Erythropoietin Extra credit report (699 word count) Introduction to Biochemistry Michael Prentice April 26, 2017

Erythropoietin (EPO) is naturally occurring protein hormone the body uses every day, however, its abuse

in synthetic form is a type of blood doping that has been the subject of many recent sporting fraud

cases, most notably, multiple Tour de France winner Lance Armstrong, but has also been abused in other

sporting venues, particularly the Olympic games (1).

Erythropoietin is a type I cytokine protein hormone which is created primarily in the kidney but also less

so in the liver (2). Endogenous EPO was first isolated in 1977, and its gene was first cloned in 1985.The

gene for human erythropoietin is located at chromosome 7q11-22. It is composed of four introns and

five exons, resulting in a post-transcriptional single polypeptide of 193 amino acids. This single amino

acid backbone undergoes post-translational modification whereby one O-glycosylation and three

N-glycosylation sites are added and 28 amino acids are removed. This results in the final primary

structure of mature EPO containing 165 amino acids in a polypeptide chain with a molecular mass

estimated to be 30 kilodaltons (3).

EPO primary structure (4)

 

 

EPO folds into a globular three-dimensional structure consisting of four amphipathic α helices connected

by loops that lack secondary structure. The structure is stabilized by a disulphide bridge between the

amino-terminal and carboxy-terminal helices (5).

EPO ribbon structure (6)

EPO acts on erythrocytes, commonly known as red blood cells, which are disc-shaped cells that are

responsible for carrying oxygen via embedded hemoglobin throughout the body (7). When oxygen is

inhaled through the lungs, it is delivered to red blood cells and carried to cells for use in metabolism, and

the resulting carbon dioxide is then returned to the lungs for exhalation via the same red blood cells (8).

Erythrocyte (9)

Red blood cells are created in the bone marrow and in order to manufacture these red blood cells the

body uses EPO. EPO specifically targets erythroid progenitors in the bone marrow to cause maturation

into erythrocytes (3). EPO is a component of blood plasma and has a half-life of approximately 7 to 8

hours. It binds to receptors that are present in relatively small numbers (approximately 1000/cell) on the

surface of the erythroid progenitor cells. The EPO signal transduction pathway follows the classical

transduction pathway where EPO binds to an EPOR homo-dimer leading to activation of the signaling

cascade. The main signaling pathways activated by EPO are the JAK2/STAT5 pathway, protein kinase C

(PKC) pathway, RAS/MAP kinase pathway, and the phosphatidylinositol 3-kinase (PI3K) pathway (10).

 

 

EPO transduction pathway (10)

If the body does not create enough red blood cells, a condition called anemia ensues. Anemia can be

caused by several factors, one of which is low EPO production. An artificially synthesized form of EPO,

recombinant erythropoietin, can be administered via injection in patients suffering from anemia.

Recombinant erythropoietin is categorized as an erythropoietin-stimulating agent (ESA). Patients

undergoing chemotherapy or suffering from renal (kidney) failure are the most common recipients of

this drug, although other patients, such as those who refuse blood transfusions, also receive EPO

treatments (8).

 

 

EPO – erythrocyte cycle (11)

Similar to anemic patients, athletes use EPO in order to increase the number of oxygen carrying

erythrocytes circulating in their body. This increases their ability to metabolize the delivered oxygen and

gives them an unfair advantage over their competition (12).

References

1. http://www.theverge.com/2013/1/17/3886424/programming-your-body-lance-armstrong-and- doping-technology (Accessed April 26, 2017)

2. http://www.rice.edu/~jenky/sports/epo.html (Accessed April 26, 2017)

3. John, M. J., Jaison, V., Jain, K., Kakkar, N., & Jacob, J. J. (2012). Erythropoietin use and abuse. Indian

Journal of Endocrinology and Metabolism, 16(2), 220–227. http://doi.org/10.4103/2230-8210.93739

4. Lappin, T. (2003). The Cellular Biology of Erythropoietin Receptors. The Oncologist 2003; 8:15-18;

doi:10.1634/theoncologist.8-suppl_1-15

5. Bunn, H. F. (2013). Erythropoietin. Cold Spring Harbor Perspectives in Medicine, 3(3), a011619.

6. https://www.mskcc.org/blog/msk-investigators-synthesize-vital-biological-molecule-erythropoietin-first-t ime (Accessed April 26, 2017)

7. https://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0022014/ (Accessed April 26, 2017)

8. https://my.clevelandclinic.org/health/articles/erythropoietin-stimulating-agents (Accessed April 26, 2017)

9. http://www.mhhe.com/biosci/esp/2001_saladin/folder_structure/tr/m1/s4/ (Accessed April 26, 2017)

10. Debeljak, N., Solár, P., & Sytkowski, A. J. (2014). Erythropoietin and Cancer: The Unintended

Consequences of Anemia Correction. Frontiers in Immunology, 5, 563.

http://doi.org/10.3389/fimmu.2014.00563

11. http://163.178.103.176/casosberne/4dcardiovascular/caso26-2/htmlc/casosb2/ulcera/hema1.html (Accessed April 26, 2017)

12. http://www.medicinenet.com/blood_doping/views.htm (Accessed April 26, 2017)