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Cordycepin

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Cordycepin
Names
IUPAC name
3′-Deoxyadenosine
Systematic IUPAC name
(2S,3R,5S)-2-(6-Amino-9H-purin-9-yl)-5-(hydroxymethyl)oxolan-3-ol
Other names
Cordycepine
9-(3-Deoxy-β-D-ribofuranosyl)adenine
3-dA
Identifiers
3D model (JSmol)
ChEMBL
ChemSpider
ECHA InfoCard 100.000.720 Edit this at Wikidata
UNII
  • InChI=1S/C10H13N5O3/c11-8-7-9(13-3-12-8)15(4-14-7)10-6(17)1-5(2-16)18-10/h3-6,10,16-17H,1-2H2,(H2,11,12,13)/t5-,6+,10+/m0/s1 ☒N
    Key: OFEZSBMBBKLLBJ-BAJZRUMYSA-N ☒N
  • O[C@@H]1C[C@@H](CO)O[C@H]1N2C(N=CN=C3N)=C3N=C2
  • n2c1c(ncnc1n(c2)[C@@H]3O[C@@H](C[C@H]3O)CO)N
Properties
C10H13N5O3
Molar mass 251.246 g·mol−1
Melting point 225.5 °C (437.9 °F; 498.6 K)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
☒N verify (what is checkY☒N ?)

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,[1] but can now be produced synthetically.[2]

Occurrence

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It is also produced by Cordyceps kyusyuensis (a close relative of C. militaris), but not by other insect pathogenic fungi such as C. bassiana, C. confragosa, C. takaomontana, Ophiocordyceps sinensis, Isaria fumosorosea, M. robertsii, and M. rileyi.[3]

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]

It is also produced by Samsoniella hepiali (fungus identity confirmed by 18S rRNA)[5] and Aspergillus nidulans Y176-2.[3][6]

Biosynthesis

[edit]

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.

To produce cordycepin:[3]

  • The NK domain of Cns3 converts adenosine into 3′-adenosine monophosphate (3′-AMP, different from the more common 5′-AMP).
  • Cns2 removes a phosphate group from 3′-AMP and generates 2′-carbonyl-3′-deoxyadenosine (2′-C-3′-dA).
  • Cns1 reduces the carbonyl group on 2′-C-3′-dA into a hydroxyl group, yielding cordycepin.

To produce pentostatin:[3]

  • 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

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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

[edit]

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/gDW/h.[23]

Wild-type Samsoniella hepiali in submerged cultivation at 25 °C yields 0.26 mg/gDCW over 5 days. With radiation mutagenesis and screening, a mutant strain "ZJB18001" that produces 0.61 mg/g was found.[5]

Pharmacokinetics

[edit]

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]

