Department of Molecular Biosciences, University of Kansas, Lawrence, Kansas 66045, United States.
School of Pharmacy, National Defense Medical Center, Taipei, 11490, Taiwan.
J Nat Prod. 2024 Jul 26;87(7):1704-1713. doi: 10.1021/acs.jnatprod.4c00113. Epub 2024 Jul 11.
Fungal secondary metabolite (SM) biosynthetic gene clusters (BGCs) containing dimethylallyltryptophan synthases (DMATSs) produce structurally diverse prenylated indole alkaloids with wide-ranging activities that have vast potential as human therapeutics. To discover new natural products produced by DMATSs, we mined the Department of Energy Joint Genome Institute's MycoCosm database for DMATS-containing BGCs. We found a DMATS BGC in CBS 101889, which also contains a nonribosomal peptide synthetase (NRPS). This BGC appeared to have a previously unreported combination of genes, which suggested the cluster might make novel SMs. We refactored this BGC with highly inducible promoters into the model fungus . The expression of this refactored BGC in . resulted in the production of eight tryptophan-containing diketopiperazines, six of which are new to science. We have named them homomorphins A-F (, -). Perhaps even more intriguingly, to our knowledge, this is the first discovery of C4-prenylated tryptophan-containing diketopiperazines and their derivatives. In addition, the NRPS from this BGC is the first described that has the ability to promiscuously combine tryptophan with either of two different amino acids, in this case, l-valine or l--isoleucine.
真菌次级代谢产物 (SM) 生物合成基因簇 (BGCs) 包含二甲基烯丙基色氨酸合酶 (DMATSs)，可产生结构多样的具有广泛活性的烯丙基吲哚生物碱，具有巨大的人类治疗潜力。为了发现 DMATSs 产生的新天然产物，我们从能源部联合基因组研究所的 MycoCosm 数据库中挖掘了含有 DMATS 的 BGC。我们在 CBS 101889 中发现了一个 DMATS BGC，其中还包含一个非核糖体肽合成酶 (NRPS)。这个 BGC 似乎具有以前未报道过的基因组合，这表明该簇可能产生新的 SMs。我们用高度可诱导的启动子将这个 BGC 重构到模式真菌 中。这个重构的 BGC 在 中的表达导致产生了八种含有色氨酸的二酮哌嗪，其中六种是新的科学发现。我们将它们命名为 homomorphins A-F (, -)。也许更有趣的是，据我们所知，这是首次发现 C4-烯丙基色氨酸二酮哌嗪及其衍生物。此外，这个 BGC 的 NRPS 是第一个被描述为能够随意将色氨酸与两种不同氨基酸（在这种情况下是 l-缬氨酸或 l-异亮氨酸）结合的 NRPS。
