对 TrpM 和 PsiD 底物杂交性的评估揭示了新的生物催化能力。

IF 2.5 3区 生物学 Q3 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Biotechnology Progress Pub Date : 2024-06-18 DOI:10.1002/btpr.3492
Fiona C Kanis, Caroline N Broude, Elle B Hellwarth, William J Gibbons, Abhishek K Sen, Alexandra M Adams, Xin Wang, J Andrew Jones
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引用次数: 0

摘要

N-甲基化色胺(如致幻天然产物迷幻药和 N,N-二甲基色胺(DMT))因其作为治疗精神疾病的下一代药物的潜力而越来越受到医学界的关注。这些化合物的临床意义促使科学家们开发出了一些色胺候选药物的生物合成生产路线,并正在努力扩大和进一步开发这些生物合成能力。为此,我们进一步鉴定了参与色胺生物合成的两种酶的底物偏好:TrpM是一种来自银莲花的色氨酸N-甲基转移酶,而PsiD则是银环蛇素生物合成途径中的关口脱羧酶。在这里,我们发现 TrpM 可以对非原生氨基酸底物 4-hydroxytryptophan 进行 N-甲基化,而 4-hydroxytryptophan 是基于大肠杆菌的重组迷幻素生物合成途径中的一个关键中间体。然而,在测试的培养条件下,PsiD 无法使用 N,N-二甲基-4-羟基色氨酸作为底物,这阻碍了将 TrpM 纳入功能性迷幻药生物合成途径的能力,尽管它对 N-甲基化和 4-羟基色氨酸衍生物具有单独的活性。总之,这项工作扩展了 TrpM 和 PsiD 的已知底物,进一步增加了色胺生物合成产物的多样性。
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Evaluation of TrpM and PsiD substrate promiscuity reveals new biocatalytic capabilities.

N-methylated tryptamines, such as the hallucinogenic natural products, psilocybin and N,N-dimethyltryptamine (DMT), are gaining interest from the medical community due to their potential as next generation treatments for mental health disorders. The clinical relevance of these compounds has driven scientists to develop biosynthetic production routes to a number of tryptamine drug candidates, and efforts are ongoing to expand and further develop these biosynthetic capabilities. To that end, we have further characterized the substrate preferences of two enzymes involved in tryptamine biosynthesis: TrpM, a tryptophan N-methyltransferase from Psilocybe serbica, and PsiD, the gateway decarboxylase of the psilocybin biosynthesis pathway. Here, we show that TrpM can N-methylate the non-native amino acid substrate, 4-hydroxytryptophan, a key intermediate in the Escherichia coli-based recombinant psilocybin biosynthesis pathway. However, the ability to incorporate TrpM into a functional psilocybin biosynthesis pathway was thwarted by PsiD's inability to use N,N-dimethyl-4-hydroxytryptophan as substrate, under the culturing conditions tested, despite demonstrating activity on N-methylated and 4-hydroxylated tryptophan derivatives individually. Taken together, this work expands upon the known substrates for TrpM and PsiD, further increasing the diversity of tryptamine biosynthetic products.

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来源期刊
Biotechnology Progress
Biotechnology Progress 工程技术-生物工程与应用微生物
CiteScore
6.50
自引率
3.40%
发文量
83
审稿时长
4 months
期刊介绍: Biotechnology Progress , an official, bimonthly publication of the American Institute of Chemical Engineers and its technological community, the Society for Biological Engineering, features peer-reviewed research articles, reviews, and descriptions of emerging techniques for the development and design of new processes, products, and devices for the biotechnology, biopharmaceutical and bioprocess industries. Widespread interest includes application of biological and engineering principles in fields such as applied cellular physiology and metabolic engineering, biocatalysis and bioreactor design, bioseparations and downstream processing, cell culture and tissue engineering, biosensors and process control, bioinformatics and systems biology, biomaterials and artificial organs, stem cell biology and genetics, and plant biology and food science. Manuscripts concerning the design of related processes, products, or devices are also encouraged. Four types of manuscripts are printed in the Journal: Research Papers, Topical or Review Papers, Letters to the Editor, and R & D Notes.
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Non-thermal plasma decontamination of microbes: a state of the art. Mechanistic model of minute virus of mice elution behavior in anion exchange chromatography purification. Comparing in silico flowsheet optimization strategies in biopharmaceutical downstream processes. General strategies for IgG-like bispecific antibody purification. Issue Information
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