Synthesis of Ligustrazine from Acetaldehyde by a Combined Biological–Chemical Approach,ACS Synthetic Biology

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Synthesis of Ligustrazine from Acetaldehyde by a Combined Biological–Chemical Approach
ACS Synthetic Biology ( IF 3.7 ) Pub Date : 2020-11-06 , DOI: 10.1021/acssynbio.0c00113
Kai Peng _{1,

2,

3} , Dan Guo _{1,

2,

4} , Qianqian Lou _{1,

2} , Xiaoyun Lu _{1,

2} , Jian Cheng _{1,

2} , Jing Qiao _{1,

2} , Lina Lu _{1,

2} , Tao Cai _{1,

2} , Yuwan Liu _{1,

2} , Huifeng Jiang ₁

Affiliation

Ligustrazine is an important active alkaloid in medicine and in the food industry. Here, we developed a combined biological–chemical approach to produce ligustrazine from acetaldehyde. First, we constructed a whole-cell biocatalytic system to produce the precursor acetoin from acetaldehyde by overexpressing formolase (FLS). Second, a two-step strategy was developed to enhance protein expression of FLS by codon usage optimization at the first 14 codons and the introduction of an overlapping gene before the start codon. Through expression optimization and directed evolution of FLS, we improved the titer of acetoin about 40 fold when the concentration of acetaldehyde was 1.5 M. Finally, after reaction conditions optimization, the titer of acetoin and ligustrazine reached 222 g L^–1 and 94 g L^–1, with a 86.5% and 48% conversion rate from acetaldehyde, respectively. The developed one-pot synthesis for acetoin and ligustrazine is expected to be applied to industrial production in the future with the advantages of a green process, high efficiency, and low cost.

中文翻译：

生物-化学联合方法从乙醛合成川芎嗪

川芎嗪是医药和食品工业中重要的活性生物碱。在这里，我们开发了一种结合生物化学的方法，从乙醛生产川芎嗪。首先，我们构建了一个全细胞生物催化系统，通过过度表达甲醛酶（FLS）从乙醛生产前体乙偶姻。其次，开发了一种两步策略，通过优化前 14 个密码子的密码子使用和在起始密码子之前引入重叠基因来增强 FLS 的蛋白质表达。通过FLS的表达优化和定向进化，乙醛浓度为1.5 M时，我们将乙偶姻的滴度提高了约40倍。最后，经过反应条件优化，乙偶姻和川芎嗪的滴度分别达到222 g L ^–1和94 g L ^–1，乙醛的转化率分别为 86.5% 和 48%。所开发的乙偶姻和川芎嗪一锅法合成工艺具有绿色、高效、低成本等优点，有望在未来应用于工业化生产。

更新日期：2020-11-21

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