Enediyne natural products (NPs) are very scarce, and only 13 have been structurally characterized over the past 30 years. Discovery of a new enediyne NP is therefore a significant event in NP chemistry, biology, and drug discovery. The enediynes have provided an outstanding opportunity to decipher the genetic and biochemical basis for NP biosynthesis and to explore ways to make novel analogues by engineered biosynthesis. Sharing a common mode of action, the enediynes undergo an electronic rearrangement to generate a transient benzenoid diradical. When positioned within the minor groove of DNA, the diradical abstracts hydrogen atoms from the deoxyribose backbone to afford DNA-centered radicals that can cause interstrand crosslinks, react with molecular oxygen leading to DNA double-strand breaks, or both. With the exquisite mode of action and the extraordinary cytotoxicity, the enediynes have been successfully translated into clinical drugs, including two of the four FDA approved antibody-drug conjugates (ADCs) (i.e., Mylotarg® and Besponsa®). Therefore, new enediynes will be extremely valuable assets in the development of next-generation anticancer ADC therapeutics, and biosynthesis of new enediynes promises to be a rich treasure trove for discovering new chemistry and enzymology.
Since we initiated our enediyne program in 1998, we have played the central role in defining and pushing the field forward and continue to lead the field of enediyne biosynthesis, engineering, and more recently new enediyne discovery by mining actinomycetal genomes.
Using C-1027 as a model system for the 9-membered enediyne NPs and TNM as a model system for the 10-membered enediyne NPs (Figure 1), current efforts focus on: (i) deciphering the chemistry, enzymology, and mechanistic details of enediyne core biosynthesis, (ii) mining actinomycetal genomes to discover new enediyne NPs, and (iii) establishing a biotechnological platform for engineered production of the anthraquinone-fused family of designer enediyne NPs for drug discovery.
Figure 1. Key achievements in enediyne biosynthesis, engineering, and discovery. (A) The C-1027 and tiancimycin (TNM) BGCs exemplify the eight enediyne BGSs cloned to date. (B) A unified model for enediyne core biosynthesis, as exemplified by C-1027, NCS, KED, and MDP for the 9-membed cores and DYN, UCM, TNM, and YPM for the 10-membered cores, respectively. (C) Identification of a common intermediate, post-enediyne PKS and associated enzymes-catalyzed steps, resulting in a unified pathway for biosynthesis of the anthraquinone-fused family of enediynes, i.e., DYN, UCM, TNM, and YPM, and engineered production of DYN, UCM, and YPM in the TNM producer S. sp. CB03234.