How does cordycepin work?

Throughout this article, we'll be referencing two scientific papers. One is a paper we did a video review of in Cordyceps Chronicles Episode 2. This is a 2014 paper titled: Pharmacological and therapeutic potential of Cordyceps with special reference to Cordycepin. 
The other article is a 2019 paper titled: A novel nucleoside rescue metabolic pathway may be responsible for therapeutic effect of orally administered cordycepin.
When referencing the 2014 paper in the article, I will refer to this as "the 2014 paper". When referencing the 2019 paper, I will refer to this as "the 2019 paper".

Simple enough right?

If you are a science nerd like myself and are curious as to how cordycepin impacts biological systems at a molecular level, this article is for you. Certain sections of this article will have a timestamp. If there is a timestamp, this means the section written about is discussed further in the second episode of Cordyceps Chronicles. The time next to the section header is the point in the video where this information is discussed.

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Cordycepin and adenosine are nearly identical from a chemical perspective (see figure below). This similarity plays a role in many of cordycepin's therapeutic effects. The only difference being that cordycepin lacks a hydroxyl (-OH) group.

Figure - The chemical similarities of cordycepin and adenosine

Before we look at how cordycepin interacts with cellular processes inside a cell, we'll take a look at how cordycepin is absorbed into the bloodstream.

Oral Intake of Cordycepin
When consumed orally, cordycepin doesn't enter the bloodstream in its original form. The 2019 paper highlighted that after oral consumption, virtually no cordycepin is detected in the blood. Instead, it gets transformed into a related compound called 3′-deoxyinosine. This transformation happens through a process called deamination, where cordycepin sheds an amino group (-NH2). Intriguingly, once 3′-deoxyinosine is taken up by cells from the blood, it can revert back to cordycepin or its related forms (cordycepin mono, di, or triphosphate). These forms can then interact with various molecular pathways, potentially offering therapeutic benefits.
The figure below is from the 2019 paper. It gives a visualization of cordycepin being converted to 3'-deoxyinosine by shedding an amino group, then 3'-deoxyinosine being converted to 3'-deoxyinosine monophosphate by adding a phosphate group, and then 3'-deoxyinosine monophosphate being converted to different forms of cordycepin by adding back the phosphate groups.

Figure 5 from 2019 paper - Proposed Metabolic Pathways of Cordycepin

Amino Group

Phosphate Group
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The chemical evolution of cordycepin after it is ingested orally:

- Oral ingestion of cordycepin or 3'-deoxyadenosine
- Adenosine Deaminase enzyme removes amino group from cordycepin (3'-deoxyadenosine) through deamination process transforming cordycepin (3'-deoxyadenosine) to 3'-deoxyinosine. 3'-deoxyinosine is found in the bloodstream.

- Cells take in 3'-deoxyinosine from bloodstream and convert 3'-deoxyinosine to 3'-deoxyinosine monophosphate by adding a phosphate group through a process called phosphorylation.

- 3'-deoxyinosine monophosphate is converted to either cordycepin mono, di, or triphosphate within the cell by adding an amino group through an amination process. These phosphorylated cordycepin or 3'-deoxyadenosine compounds are what evoke the therapeutic effects within the cell.

How does cordycepin, once inside a cell, interact with and influence cellular processes?

How cordycepin inhibits the purine biosynthesis pathway (2:48)
When cordycepin or its derivative, 3′-deoxyinosine, enters a cell, it transforms into forms with one (mono), two (di), or three (tri) phosphate groups attached. These modified forms of cordycepin inhibit certain enzymes essential for synthesizing purines. Purines, like adenine and guanine, form the foundation of DNA and RNA and play roles in energy transfer and various biochemical reactions within cells. By inhibiting these enzymes, cordycepin disrupts the cell's ability to produce purines, potentially affecting cellular division and growth. This interference with purine production might explain one of the ways cordycepin achieves its therapeutic effects.

How cordycepin interferes with the cellular transcription process (3:51)
Transcription is when a cell copies a specific section of DNA into a corresponding RNA molecule. Cordycepin closely resembles adenosine but lacks a hydroxyl (-OH) group (see figure above). Due to this similarity, some enzymes mistakenly incorporate cordycepin instead of adenosine during transcription. When cordycepin gets added, its missing hydroxyl group prevents the RNA chain from growing further, causing an early stop in the RNA-making process. This unique ability of cordycepin to interrupt transcription contributes to its potential anti-inflammatory, anticancer, and antitumor therapeutic effects.

How cordycepin interferes in mTOR signal transduction (4:45)
mTOR, which stands for "mammalian target of rapamycin," is an enzyme that regulates vital cellular processes, including cell growth and protein synthesis. Signal transduction allows a cell to sense changes in its environment and respond accordingly. The mTOR signaling pathway is intricate and responds to various factors, including proteins that promote cell growth and division, nutrients like amino acids or glucose, and hormones in the bloodstream. Under certain conditions, cordycepin activates a molecule known as AMP-activated protein kinase (AMPK). AMPK then inhibits mTOR-related processes, such as protein synthesis, cell growth, and cell division. This inhibition of mTOR processes is one of the ways cordycepin might produce its therapeutic effects.

So there you have it!

You've just delved into the intricate molecular world of cordycepin. Keep in mind, cordycepin research is still in its early stages in the western world. At Bffd, part of our mission is to further encourage the study and research of cordyceps and cordycepin.

Key takeaways:
- Cordycepin and adenosine are molecularly similar, but cordycepin lacks a hydroxyl (-OH) group
- Cordycepin is also known as 3'-deoxyadenosine
- After oral intake, cordycepin mostly transforms into 3′-deoxyinosine before entering the bloodstream
- Inside cells, 3'-deoxyinosine can transform to 3'-deoxyinosine monophosphate and then to cordycepin mono, di, or triphosphate
- Cordycepin's therapeutic actions include:
-- Purine production inhibition
-- Cellular transcription process interference
-- mTOR signal transduction disruption

Thank you for reading!

Check out episode 2 of the Cordyceps Chronicles here
Here is the link to the slides from episode 2 
Here is the link to the 2014 paper 
Here is the link to the 2019 paper 
I had a conversation with ChatGPT when creating this blog post... 
See this conversation and continue on with it here

Much love,

Johnny