<br>来自黑曲霉的混杂黄素依赖性单加氧酶 PboD 增加了羟基化吡咯并吲哚啉二酮哌嗪的结构多样性,Journal of Natural Products

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来自黑曲霉的混杂黄素依赖性单加氧酶 PboD 增加了羟基化吡咯并吲哚啉二酮哌嗪的结构多样性
Journal of Natural Products ( IF 3.3 ) Pub Date : 2024-04-01 , DOI: 10.1021/acs.jnatprod.4c00127
Meiting Wu ₁ , Daniel J Janzen ₁ , Zhenhua Guan ₂ , Ying Ye ₂ , Yonghui Zhang ₂ , Shu-Ming Li ₁

Affiliation

天然产物作为药物和农业制剂的潜力基于其巨大的结构多样性，部分原因是在生物合成过程中通过调整酶来修饰主链结构。黄素依赖性单加氧酶（FMO）作为这样的一类酶，在包括环二肽（CDP）衍生物在内的多种天然产物的生物合成中发挥着重要作用。 FMO PboD 在 protubonines 的生物合成中催化环-l -Trp- l -Leu 吲哚环上的 C-3 羟基化，并伴随吡咯烷环的形成。本研究通过测试其对额外的含色氨酸的 CDP 的体外催化活性以及在带有带有pboD和两个乙酰转移酶基因的截短的 protubonine 基因簇的构巢曲霉转化体中的生物转化来研究 PboD 底物混杂性。检测到 PboD 对 5 个 CDP 的接受度很高，尤其是那些具有第二个芳香族部分的 CDP。五个吡咯烷二酮哌嗪产物的分离和结构解析，其中两个新结构，证明了预期的立体定向羟基化和吡咯烷环的形成。动力学参数测定表明，PboD对由芳香族氨基酸组成的三种CDPs的催化效率高于其天然底物环-l -Trp- l -Leu。在构巢曲霉转化体的生物转化实验中，还检测到了适度的羟基化和乙酰化产物的形成。

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The Promiscuous Flavin-Dependent Monooxygenase PboD from Aspergillus ustus Increases the Structural Diversity of Hydroxylated Pyrroloindoline Diketopiperazines

The potential of natural products as pharmaceutical and agricultural agents is based on their large structural diversity, resulting in part from modifications of the backbone structure by tailoring enzymes during biosynthesis. Flavin-dependent monooxygenases (FMOs), as one such group of enzymes, play an important role in the biosynthesis of diverse natural products, including cyclodipeptide (CDP) derivatives. The FMO PboD was shown to catalyze C-3 hydroxylation at the indole ring of cyclo-l-Trp-l-Leu in the biosynthesis of protubonines, accompanied by pyrrolidine ring formation. PboD substrate promiscuity was investigated in this study by testing its catalytic activity toward additional tryptophan-containing CDPs in vitro and biotransformation in Aspergillus nidulans transformants bearing a truncated protubonine gene cluster with pboD and two acetyltransferase genes. High acceptance of five CDPs was detected for PboD, especially of those with a second aromatic moiety. Isolation and structure elucidation of five pyrrolidine diketopiperazine products, with two new structures, proved the expected stereospecific hydroxylation and pyrrolidine ring formation. Determination of kinetic parameters revealed higher catalytic efficiency of PboD toward three CDPs consisting of aromatic amino acids than of its natural substrate cyclo-l-Trp-l-Leu. In the biotransformation experiments with the A. nidulans transformant, modest formation of hydroxylated and acetylated products was also detected.

更新日期：2024-04-01

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