Biosynthetic Pathways of Enediyne Natural Products

Enediyne natural products are distinguished by a highly strained bicyclic core containing two conjugated triple bonds flanking a double bond, which upon cycloaromatization generate diradical species capable of cleaving DNA. These molecules fall broadly into nine-membered and ten-membered subclasses, each assembled by an iterative type I polyketide synthase (PKS) that constructs a polyene precursor. Following chain release, auxiliary enzymes such as thioesterases, oxygenases and glycosyltransferases tailor the core scaffold through hydrolysis, oxidation, glycosylation and acylation. A hallmark step is the Bergman cycloaromatization, which converts the enediyne precursor into a reactive benzene diradical. The diversity of peripheral substituents—ranging from sugars and chlorides to anthraquinone or β-carboline appendages—governs cellular uptake, DNA binding and overall cytotoxic potency. Foundational examples include calicheamicin, C-1027 and the recently characterised tiancimycins, which have inspired potent payloads for antibody-drug conjugates. Advances in genome sequencing have revealed a wealth of cryptic biosynthetic gene clusters (BGCs) in actinomycetes, highlighting the untapped potential for novel enediynes. Understanding the orchestration of PKS domains and tailoring enzymes is central to harnessing these pathways for scalable production and drug development.

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Biosynthetic Pathways of Enediyne Natural Products publication trend

The graph below shows the total number of articles in biosynthetic pathways of enediyne natural products across all publications each year (not limited to Nature Index journals).

Technical terms

Enediyne: A specialised metabolite featuring two triple bonds separated by a double bond, capable of cycloaromatizing to form DNA-cleaving diradicals.

Biosynthetic Gene Cluster (BGC): A contiguous set of genes encoding all enzymes required for the assembly and modification of a natural product.

Polyketide Synthase (PKS): A multi-enzyme assembly line that iteratively condenses simple acyl-CoA units into complex carbon backbones.

Thioesterase: An enzyme that hydrolyses the thioester bond between the PKS and its polyketide product, releasing the nascent molecule.

Bergman Cycloaromatization: A chemical transformation in which an enediyne undergoes cyclisation to generate a benzene diradical intermediate.

References

1. Combinatorial metabolic engineering of Streptomyces sp. CB03234-S for the enhanced production of anthraquinone-fused enediyne tiancimycins. Microbial Cell Factories (2024).
2. Strain Prioritization and Genome Mining for Enediyne Natural Products. mBio (2016).
3. Structure and Catalytic Mechanism of the Thioesterase CalE7 in Enediyne Biosynthesis*. Journal of Biological Chemistry (2009).