Department of Chemistry, City University of Hong Kong, Tat Chee Avenue, Kowloon, Hong Kong SAR 999077, People's Republic of China.
Key Laboratory of Chemistry in Ethnic Medicinal Resources, State Ethnic Affairs Commission and Ministry of Education, Yunnan Minzu University, Kunming 650031, People's Republic of China.
J Nat Prod. 2021 May 28;84(5):1544-1549. doi: 10.1021/acs.jnatprod.1c00022. Epub 2021 Apr 23.
Tetrahydroxanthone dimers are fungal products, among which secalonic acid D () is one of the most studied compounds because of its potent biological activity. Because the biosynthetic gene cluster of has been previously identified, we sought to heterologously produce in by expressing the relevant biosynthetic genes. However, our initial attempt of the total biosynthesis of failed; instead, it produced four isomers of due to the activity of an endogenous enzyme of . Subsequent overexpression of the Baeyer-Villiger monooxygenase, AacuH, which competes with the endogenous enzyme, altered the product profile and successfully generated . Characterization of the key biosynthetic enzymes revealed the surprising substrate promiscuity of the dimerizing enzyme, AacuE, and indicated that efficient synthesis of requires highly selective preparation of the tetrahydroxanthone monomer, which is apparently controlled by AacuH. This study facilitates engineered biosynthesis of tetrahydroxanthone dimers both in a selective and divergent manner.
四氢蒽酮二聚体是真菌产物，其中 secalonic 酸 D () 是研究最多的化合物之一，因为它具有很强的生物活性。由于 的生物合成基因簇已被先前鉴定，我们试图通过表达相关的生物合成基因在 中异源产生 。然而，我们最初尝试 的全生物合成失败了；相反，由于 的内源性酶的活性，它产生了 的四个异构体。随后过表达 Baeyer-Villiger 单加氧酶 AacuH，与内源性酶竞争，改变了产物谱，并成功生成 。关键生物合成酶的表征揭示了二聚酶 AacuE 出人意料的底物混杂性，并表明 的有效合成需要四氢蒽酮单体的高度选择性制备，这显然由 AacuH 控制。这项研究促进了四氢蒽酮二聚体的工程生物合成，既具有选择性又具有发散性。
