Fungal Cordycepin Biosynthesis Is Coupled with the Production of the Safeguard Molecule Pentostatin

Abstract

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.

Cyclosporine Biosynthesis in Tolypocladium inflatum Benefits Fungal Adaptation to the Environment

“…To determine the functions of the clustered genes, gene deletions were individually performed by using Agrobacterium -mediated transformation of T. inflatum (37). To generate the deletion vectors, the 5′- and 3′-flanking regions of the target gene were amplified by PCR using different primer pairs (see Table S2 in the supplemental material).…”

Entomopathogenic fungi: unconventional applications

“…It has been used in Chinese medicine for many years because of its antioxidant, anti-inflammatory, antitumor, and neuroprotective properties (Wang et al 2019b). As cordycepine is similar to adenosine in structure, it can inhibit processes in which adenosine is involved (Xia et al 2017). Cordycepin reduces osteoarthritis symptoms, i.e., synovial inflammation, joint pathology, and pain behavior (Ashraf et al 2019).…”

Comparative investigation into formycin A and pyrazofurin A biosynthesis reveals branch pathways for the construction ofC-nucleoside scaffolds

“…This intriguing co-biosynthetic phenomenon was also documented for other purine nucleoside antibiotics pairs, including pentostatin (PTN) and arabinofuranosyl adenine (Ara-A) (produced by Streptomyces antibioticus NRRL 3238) (11), 2’-Cl PTN and 2’-amino-2’-deoxyadenosine (produced by Actinomadura sp. ATCC 39365) (12), and fungus-produced PTN and cordycepin (13), which all employ an unusual but general protector-protégé strategy, i.e. PTN may protect Ara-A (taking this antibiotic-pair as example) from deamination by the housekeeping adenosine deaminase (11–13).…”

“…ATCC 39365) (12), and fungus-produced PTN and cordycepin (13), which all employ an unusual but general protector-protégé strategy, i.e. PTN may protect Ara-A (taking this antibiotic-pair as example) from deamination by the housekeeping adenosine deaminase (11–13).…”