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,[4] unlike the later study reporting on its absence in this species.[3]
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.[3]
The biosynthetic cluster consists of four genes:[3]
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 (9–101 aa) nucleoside/nucleotide kinase (NK) domain and a C-terminal (681-851 aa) HisG-family ATP phosphoribosyltransferase domain.
Cns4 is an ABC transporter, specifically of the putative pleiotropic drug resistance (PDR) family.
The HisG domain of Cns3 converts adenosine into 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).[3]
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.[3]
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.[7]
Because cordycepin is similar to adenosine, some enzymes 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).[8][9] Cordycepin has displayed cytotoxicity against some leukemic cell lines in vitro.[10][11][12] Additionally, cordycepin displays an effect in cancers, such as lung,[13] renal,[14] colon,[15] and breast cancer.[16] Cordycepin reduces viable A549 lung cancer cell populations by 50%.[13]
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.[17]
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.[18] Increased amounts of GSK3β and β-catenin could be another mechanism.[19] Yet another article argues for a role of the gut microbiome while also showing an effect on adipose tissue.[20]
Cordycepin has anti-inflammatory qualities,[21] as well as the ability to defend against injury from cerebral ischemia in mice.[22]
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 0.3776g/L (over 7 days). The model-estimated maximal cordycepin production flux was 0.7mmol/gDW/h.[23]
Wild-type Samsoniella hepiali in submerged cultivation at 25°C yields 0.26mg/gDCW over 5 days. With radiation mutagenesis and screening, a mutant strain "ZJB18001" that produces 0.61mg/g was found.[5]
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.[17]
1 2 3 4 5 6 7 8 9 Xia Y, Luo F, Shang Y, Chen P, Lu Y, Wang C (December 2017). "Fungal Cordycepin Biosynthesis Is Coupled with the Production of the Safeguard Molecule Pentostatin". Cell Chemical Biology. 24 (12): 1479–1489.e4. doi:10.1016/j.chembiol.2017.09.001. PMID29056419.
↑ Zhou X, Luo L, Dressel W, Shadier G, Krumbiegel D, Schmidtke P, Zepp F, Meyer CU (2008). "Cordycepin is an immunoregulatory active ingredient of Cordyceps sinensis". The American Journal of Chinese Medicine. 36 (5): 967–80. doi:10.1142/S0192415X08006387. PMID19051361.
↑ Wu P, Wan D, Xu G, Wang G, Ma H, Wang T, Gao Y, Qi J, Chen X, Zhu J, Li YQ, Deng Z, Chen W (February 2017). "An Unusual Protector-Protégé Strategy for the Biosynthesis of Purine Nucleoside Antibiotics". Cell Chemical Biology. 24 (2): 171–181. doi:10.1016/j.chembiol.2016.12.012. PMID28111097.
↑ National Cancer Institute (2 February 2011). "Definition of cordycepin". NCI Drug Dictionary. Retrieved 21 December 2015.
↑ Kodama E, McCaffrey RP, Yusa K, Mitsuya H (February 2000). "Antileukemic activity and mechanism of action of cordycepin against terminal deoxynucleotidyl transferase-positive (TdT+) leukemic cells". Biochemical Pharmacology. 59 (3): 273–281. doi:10.1016/S0006-2952(99)00325-1. PMID10609556.
↑ Chou S, Lai WJ, Hong TW, Lai JY, Tsai SH, Chen Y, Yu SH, Kao CH, Chu R, Ding ST, Li TK, Shen TL (October 2014). "Synergistic property of cordycepin in cultivated Cordyceps militaris-mediated apoptosis in human leukemia cells". Phytomedicine. 21 (12): 1516–1524. doi:10.1016/j.phymed.2014.07.014. PMID25442260.
1 2 Ju D, Zhang W, Yan J, Zhao H, Li W, Wang J, Liao M, Xu Z, Wang Z, Zhou G, Mei L, Hou N, Ying S, Cai T, Chen S, Xie X, Lai L, Tang C, Park N, Takahashi JS, Huang N, Qi X, Zhang EE (6 May 2020). "Chemical perturbations reveal that RUVBL2 regulates the circadian phase in mammals". Science Translational Medicine. 12 (542): eaba0769. doi:10.1126/scitranslmed.aba0769. PMID32376767. S2CID218533423.
↑ Wang Y, Deng Y, Feng M, Chen J, Zhong M, Han Z, Zhang Q, Sun Y (January 2025). "Cordycepin Extracted from Cordyceps militaris mitigated CUMS-induced depression of rats via targeting GSK3β/β-catenin signaling pathway". Journal of Ethnopharmacology. 340 119249. doi:10.1016/j.jep.2024.119249. PMID39689748.
This page is based on this Wikipedia article Text is available under the CC BY-SA 4.0 license; additional terms may apply. Images, videos and audio are available under their respective licenses.