Hi everyone and welcome to this week's blog article. This week, I will be discussing the use of enzyme inhibition in chemotherapy. I will first explain what enzyme inhibition is and how it works, before moving onto its uses in cancer therapy and epilepsy, as well as its controversial use in pesticides.
Enzymes, as I'm sure you all know, are proteins that act as biological catalysts, speeding up the rate of reactions by providing an alternative energy pathway with a lower activation energy. For that reason, enzymes are essential to life as they speed up reactions that normally happen too slowly to support life.
Nevertheless, the function and effectiveness of these enzymes can be reduced, either purposely by the body itself, or by foreign bodies such as pathogens or toxins. This inhibition can broadly be split into two types - competitive inhibition and non-competitive inhibition.
Competitive inhibition occurs when an inhibitor "competes" with a substrate to enter the active site. As such, since the active site is occupied by the inhibitor, the substrate can't enter and be broken down into products, and thus the rate of reaction is decreased. Nevertheless, the effect of a competitive inhibitor can be reversed by increasing the substrate concentration. This is because the inhibitor is 'diluted' with substrate, thus making it more likely that a substrate will bind to the enzyme before the inhibitor.
Meanwhile, non-competitive inhibition occurs when an inhibitor binds to a different area of the enzyme called the allosteric site. When a non-competitive inhibitor binds to the allosteric site, it causes a conformational change in the 3D shape of the active site of the enzyme, thus preventing any substrates from entering the active site. As such, since it doesn't compete with the substrate to enter the active site, increasing the substrate concentration has no effect on the rate of reaction. Moreover, while what I have described is known as allosteric inhibition, allosteric activation can also occur. This is where the active site is altered in its normal state (before an activator binds to it). When an activator binds to the allosteric site, the shape of the active site is changed to be complementary to the shape of the substrate, thus allowing the reaction to be catalysed.
The most common uses of enzyme inhibitors are as medicinal drugs, especially to treat cancer. To understand how certain types of chemotherapy drug use enzyme inhibition to treat cancer, we first must explain how chemotherapy drugs work. These drugs work by targeting cells at different stages in the cell cycle (the process of forming new cells in the body). As cancerous cells replicate faster than non-cancerous ones, we can target them with drugs that influence the cell cycle. However, as chemotherapy medication can't distinguish between cancerous and non-cancerous cells, the non-cancerous cells are also damaged causing side effects.
One specific group of chemotherapy drugs are called anti-tumour antibiotics. Despite their name, anti-tumour antibiotics are not like other antibiotics which target bacterial infections. Instead, they work by disrupting DNA inside cells, thus slowing the growth and multiplication of these cancerous cells. One major group of anti-tumour antibiotics is called anthracyclines. Anthracyclines specifically inhibit the enzymes responsible for copying DNA during the cell cycle, thus preventing cancerous cells from both dividing and growing by producing more protein.
Nevertheless, the first modern anticancer drugs were antifolates, which represented the first use of enzyme inhibition in chemotherapy. Antifolates, such as methotrexate (which is used to treat bone cancer), are named as they have very close structural similarity with folic acid. Folic acid is the substrate that is accepted by the enzyme dihydrofolate reductase, which is responsible for making nucleotides. However, methotrexate is a competitive inhibitor of dihydrofolate reductase, thus preventing the enzyme from speeding up the production of nucleotides, thus restricting protein synthesis and DNA replication. While this does affect normal cells as well, as cancerous cells replicate faster, they are affected more.
On the other hand, anti-epileptic drugs are not enzyme inhibitors. Instead, they work by either increasing or decreasing the production of the necessary enzymes themselves, thus affecting the rate of reaction.
Enzyme inhibitors are also used more widely, for a variety of uses, including for many pesticides. One such pesticide blocks the function of the enzyme acetylcholinesterase. Acetylcholinesterase is essential to nervous function as it is responsible for breaking down acetylcholine (a neurotransmitter). Because of this, pesticides which inhibit acetylcholinesterase can paralyse the nervous system of insects.
Furthermore, some of these inhibitors, such as those found in organophosphate pesticides, are irreversible, causing permanent damage to the nervous system. This, however, can be incredibly dangerous for human life, as since acetylcholine is important both for insect and the human immune system, if these 'paralysing agents' spread to humans, then they can cause catastrophic damage to human life. Indeed, in 2013 a study was conducted on 423 patients who had been diagnosed with acute insecticide poisoning, due to accidental inhalation and skin contact. Of the 372 adults in the study, 138 had severe poisoning of their blood samples, thus confirming how deadly enzyme inhibition based pesticides can be.
In conclusion, enzyme inhibitors are essential to our lives, both in natural and artificial terms. Furthermore, research into inhibiting telomerase (an enzyme involved in production of telomeres), while at an early stage, clearly underlines how the science behind enzyme inhibition can be used to prevent cancer (as telomerase is produced in vast quantities by cancerous cells). Nevertheless, this research is still in early stages. Moreover, we must think carefully of the consequences that having enzyme inhibitors in pesticides can have and reflect on how we can minimise the possible threat.
Sources:
Comments