See also

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References

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  1. ^ Cunningham, K. G., Manson, W., Spring, F. S., Hutchinson, S. A. (1950). "Cordycepin, a Metabolic Product isolated from Cultures of Cordyceps militaris (Linn.) Link". Nature. 166 (4231): 949. Bibcode:1950Natur.166..949C. doi:10.1038/166949a0. PMID 14796634.
  2. ^ Huang S, Liu H, Sun Y, Chen J, Li X, Xu J, Hu Y, Li Y, Deng Z, Zhong S (2018-01-01). "An effective and convenient synthesis of cordycepin from adenosine". Chemical Papers. 72 (1): 149–160. doi:10.1007/s11696-017-0266-9. ISSN 1336-9075. S2CID 90915876.
  3. ^ a b c d e f g h i 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.
  4. ^ 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. PMID 19051361.
  5. ^ a b Cai X, Jin JY, Zhang B, Liu ZQ, Zheng YG (2021-11-01). "Improvement of cordycepin production by an isolated Paecilomyces hepiali mutant from combinatorial mutation breeding and medium screening". Bioprocess and Biosystems Engineering. 44 (11): 2387–2398. doi:10.1007/s00449-021-02611-w. ISSN 1615-7605. PMID 34268619. S2CID 235917116.
  6. ^ 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.
  7. ^ https://www.mdpi.com/2076-2607/9/4/681
  8. ^ Siev, M., Weinberg, R., Penman, S. (1969). "The selective interruption of nucleolar RNA synthesis in HeLa cells by cordycepin". J. Cell Biol. 41 (2): 510–520. doi:10.1083/jcb.41.2.510. PMC 2107749. PMID 5783871.
  9. ^ Kondrashov A, Meijer HA, Barthet-Barateig A, Parker HN, Khurshid A, Tessier S, et al. (2012). "Inhibition of polyadenylation reduces inflammatory gene induction". RNA. 18 (12): 2236–50. doi:10.1261/rna.032391.112. PMC 3504674. PMID 23118416.
  10. ^ National Cancer Institute (2011-02-02). "Definition of cordycepin". NCI Drug Dictionary. Retrieved 21 December 2015.
  11. ^ Kodama E, McCaffrey R, 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. PMID 10609556.
  12. ^ Chou S, Lai W, Hong T, Lai J, Tsai S, Chen Y, Yu S, Kao C, Chu R, Ding S, Li T, Shen T (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. PMID 25442260.
  13. ^ a b Tuli HS, Kumar G, Sandhu SS, Sharma AK, Kashyap D (2015). "Apoptotic effect of cordycepin on A549 human lung cancer cell line". Turkish Journal of Biology. 39: 306–311. doi:10.3906/biy-1408-14.
  14. ^ Hwang IH, Oh SY, Jang HJ, Jo E, Joo JC, Lee KB, Yoo HS, Lee MY, Park SJ, Jang IS (2017-10-18). Ahmad A (ed.). "Cordycepin promotes apoptosis in renal carcinoma cells by activating the MKK7-JNK signaling pathway through inhibition of c-FLIPL expression". PLOS ONE. 12 (10): e0186489. Bibcode:2017PLoSO..1286489H. doi:10.1371/journal.pone.0186489. ISSN 1932-6203. PMC 5646797. PMID 29045468.
  15. ^ Lee SY, Debnath T, Kim SK, Lim BO (October 2013). "Anti-cancer effect and apoptosis induction of cordycepin through DR3 pathway in the human colonic cancer cell HT-29". Food and Chemical Toxicology. 60: 439–447. doi:10.1016/j.fct.2013.07.068. PMID 23941773.
  16. ^ Lee D, Lee WY, Jung K, Kwon Y, Kim D, Hwang G, Kim CE, Lee S, Kang K (2019-08-26). "The Inhibitory Effect of Cordycepin on the Proliferation of MCF-7 Breast Cancer Cells, and Its Mechanism: An Investigation Using Network Pharmacology-Based Analysis". Biomolecules. 9 (9): 414. doi:10.3390/biom9090414. ISSN 2218-273X. PMC 6770402. PMID 31454995.
  17. ^ a b 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. PMID 32376767. S2CID 218533423.
  18. ^ Li B, Hou Y, Zhu M, Bao H, Nie J, Zhang GY, Shan L, Yao Y, Du K, Yang H, Li M, Zheng B, Xu X, Xiao C, Du J (2016). "3'-Deoxyadenosine (Cordycepin) Produces a Rapid and Robust Antidepressant Effect via Enhancing Prefrontal AMPA Receptor Signaling Pathway". International Journal of Neuropsychopharmacology. 19 (4): pyv112. doi:10.1093/ijnp/pyv112. ISSN 1461-1457. PMC 4851261. PMID 26443809.
  19. ^ 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.
  20. ^ Jing X, Hong F, Xie Y, Xie Y, Shi F, Wang R, Wang L, Chen Z, Liu Xa (December 2023). "Dose-dependent action of cordycepin on the microbiome-gut-brain-adipose axis in mice exposed to stress". Biomedicine & Pharmacotherapy. 168: 115796. doi:10.1016/j.biopha.2023.115796.
  21. ^ Tan L, Song X, Ren Y, Wang M, Guo C, Guo D, Gu Y, Li Y, Cao Z, Deng Y (March 2021). "Anti-inflammatory effects of cordycepin: A review". Phytotherapy Research. 35 (3): 1284–1297. doi:10.1002/ptr.6890. ISSN 0951-418X. PMID 33090621. S2CID 224828245.
  22. ^ Cheng Z, He W, Zhou X, Lv Q, Xu X, Yang S, Zhao C, Guo L (2011-08-16). "Cordycepin protects against cerebral ischemia/reperfusion injury in vivo and in vitro". European Journal of Pharmacology. 664 (1): 20–28. doi:10.1016/j.ejphar.2011.04.052. PMID 21554870.
  23. ^ Raethong N, Wang H, Nielsen J, Vongsangnak W (2020). "Optimizing cultivation of Cordyceps militaris for fast growth and cordycepin overproduction using rational design of synthetic media". Computational and Structural Biotechnology Journal. 18: 1–8. doi:10.1016/j.csbj.2019.11.003. PMC 6926140. PMID 31890138.
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