Cordycepin
Cordycepin, or 3'-deoxyadenosine, is a derivative of the nucleoside adenosine, differing from the latter by the replacement of the hydroxy group in the 3' position with a hydrogen. It was initially extracted from the fungus Cordyceps militaris, but can now be produced synthetically.
Occurrence
It is also produced by Cordyceps kyusyuensis, but not by other insect pathogenic fungi such as C. bassiana, C. confragosa, C. takaomontana, Isaria fumosorosea, M. robertsii, and M. rileyi.Evidence for cordycepin in Ophiocordyceps sinensis has been mixed, and its presence in this species was long considered controversial. More recent analyses using authenticated material and sensitive methods have detected low but measurable amounts: an HPLC–MS/MS study quantified cordycepin at 0.0076–0.029% in authenticated wild material, a PLOS ONE comparison reported cordycepin in both cultivated and wild forms, and independent HPLC work found ~3 ppm in both wild and in‑vitro‑cultured O. sinensis mycelium. Overall, reported detection appears to be sample‑ and method‑dependent.
It is also produced by Samsoniella hepiali and Aspergillus nidulans Y176-2.
Biosynthesis
The biosynthetic genes for cordycepin were fully characterized in 2017. The same set of genes also produce pentostatin, another adenosine derivative. Pentostatin protects cordycepin from being deaminated in the fungus, allowing the latter to accumulate.The biosynthetic cluster consists of four genes:Cns1 is a oxidoreductase/dehydrogenase.Cns2 is a HDc-family metal-dependent phosphohydrolase. There is a binding interaction between Cns1 and Cns2.Cns3 is a bifunctional protein. It has an N-terminal nucleoside/nucleotide kinase domain and a C-terminal HisG-family ATP phosphoribosyltransferase domain.Cns4 is an ABC transporter, specifically of the putative pleiotropic drug resistance family.
To produce cordycepin:
- The NK domain of Cns3 converts adenosine into 3′-adenosine monophosphate.Cns2 removes a phosphate group from 3′-AMP and generates 2′-carbonyl-3′-deoxyadenosine.Cns1 reduces the carbonyl group on 2′-C-3′-dA into a hydroxyl group, yielding cordycepin.
- The HisG domain of Cns3 converts adenosine into pentostatin.
Intriguingly, the industrial fungus Acremonium chrysogenum features a gene cluster with high conservation with the Cns cluster, yet the fungus is not observed to produce cordycepin.
Biological activity
Cordyceps fungi produce cordycepin as a means of infecting insect populations, due to its biological activity. Precisely how it works in insects is unknown, but higher cordycepin production is associated with higher larval mortality and more fungus growth. When cordycepin is added to an insect infected by a fungus unable to produce cordycepin, the infection is also enhanced.Because cordycepin is similar to adenosine, some enzymes cannot discriminate between the two. It can therefore participate in certain biochemical reactions. Cordycepin has displayed cytotoxicity against some leukemic cell lines in vitro. Additionally, cordycepin displays an effect in cancers, such as lung, renal, colon, and breast cancer. Cordycepin reduces viable A549 lung cancer cell populations by 50%.
By acting at RUVBL2, cordycepin is the most potent molecular circadian clock resetter out of several screened compounds. In mice, administration of cordycepin greatly accelerated the adaptation to 8-hour jet lags.
Cordycepin produces rapid, robust imipramine-like antidepressant effects in animal models of depression, and these effects, similarly to those of imipramine, are dependent on enhancement of AMPA receptor signaling. Increased amounts of GSK3β and β-catenin could be another mechanism. Yet another article argues for a role of the gut microbiome while also showing an effect on adipose tissue.
Cordycepin has anti-inflammatory qualities, as well as the ability to defend against injury from cerebral ischemia in mice.
Biotechnology
There is a genome-scale metabolic model of Cordyceps militaris called iNR1329. It has been used to find the optimal media C:N ratio for fast growth and cordycepin overproduction of the fungus, at 8:1, with glucose as the carbon source and ammonia as the nitrogen source. The maximal extracellular cordycepin production achieved at the level was 0.3776 g/L. The model-estimated maximal cordycepin production flux was 0.7 mmol/g/h.Wild-type Samsoniella hepiali in submerged cultivation at 25 °C yields 0.26 mg/g over 5 days. With radiation mutagenesis and screening, a mutant strain "ZJB18001" that produces 0.61 mg/g was found.