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Engineering yeast metabolism for the discovery and production of polyamines and polyamine analogues
Nature Catalysis ( IF 37.8 ) Pub Date : 2021-06-17 , DOI: 10.1038/s41929-021-00631-z
Jiufu Qin , Anastasia Krivoruchko , Boyang Ji , Yu Chen , Mette Kristensen , Emre Özdemir , Jay D. Keasling , Michael Krogh Jensen , Jens Nielsen

Structurally complex and diverse polyamines and polyamine analogues are potential therapeutics and agrochemicals that can address grand societal challenges, for example, healthy ageing and sustainable food production. However, their structural complexity and low abundance in nature hampers either bulk chemical synthesis or extraction from natural resources. Here we reprogrammed the metabolism of baker’s yeast Saccharomyces cerevisiae and recruited nature’s diverse reservoir of biochemical tools to enable a complete biosynthesis of multiple polyamines and polyamine analogues. Specifically, we adopted a systematic engineering strategy to enable gram-per-litre-scale titres of spermidine, a central metabolite in polyamine metabolism. To demonstrate the potential of our polyamine platform, various polyamine synthases and ATP-dependent amide-bond-forming systems were introduced for the biosynthesis of natural and unnatural polyamine analogues. The yeast platform serves as a resource to accelerate the discovery and production of polyamines and polyamine analogues, and thereby unlocks this chemical space for further pharmacological and insecticidal studies.



中文翻译:

工程酵母代谢以发现和生产多胺和多胺类似物

结构复杂且多样化的多胺和多胺类似物是潜在的治疗剂和农用化学品,可以应对重大的社会挑战,例如健康老龄化和可持续粮食生产。然而,它们在自然界中的结构复杂性和低丰度阻碍了大宗化学合成或从自然资源中提取。在这里,我们重新编程了面包酵母Saccharomyces cerevisiae的代谢并利用自然界中多样化的生化工具库来实现多种多胺和多胺类似物的完整生物合成。具体来说,我们采用了一种系统的工程策略来实现以克/升为单位的亚精胺滴度,亚精胺是多胺代谢的中心代谢物。为了证明我们的多胺平台的潜力,引入了各种多胺合酶和 ATP 依赖性酰胺键形成系统,用于天然和非天然多胺类似物的生物合成。酵母平台可作为加速多胺和多胺类似物发现和生产的资源,从而为进一步的药理学和杀虫研究打开这一化学空间。

更新日期:2021-06-17
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