diastereomer. In this viewpoint, we highlight that exceptions are present in some salvage pathways and many SAM-utilising enzymes tolerate alternative configurations at the two stereogenic centres of the methionine-derived moiety. This reveals stereochemical flexibility with important implications for enzyme function and natural product biosyntheses.
Covering: up to 2026Over the past decades, research on S-adenosyl-L-methionine (SAM)-dependent methyltransferases (MTs) has led to their emergence as highly selective biocatalysts for late-stage methylation reactions, serving as new tools within the chemoenzymatic synthesis of complex natural products and chemical scaffolds. Studies focussing on the identification of novel MTs, their engineering and process optimisation, have not only expanded the accessible chemical space for biocatalytic methylations but have also significantly improved their applicability for reactions conducted at preparative scale. This includes innovations in enzyme-coupled SAM recycling systems and SAM analogue generation which have additionally enabled alkylation beyond methyl transfer. Structure-guided MT mutagenesis campaigns, together with the development of novel activity assays, have contributed to the expansion of the catalytic repertoire of MTs, thereby unlocking new reactivities. This highlight article provides a brief overview of recent developments in MT biocatalysis, with particular focus on their application in the chemoenzymatic synthesis of natural products at preparative scale. Current limitations associated with MT biocatalysis are examined, and future opportunities for the implementation of MT-catalysed transformations in industrial applications are discussed.
Covering: up to the end of 2025Natural products have long served as valuable therapeutic agents owing to their high structural complexity, rich stereochemistry, and three-dimensional architecture. Nevertheless, the difficulty of isolating novel natural products in substantial quantities has shifted drug-discovery efforts over the past two decades toward simpler synthetic libraries, often at the expense of biologically relevant chemical space. The complexity-to-diversity (CtD) strategy offers a compelling alternative: by distorting and reorganizing natural-product scaffolds, CtD efficiently generates structurally diverse, highly complex small molecules capable of engaging challenging biological targets. Recent advances have demonstrated the power of this approach, enabling concise, scalable syntheses of diverse libraries through strategic skeletal rearrangements. This viewpoint highlights the unique potential of CtD predominantly derived from alkaloidal and terpenoidal nuclei, examines representative synthetic examples, and discusses the opportunities and challenges inherent to scaling both structural complexity and molecular diversity. This perspective aims to underscore the relevance of CtD for natural product, synthetic, and medicinal chemists seeking new avenues for innovative lead discovery.
Covering: 1920 to 2026The discovery of antibiotics has historically centered on a core set of physiological targets, including cell wall synthesis, protein translation, and DNA replication. As resistance accelerates and new drug classes remain scarce, there is a growing need to expand into alternative target spaces. One such unexplored area is bacterial nutrient biosynthesis and utilization. Although their therapeutic potential is increasingly recognized, these pathways have yet to be fully integrated into antibiotic discovery pipelines, due in part to longstanding methodological biases, including the widespread use of nutrient-rich screening media that obscure nutrient-targeting activity. In this review, we highlight an overlooked subset of natural product antibiotics that inhibit nutrient metabolism. We consolidate 73 compound classes primarily retrieved from the Dictionary of Natural Products and categorize them into four mechanistic classes: biosynthesis inhibitors, antimetabolites, pro-antimetabolites, and riboswitch inhibitors. Many display whole-cell activity, including against Gram-negative pathogens, and reveal underappreciated structural and functional diversity. Recent advances in defined media design, genome mining, and synthetic biology make these compounds more readily accessible for systematic re-evaluation and optimization. Nutrient pathway inhibitors offer a source of novel antibiotic scaffolds and a foundation for therapeutic strategies such as drug potentiation and resistance reversal. Reintegrating these compounds into discovery pipelines can help diversify antibacterial options and address pressing resistance challenges.
This review surveys representative C 7 –C 9 aromatic compounds, outlining their microbial biosynthetic pathways, key metabolic challenges, and recent advances in metabolic engineering for their microbial production.
Covering: up to 2026Bisretinoids are a chemically distinct class of endogenous natural products formed by the non-enzymatic condensation of visual-cycle retinoids. Derived from dietary provitamin A carotenoids via retinaldehyde intermediates, these pigments form spontaneously within the photoreceptor disc membranes through Schiff base chemistry with phosphatidylethanolamine, generating structurally diverse pyridinium, dihydropyridine and retinal dimer species. In contrast to enzyme-directed biosynthesis, bisretinoid biogenesis is governed by the intrinsic electrophilicity of the conjugated retinaldehydes within a lipid-dense environment. Their extended polyene systems endow them with distinctive excited-state properties, enabling efficient intersystem crossing and photosensitized generation of singlet oxygen under visible light. Subsequent oxidative fragmentation produces reactive electrophilic carbonyl species, including methylglyoxal and glyoxal, which covalently modify biomolecules and contribute to retinal pigment epithelium dysfunction and drusen formation. Despite their well-documented pathological roles, bisretinoids have not been systematically examined within a natural product framework. Here, we integrate the current knowledge of their biogenesis, electronic structure, and photochemical reactivity and consider how factors such as retinaldehyde flux, membrane composition, and iron homeostasis modulate their accumulation and reactivity. By framing bisretinoids as autochthonous natural products governed by intrinsic chemical principles, this review highlights new opportunities for mechanistically informed therapeutic intervention in retinal degeneration.
Covering: up to 2026Strigolactones dominate the research on parasitic plant germination. Nevertheless, other types of natural products have roles in stimulating or inhibiting the germination and subsequent growth of parasitic weeds, including synergistic interactions with other compounds released by host roots that mediate host recognition and chemotropism. This review focuses on the bioactive non-strigolactone compounds, classified as terpenes and terpenoids, aromatic metabolites, N-containing metabolites and miscellaneous structures. Terpenes and terpenoids are the most common germination stimulants (51.0% of the total, among which sesquiterpene lactones represent the most common structures), while aromatic (41.7%) and N-containing (36.5%) metabolites are the leading inhibitors of germination or seedling development. The clog P trends suggest that molecular lipophilicity alone does not allow distinguishing between stimulants or inhibitors, but the data showed that two main intervals are particularly enriched in bioactive structures: moderately lipophilic compounds (47%, with clog P values between 1.0 and 3.0) and hydrophilic molecules (24%, with clog P below 0). An evaluation of germination-induced specificity indicated that sesquiterpene lactones are the strongest elicitors for O. cumana, P. aegyptiaca and S. asiatica, karrikin1 and different terpenoids for O. minor and S. hermonthica, and isothiocyanates for P. ramosa. Notably, several sesquiterpene lactones and isothiocyanates induced germination at concentrations comparable to those of natural strigolactones. Beyond germination, recent findings implicate non-strigolactone cues in haustorium initiation and host chemotropism, underscoring the complexity of chemical signaling in parasitic plant development. Overall, the evidence gathered herein shows that parasitic development is influenced by a wider chemical space than strigolactones alone, opening perspectives for eco-rational bioherbicide development and for understanding host-parasite communication.
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.
