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串联重复的 CYP82D 酶在生物合成雷公藤红素和酵母前体生产中催化 14-羟化反应。

Tandemly duplicated CYP82Ds catalyze 14-hydroxylation in triptolide biosynthesis and precursor production in Saccharomyces cerevisiae.

机构信息

State Key Laboratory of Dao-di Herbs, National Resource Center for Chinese Materia Medica, Chinese Academy of Chinese Medical Sciences, Beijing, China.

School of Traditional Chinese Medicine, Capital Medical University, Beijing, China.

出版信息

Nat Commun. 2023 Feb 16;14(1):875. doi: 10.1038/s41467-023-36353-y.

DOI:10.1038/s41467-023-36353-y
PMID:36797237
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9936527/
Abstract

Triptolide is a valuable multipotent antitumor diterpenoid in Tripterygium wilfordii, and its C-14 hydroxyl group is often selected for modification to enhance both the bioavailability and antitumor efficacy. However, the mechanism for 14-hydroxylation formation remains unknown. Here, we discover 133 kb of tandem duplicated CYP82Ds encoding 11 genes on chromosome 12 and characterize CYP82D274 and CYP82D263 as 14-hydroxylases that catalyze the metabolic grid in triptolide biosynthesis. The two CYP82Ds catalyze the aromatization of miltiradiene, which has been repeatedly reported to be a spontaneous process. In vivo assays and evaluations of the kinetic parameters of CYP82Ds indicate the most significant affinity to dehydroabietic acid among multiple intermediates. The precursor 14-hydroxy-dehydroabietic acid is successfully produced by engineered Saccharomyces cerevisiae. Our study provides genetic elements for further elucidation of the downstream biosynthetic pathways and heterologous production of triptolide and of the currently intractable biosynthesis of other 14-hydroxyl labdane-type secondary metabolites.

摘要

雷公藤内酯醇是雷公藤中一种有价值的多功能抗肿瘤二萜，其 C-14 羟基基团常被选择进行修饰，以提高生物利用度和抗肿瘤功效。然而，14-羟化形成的机制仍不清楚。在这里，我们在第 12 号染色体上发现了长达 133kb 的串联重复 CYP82D 编码 11 个基因，并鉴定出 CYP82D274 和 CYP82D263 为 14-羟化酶，它们催化雷公藤内酯醇生物合成中的代谢网格。这两个 CYP82D 催化海松二烯的芳构化，海松二烯已被反复报道为一个自发过程。体内实验和 CYP82D 动力学参数的评估表明，它们对多种中间产物中的去氢松香酸具有最显著的亲和力。通过工程化酿酒酵母成功生产出前体 14-羟基-去氢松香酸。我们的研究为进一步阐明下游生物合成途径以及雷公藤内酯醇和其他目前难以合成的 14-羟基贝壳杉烷型次生代谢物的异源生产提供了遗传元件。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5345/9936527/26b9a3684b08/41467_2023_36353_Fig7_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5345/9936527/26b9a3684b08/41467_2023_36353_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5345/9936527/24d105c61b7d/41467_2023_36353_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5345/9936527/a7fad609d5ef/41467_2023_36353_Fig2_HTML.jpg
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