Engineering a universal and efficient platform for terpenoid synthesis in yeast

文献类型： 外文期刊

第一作者： Ma, Yongshuo

作者： Ma, Yongshuo;Zu, Yuexuan;Stephanopoulos, Gregory;Ma, Yongshuo;Huang, Sanwen;Huang, Sanwen

作者机构：

关键词： terpenoids; metabolic engineering; isopentenol utilization pathway; prenyl phosphates; flux redirection

期刊名称：PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA （ 影响因子：11.1； 五年影响因子：12.0 ）

ISSN： 0027-8424

年卷期： 2023 年 120 卷 1 期

页码：

收录情况： SCI

摘要： Engineering microbes for the production of valuable natural products is often hindered by the regulation of native competing metabolic networks in host. This is particularly evident in the case of terpenoid synthesis in yeast, where the canonical terpenoid precursors are tightly coupled to the biosynthesis of sterols essential for yeast viability. One way to circumvent this limitation is by engineering product pathways less connected to the host native metabolism. Here, we introduce a two-step isopentenol utilization pathway (IUP) in Saccharomyces cerevisiae to augment the native mevalonate pathway by providing a shortcut to the synthesis of the common terpenoid precursors, isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP). As such, the IUP was capable of elevating the IPP/DMAPP pool by 147-fold compared with the native pathway. We further demonstrate that cofeeding isoprenol and prenol enhances geranyl diphosphate (GPP) content for monoterpene biosynthesis. More importantly, we established a synthetic three-step route for efficient synthesis of di-and tetraterpene precursor geranylgeranyl diphosphate (GGPP), circumventing the competition with farnesyl diphosphate (FPP) for sterol biosynthesis and elevating the GGPP level by 374-fold. We combine these IUP-supported precursor-forming platforms with downstream terpene synthases to harness their potential and improve the production of industrially relevant terpenoids by several fold. Our exploration provides a universal and effective platform for supporting terpenoid synthesis in yeast.

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