Enediyne natural products are renowned for their potent cytotoxicities but the biosynthesis of their defining 1,5-diyne-3-ene core moiety remains largely enigmatic. Since the discovery of the enediyne polyketide synthase cassette in 2002, genome sequencing has revealed thousands of distinct enediyne biosynthetic gene clusters, each harboring the conserved enediyne polyketide synthase cassette. Here we report that (1) the products of this cassette are an iodoheptaene, a diiodotetrayne and two pentaynes; (2) the diiodotetrayne represents a common biosynthetic intermediate for all known enediynes; and (3) cryptic iodination can be exploited to increase enediyne titers. These findings establish a unified biosynthetic pathway for the enediynes, set the stage to further advance enediyne core biosynthesis and enable fundamental breakthroughs in chemistry, enzymology and translational applications of enediyne natural products.

烯二炔天然产物以其强大的细胞毒性而闻名，但其决定性的 1,5-二炔-3-烯核心部分的生物合成在很大程度上仍然是个谜。自 2002 年发现 enediyne 聚酮合酶盒以来，基因组测序已经揭示了数千个不同的 enediyne 生物合成基因簇，每个基因簇都含有保守的 enediyne 聚酮合酶盒。在这里，我们报告了 （1） 该盒的产物是一种碘庚烯、一种二碘四炔和两种戊炔;（2） 二碘四炔代表所有已知烯二炔的常用生物合成中间体;（3） 可以利用隐蔽的碘化来提高 enediyne 滴度。这些发现为烯二炔建立了统一的生物合成途径，为进一步推进烯二炔核心生物合成奠定了基础，并在烯二炔天然产物的化学、酶学和转化应用方面取得了根本性突破。