Phytocannabinoids are natural products with highly interesting pharmacological properties mainly produced by plants. The production of cannabinoids in a heterologous host system has gained interest in recent years as a promising alternative to production from plant material. However, the systems reported so far do not achieve industrially relevant titers, highlighting the need for alternative systems. Here, we show the production of the cannabinoids cannabigerolic acid and cannabigerol from glucose and hexanoic acid in a heterologous yeast system using the aromatic prenyltransferase NphB from Streptomyces sp. strain CL190. The production was significantly increased by introducing a fusion protein consisting of ERG20WW and NphB. Furthermore, we improved the production of the precursor olivetolic acid to a titer of 56 mg L−1. The implementation of the cannabinoid synthase genes enabled the production of Δ9‐tetrahydrocannabinolic acid, cannabidiolic acid as well as cannabichromenic acid, where the heterologous biosynthesis of cannabichromenic acid in a yeast system was demonstrated for the first time. In addition, we found that the product spectrum of the cannabinoid synthases localized to the vacuoles of the yeast cells was highly dependent on extracellular pH, allowing for easy manipulation. Finally, using a fed‐batch approach, we showed cannabigerolic acid and olivetolic acid titers of up to 18.2 mg L−1 and 117 mg L−1, respectively.

中文翻译：

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酿酒酵母中的工程大麻素生产

植物大麻素是主要由植物产生的具有高度有趣药理特性的天然产物。近年来，在异源宿主系统中生产大麻素作为植物材料生产的一种有前途的替代方案引起了人们的兴趣。然而，迄今为止报道的系统尚未达到工业相关的滴度，这凸显了对替代系统的需求。在这里，我们展示了在异源酵母系统中使用芳香异戊烯基转移酶 NphB 从葡萄糖和己酸生产大麻素大麻酚酸和大麻酚链霉菌属sp。菌株 CL190。通过引入由 ERG20 组成的融合蛋白，产量显着增加WW和 NphB。此外，我们将前体橄榄酸的产量提高到 56 mg/L−1。大麻素合酶基因的实施使得 Δ 的产生成为可能9‐四氢大麻酚酸、大麻二酚酸以及大麻色素酸，其中首次证明了酵母系统中大麻色素酸的异源生物合成。此外，我们发现位于酵母细胞液泡的大麻素合酶的产物谱高度依赖于细胞外 pH 值，因此易于操作。最后，使用分批补料方法，我们发现大麻二酚酸和橄榄叶酸滴度高达 18.2 mg/L−1和 117 毫克/升−1， 分别。