Natural Product Reports最新文献

The cofactor S-adenosylmethionine (SAM, AdoMet) is generally considered to be only its canonical (S_S,S_Cα)-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 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: 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 2026Assembly-line polyketide synthases (PKSs) are among the most sophisticated catalysts in nature, responsible for the biosynthesis of many medicinally important natural products including antibiotics, anticancer agents, immunosuppressants and veterinary agents. While conventional methods for polyketide natural product discovery have fallen out of favor, the rapid expansion of microbial genome sequencing has revealed a vast untapped diversity of assembly-line PKSs, most of which can be regarded as "orphans" in that their product identity is unknown. A clear picture of how this sequence diversity reflects the evolutionary history of assembly-line PKSs could enable judicious prioritization of experimental efforts aimed at decoding these orphans. To this end we have used a scalable curation workflow to hand-curate an updated catalogue, PKSClusterDB, that includes 16 633 non-redundant assembly-line PKSs. We have also formulated an automatable "anchor-window" framework based on conserved multimodular segments of assembly-line PKSs to identify and interrogate PKS families of interest. Application of this framework to three different PKS families extracted from PKSClusterDB revealed lineage-dependent patterns of diversification, ranging from broadly diversified families to more compact or sharply bounded lineages. PKSClusterDB has also proven useful in exploring other aspects of PKS diversity, including scaffold architecture, extender-unit specificity, reductive-state programming, stereochemical control and modular organization. In closing, we consider how advances in machine learning could be harnessed to accelerate our understanding of assembly-line PKS evolution, diversity and biosynthetic mechanisms.

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