December 12, 2022

Curing African Sickness Using Biological Trojan Horse

On my previous post, I mentioned that I will be shariing some of the topics on my #RoadToMSChemistry Journey. Here is one of the topics and this is how it was written including the references.

Curing African Sickness Using Biological Trojan Horse

When we hear or read the word Trojan Horse, we usually referred to the wooden horse used by the Greeks during the Trojan War. However, in the modern era, it is known as a computer malware that mimics a legitimate program ending up with phishing and spying of a computer’s content. (“What Is a Trojan Horse? Trojan Virus and Malware Explained”).

‌Since Trojan Horse is related to a virus, how about living things- humans and animals? Can there be also the so-called biological Trojan Horse?

Studying enzymes, particularly in irreversible inhibitors, lead to the discovery of new drugs and is considered to be one of the Biological Trojan Horses. These inhibitors react by attaching themselves to the functional groups of enzymes which are responsible for the primary enzyme’s activity. Once the covalent bond was formed between the active sites of the enzyme and irreversible inhibitor, the former will be deactivated halting the cell’s growth and reproduction (Nelson 571–572).

One type of irreversible inhibitor is the suicide inactivator or also called mechanism-based inactivators. These inactivators react only upon binding with the enzyme’s active site. Upon reacting with the active site, instead of producing a common product from an enzymatic reaction, it will create a highly reactive substance that will combine and inactivates the enzyme.

How do these Biological Trojan Horses use in the field of medicine? One example of the study of enzymes and suicide inactivators is in the treatment of African Sleeping Sickness.

African Sleeping Sickness, is commonly observed in the East and West parts of the African Continent. It is caused by a unicellular protozoan trypanosome (T. brucei rhodesience and T. brucei gambiense,) carried by the tsetse fly (Pascholati et al.). At first, this illness is manageable not until the late 20th century. With the continuous changes in the virus’ protection coat or antigen, vaccines are no longer effective as they should be (Nelson 571–72).

One mechanism studied in the treatment of African Sleeping Sickness is the reaction catalyzed by ornithine decarboxylase with diflouromethylornithine (DMFO) as suicide inactivators (Reddy, ch.2).

How does the reaction go?

Figure 1. ODC-catalyzed biosynthesis pathway forming putrescine and regeneration of PLP.

The primary step in decarboxylation of ornithine, with pyridoxal phosphate (PLP) as a co-factor, is the formation of Schiff base, an imine intermediate. This will go a rapid reaction forming putrescine, diamime and regenerates PLP (Figure 1) (Reddy, ch.2)

Putrescine is the diamine needed in the biosynthesis as precursor of polyamines spermine and spermidine which is an essential part of eukaryotic cells (Poulin et al.). 

The presence of a suicide inactivator diflouromethylornithine (DMFO) in the reaction with PLP forms a Schiff base which proceeds with the elimination of fluorine atom and carbon dioxide forming a secondary metabolite flouroolefin derivative. This terminal flouroolefin part will become highly reactive with the nuclephilic thiol residue at the enzyme’s active site. This will undergo Michael’s addition followed by a fast elimination of the fluorine atom forming an inactivated enzyme (Figure 2)(Reddy, ch.2).

Figure 2. Reaction pathway of DFMO and PLP forming a highly reactive Schiff base. Upon further reaction with the enzyme active site, it will for an inactivated ezyme.

With the continuous study and research in enzymology and metabolism, more and more drugs or treatments will be discovered especially to the diseases that are currently incurable. Although it will take several times, Biological Trojan Horses are just around the corner waiting to be found.

References:

Nelson, David. Lehninger Principles of Biochemistry. 7th ed., W.H. Freeman, 2017.


Pascholati, CauĂȘ P., et al. “The Interaction of an Antiparasitic Peptide Active against African Sleeping Sickness with Cell Membrane Models.” Colloids and Surfaces B: Biointerfaces, vol. 74, no. 2, 2009, pp. 504–10. Crossrefhttps://doi.org/10.1016/j.colsurfb.2009.08.018.


Poulin, R., et al. “Mechanism of the Irreversible Inactivation of Mouse Ornithine Decarboxylase by Alpha-Difluoromethylornithine. Characterization of Sequences at the Inhibitor and Coenzyme Binding Sites.” Journal of Biological Chemistry, vol. 267, no. 1, 1992, pp. 150–58. Crossrefhttps://doi.org/10.1016/s0021-9258(18)48472-4.


Reddy, Prakash. Organofluorine Compounds in Biology and Medicine. Elsevier Gezondheidszorg, 2015.


“What Is a Trojan Horse? Trojan Virus and Malware Explained.” Fortinet, www.fortinet.com/resources/cyberglossary/trojan-horse-virus. Accessed 17 Mar. 2022.



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