Cordycepin (COR) and pentostatin (PTN) are adenosine analogs with related bioactivity profiles as both mimic adenosine and can inhibit some of the processes that are adenosine dependent. Both COR and PTN are also natural products and were originally isolated from the fungusCordyceps militarisand the bacteriumStreptomyces antibioticus, respectively. Here, we report that not only is PTN produced byC. militarisbut that biosynthesis of COR is coupled with PTN production by a single gene cluster. We also demonstrate that this coupling is an important point of metabolic regulation where PTN safeguards COR from deamination by inhibiting adenosine deaminase (ADA) activity. ADA is not inhibited until COR reaches self-toxic levels, at which point ADA derepression occurs allowing for detoxification of COR to 3′-deoxyinosine. Finally, we show that using our biosynthetic insights, we can engineerC. militaristo produce higher levels of COR and PTN.

中文翻译：

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真菌虫草素的生物合成与保障分子戊抑素的生产有关

虫草素（COR）和喷司他丁（PTN）是具有相关生物活性特征的腺苷类似物，既可以模拟腺苷，又可以抑制某些依赖腺苷的过程。COR和PTN均为天然产物，最初分别是从虫菌和抗生素链霉菌中分离得到的。在这里，我们报告说，不仅C生产了PTN。但是，通过单一基因簇，COR的生物合成与PTN的产生有关。我们还证明了这种耦合是PTN通过抑制腺苷脱氨酶（ADA）活性来保护COR免受脱氨作用的代谢调控的重要点。直到COR达到自身毒性水平，ADA才被抑制，此时ADA发生抑制作用，从而使COR可以解毒为3'-脱氧肌苷。最后，我们证明，利用我们的生物合成见解，我们可以进行工程学C。militaristo产生较高水平的COR和PTN。