Heterologous Biosynthesis of Tetrahydroxanthone Dimers: Determination of Key Factors for Selective or Divergent Synthesis
Heterologous Biosynthesis of Tetrahydroxanthone Dimers: Determination of Key Factors for Selective or Divergent Synthesis
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DOI：
10.1021/acs.jnatprod.1c00022
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发表时间：
2021-04-23
影响因子：
5.1
通讯作者：
Matsuda, Yudai
中科院分区：
文献类型：
--
作者：
Wei, Xingxing;Chen, Xiaoxuan;Matsuda, Yudai
四羟基蒽酮二聚体是一类真菌代谢产物，其中裂酮醛酸D（1）因其生物活性而成为研究最多的化合物之一。由于1的生物合成基因簇先前已被鉴定，我们试图通过表达相关的生物合成基因在曲霉中异源产生1。然而，我们最初的尝试1的全生物合成失败;相反，它产生了四个异构体的1由于活性的内源酶的A。米。随后过表达的Baeyer-Villiger单加氧酶，AacuH，这与内源性酶的竞争，改变了产品的配置文件，并成功地产生1。关键生物合成酶的表征揭示了二聚酶AacuE的令人惊讶的底物混杂性，并表明1的有效合成需要高度选择性地制备四羟基蒽酮单体，这显然是由AacuH控制的。这项研究有利于工程生物合成四羟基蒽酮二聚体在选择性和发散的方式。
Tetrahydroxanthone dimers are fungal products, among which secalonic acid D (1) is one of the most studied compounds because of its potent biological activity. Because the biosynthetic gene cluster of 1 has been previously identified, we sought to heterologously produce 1 in Aspergillus oryzae by expressing the relevant biosynthetic genes. However, our initial attempt of the total biosynthesis of 1 failed; instead, it produced four isomers of 1 due to the activity of an endogenous enzyme of A. oryzae. Subsequent overexpression of the Baeyer-Villiger monooxygenase, AacuH, which competes with the endogenous enzyme, altered the product profile and successfully generated 1. Characterization of the key biosynthetic enzymes revealed the surprising substrate promiscuity of the dimerizing enzyme, AacuE, and indicated that efficient synthesis of 1 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.