Fungal Cordycepin Biosynthesis Is Coupled with the Production of the Safeguard Molecule Pentostatin. Issue 12 (21st December 2017)

• Record Type: Journal Article
• Authors: Xia, Yongliang; Luo, Feifei; Shang, Yanfang; Chen, Peilin; Lu, Yuzhen; Wang, Chengshu
• Is Part Of: Cell chemical biology. Volume 24:Issue 12(2017)
• Page Start: 1479
• Page End: 1489.e4
• Publication Date: 2017-12-21
• Subjects: Cordyceps militaris -- cordycepin -- pentostatin -- 3′-deoxyinosine -- dual biosynthesis -- deoxygenation -- deamination -- detoxification -- genetic engineering; Biochemistry -- Periodicals; 572.05
• DOI: 10.1016/j.chembiol.2017.09.001
• Languages: English
• ISSNs: 2451-9456

Abstract

Summary: 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 fungus Cordyceps militaris and the bacterium Streptomyces antibioticus, respectively. Here, we report that not only is PTN produced by C. militaris but 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 engineer C. militaris to produce higher levels of COR and PTN. Graphical Abstract: Highlights: Cordyceps militaris can produce both cordycepin and pentostatin Dual biosynthesis of cordycepin and pentostatin is mediated by a single gene cluster The safeguarded cordycepin can be deaminated for fungal cell self-detoxification A bacterial-like protector-protégé strategy is found in eukaryotes Abstract : Xia et al. report the coupled biosynthesis of cordycepin and pentostatin by a single gene cluster in the medicinal fungus Cordyceps militaris . Dual production of these two adenosine analogs is following a bacterial-like protector-protégé strategy of purine metabolism. The safeguarded cordycepin can be deaminated to 3′-deoxyinosine once the former reaches a self-toxic level in fungal cells.