Efficient 7-Dehydrocholesterol Production by Multiple Metabolic Engineering of Diploid Saccharomyces cerevisiae.

IF 5.7 1区 农林科学 Q1 AGRICULTURE, MULTIDISCIPLINARY Journal of Agricultural and Food Chemistry Pub Date : 2024-11-13 Epub Date: 2024-10-31 DOI:10.1021/acs.jafc.4c07609
Ziqi Ye, Xianhao Xu, Yaokang Wu, Yanfeng Liu, Jianghua Li, Guocheng Du, Long Liu, Xueqin Lv
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Abstract

7-Dehydrocholesterol (7-DHC), a direct precursor of vitamin D3, has attracted increasing attention in microbial fermentation recently. In this study, 7-DHC biosynthesis in diploid Saccharomyces cerevisiae with robust ergosterol production was achieved by heterologous 24-dehydrocholesterol reductase expression, generating 44.1 mg/L 7-DHC, whereas the titer of ergosterol decreased by 40.5%. The ergosterol biosynthetic pathway was completely blocked by knocking out ERG6 and ERG5, affording a 4.2-fold increase in the 7-DHC titer. Subsequently, the facilitation of the mevalonate and the postsqualene pathways accompanied by elimination of transcriptional repressors enhanced 7-DHC synthesis, and the 7-DHC titer reached 738.5 mg/L in a shake flask. Further validation in a 50 L fermenter demonstrated that the 7-DHC titer reached 3.80 g/L within just 24 h, with productivity reaching 158.3 mg/L/h, setting a new benchmark as the highest reported to date. This study paves the way toward a large-scale and cost-effective manufacture of 7-DHC.

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通过二倍体酿酒酵母的多重代谢工程高效生产 7-去氢胆固醇
7-脱氢胆固醇(7-DHC)是维生素 D3 的直接前体,近年来在微生物发酵中越来越受到关注。本研究通过异源表达 24-脱氢胆固醇还原酶,在二倍体酿酒酵母中实现了 7-DHC 的生物合成,并产生了大量麦角固醇,产生了 44.1 mg/L 的 7-DHC,而麦角固醇的滴度则下降了 40.5%。通过敲除 ERG6 和 ERG5,麦角甾醇生物合成途径被完全阻断,从而使 7-DHC 滴度增加了 4.2 倍。随后,在消除转录抑制因子的同时,促进了甲羟戊酸和后葵醛途径,增强了 7-DHC 的合成,在振荡烧瓶中 7-DHC 滴度达到 738.5 毫克/升。在 50 升发酵罐中的进一步验证表明,7-DHC 滴度在短短 24 小时内就达到了 3.80 克/升,生产率达到 158.3 毫克/升/小时,为迄今为止报道的最高生产率设定了新的基准。这项研究为大规模、经济高效地生产 7-DHC 铺平了道路。
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来源期刊
Journal of Agricultural and Food Chemistry
Journal of Agricultural and Food Chemistry 农林科学-农业综合
CiteScore
9.90
自引率
8.20%
发文量
1375
审稿时长
2.3 months
期刊介绍: The Journal of Agricultural and Food Chemistry publishes high-quality, cutting edge original research representing complete studies and research advances dealing with the chemistry and biochemistry of agriculture and food. The Journal also encourages papers with chemistry and/or biochemistry as a major component combined with biological/sensory/nutritional/toxicological evaluation related to agriculture and/or food.
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