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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.
A 2008 paper reports that it is also found in Ophiocordyceps sinensis. However, this study uses store-bought material labeled as O. sinensis without any molecular confirmation that it is indeed the species, unlike the later study reporting on its absence in this species.
It is also produced by Samsoniella hepiali (fungus identity confirmed by 18S rRNA) and Aspergillus nidulans Y176-2.
The biosynthetic cluster consists of four genes:
To produce cordycepin:
To produce pentostatin:
Cns4 is able to pump pentostatin out of the cell. One reasonable guess for its function would be that pumping out pentostatin allows cordycepin to be detoxified by deamination (cordycepin is toxic to the fungal cell in excessive concentrations).
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.
Because cordycepin is similar to adenosine, some cannot discriminate between the two. It can therefore participate in certain biochemical reactions (for example, 3-dA can trigger the premature termination of mRNA synthesis). Cordycepin has displayed cytotoxicity against some Leukemia 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 (at 1 hour before lights-out for; 1 hour before lights-on for phase delay) 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.
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.
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.
Biological activity
Cordyceps
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Biotechnology
There is a genome-scale metabolic model (GEM) 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 (over 7 days). The model-estimated maximal cordycepin production flux was 0.7 mmol/g/h.
Pharmacokinetics
Cordycepin readily crosses the blood-brain barrier. It has a very short half-life (between 1 and 2h in cell culture). Pentostatin greatly enhances its clock-resetting effects in cell cultures, likely by preventing deamination.
See also
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