Development of an E. coli-based norbaeocystin production platform and evaluation of behavioral effects in rats

IF 3.7 Q2 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Metabolic Engineering Communications Pub Date : 2022-06-01 DOI:10.1016/j.mec.2022.e00196
Alexandra M. Adams , Nicholas A. Anas , Abhishek K. Sen , Jordan D. Hinegardner-Hendricks , Philip J. O’Dell , William J. Gibbons Jr. , Jessica E. Flower , Matthew S. McMurray , J. Andrew Jones
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引用次数: 9

Abstract

Interest in the potential therapeutic efficacy of psilocybin and other psychedelic compounds has escalated significantly in recent years. To date, little is known regarding the biological activity of the psilocybin pathway intermediate, norbaeocystin, due to limitations around sourcing the phosphorylated tryptamine metabolite for in vivo testing. To address this limitation, we first developed a novel E. coli platform for the rapid and scalable production of gram-scale amounts of norbaeocystin. Through this process we compare the genetic and fermentation optimization strategies to that of a similarly constructed and previously reported psilocybin producing strain, uncovering the need for reoptimization and balancing upon even minor genetic modifications to the production host. We then perform in vivo measurements of head twitch response to both biosynthesized psilocybin and norbaeocystin using both a cell broth and water vehicle in Long-Evans rats. The data show a dose response to psilocybin while norbaeocystin does not elicit any pharmacological response, suggesting that norbaeocystin and its metabolites may not have a strong affinity for the serotonin 2A receptor. The findings presented here provide a mechanism to source norbaeocystin for future studies to evaluate its disease efficacy in animal models, both individually and in combination with psilocybin, and support the safety of cell broth as a drug delivery vehicle.

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基于大肠杆菌的去baeocystin生产平台的建立及其对大鼠行为影响的评价
近年来,对裸盖菇素和其他致幻剂的潜在治疗效果的兴趣显著增加。迄今为止,关于裸盖菇素途径中间体去甲盖菇素的生物活性知之甚少,这是由于体内试验中磷酸化色胺代谢物来源的限制。为了解决这一限制,我们首先开发了一种新的大肠杆菌平台,用于快速和可扩展地生产克级量的去甲黄囊素。通过这一过程,我们将遗传和发酵优化策略与类似构建和先前报道的裸盖菇素生产菌株进行比较,发现即使对生产宿主进行微小的遗传修饰也需要重新优化和平衡。然后,我们在Long-Evans大鼠体内使用细胞培养液和水载体对生物合成的裸盖菇素和去甲盖菇素进行了头抽搐反应的测量。数据显示裸盖菇素有剂量反应,而去甲毛囊素没有引起任何药理反应,提示去甲毛囊素及其代谢物可能对5 -羟色胺2A受体没有很强的亲和力。本文的研究结果为未来的动物模型研究提供了去甲盖菇素来源的机制,以评估其疾病疗效,无论是单独还是与裸盖菇素联合,并支持细胞汤作为药物递送载体的安全性。
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来源期刊
Metabolic Engineering Communications
Metabolic Engineering Communications Medicine-Endocrinology, Diabetes and Metabolism
CiteScore
13.30
自引率
1.90%
发文量
22
审稿时长
18 weeks
期刊介绍: Metabolic Engineering Communications, a companion title to Metabolic Engineering (MBE), is devoted to publishing original research in the areas of metabolic engineering, synthetic biology, computational biology and systems biology for problems related to metabolism and the engineering of metabolism for the production of fuels, chemicals, and pharmaceuticals. The journal will carry articles on the design, construction, and analysis of biological systems ranging from pathway components to biological complexes and genomes (including genomic, analytical and bioinformatics methods) in suitable host cells to allow them to produce novel compounds of industrial and medical interest. Demonstrations of regulatory designs and synthetic circuits that alter the performance of biochemical pathways and cellular processes will also be presented. Metabolic Engineering Communications complements MBE by publishing articles that are either shorter than those published in the full journal, or which describe key elements of larger metabolic engineering efforts.
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