Metabolic engineering of Saccharomyces cerevisiae for high-level production of gastrodin from glucose
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(2020) 19:218 Yin et al. Microb Cell Fact https://doi.org/10.1186/s12934-020-01476-0
Open Access
RESEARCH
Metabolic engineering of Saccharomyces cerevisiae for high‑level production of gastrodin from glucose Hua Yin1,2, Tiandong Hu1,2, Yibin Zhuang1,2 and Tao Liu1,2*
Abstract Background: The natural phenolic glycoside gastrodin is the major bioactive ingredient in the well-known Chinese herb Tianma and is widely used as a neuroprotective medicine in the clinic. Microbial production from sustainable resources is a promising method to replace plant extraction and chemical synthesis which were currently used in industrial gastrodin production. Saccharomyces cerevisiae is considered as an attractive host to produce natural plant products used in the food and pharmaceutical fields. In this work, we intended to explore the potential of S. cerevisiae as the host for high-level production of gastrodin from glucose. Results: Here, we first identified the plant-derived glucosyltransferase AsUGT to convert 4-hydroxybenzyl alcohol to gastrodin with high catalytic efficiency in yeast. Then, we engineered de novo production of gastrodin by overexpressing codon-optimized AsUGTsyn, the carboxylic acid reductase gene CARsyn from Nocardia species, the phosphopantetheinyl transferase gene PPTcg-1syn from Corynebacterium glutamicum, the chorismate pyruvate-lyase gene UbiCsyn from Escherichia coli, and the mutant ARO4K229L. Finally, we achieved an improved product titer by a chromosomal multiple-copy integration strategy and enhancement of metabolic flux toward the aglycon 4-hydroxybenzyl alcohol. The best optimized strain produced 2.1 g/L gastrodin in mineral medium with glucose as the sole carbon source by flask fermentation, which was 175 times higher than that of the original gastrodin-producing strain. Conclusions: The de novo high-level production of gastrodin was first achieved. Instead of chemical synthesis or plants extraction, our work provides an alternative strategy for the industrial production of gastrodin by microbial fermentation from a sustainable resource. Keywords: Saccharomyces cerevisiae, Gastrodin, AsUGT, Phenolic glycoside, Chromosomal integration, Metabolic engineering Background The phenolic glycoside gastrodin is the major bioactive ingredient in the famous Chinese herb Tianma (the tuber of Gastrodia elata Blume), which has been widely used to treat nervous system diseases, such as ischemic stroke, epilepsy, dizziness, and dementia, for centuries in China *Correspondence: [email protected] 1 Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Tianjin 300308, China Full list of author information is available at the end of the article
[1, 2]. In addition to its neuroprotective effects [3], gastrodin has been proven to show memory improvement [4], anti-inflammation, and antioxidant effects [5, 6]. To date, gastrodin is produced mainly by chemical synthesis or direct extraction from Tianma, although different processing methods have also been explored and applied [7, 8]. Howev
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