Alexandra S., Grade 12
*Terms for clarification can be found at the bottom of the article*
Whether it be in school or with friends or family, we all have definitely been in a situation where we felt out of control. This always brings a sense of unease, physically, emotionally, or even both. Now imagine feeling like this every day. Every step, every conversation, every action could result in an unintended or uncontrolled shake or tremor. And instead of getting better, your age worsens your symptoms.
Parkinson’s Disease stems from the lack of dopamine that is kept in the brain, a hormone which controls movement, speech, and overall emotions of happiness and relief. This occurs due to death of nerve cells in the basal ganglia (an area of the brain that controls movement and where dopamine is stored and synthesized). However, the reason for why these nerve cells die is still unknown for scientists, which is why examining the efficiency and method of modes for medicine is even more vital for this disease as it is the one form of hope that can be given to the patients in which this disease takes over.
This neurological disease is extremely prominent in our society today, affecting more than 10 million people worldwide today, and at least 200,000 of these reside in Germany alone. While it might be difficult to pick up on these symptoms as an individual when you are passing thousands of people per day, it is relevant to understand how this disease specifically works. By comprehending the biological differences between someone with Parkinson’s and someone without it, the disease no longer becomes an unknown, unnatural phenomenon. Instead, we are able to understand that there is just a difference in the biological processes occurring in this patient’s brain, and this plays no role in determining how we are to judge this person’s personality or identity.
Monoamine oxidase (MOA) was recognized as an enzyme of crucial interest to pharmacologists because it catalyzed the major inactivation pathway for the neurotransmitters, such as dopamine, noradrenaline and adrenaline.
Dopamine is released into the synaptic cleft but does not persist for long before it is re-taken by specific dopamine transporters such as Dihydroxyphenyl acetic acid in the pre-synaptic terminals. This is done by a specific enzyme with the name of mono-amine oxidase.
Monoamine Oxidase B (MOAB) is a dimer of two identical polypeptide chains each consisting of 520 amino acids. Approximately 31 of these amino acids form an alpha helix that is responsible for the integration into the mitochondrial outer layer membrane. This is also known as the membrane domain. Four amino acids in MAO-B are responsible for the separation of cavities of the enzyme’s active site*, one of these being called isoleucine.
Isoleucine acts as a gate, in the sense that it can be in an open/closed position, allowing substrates to move from the entrance cavity into the active substrate* cavity. The active site of each sub-unit of the amino acid contains such an entrance cavity and substrate cavity, and each subunit also contains a covalently bound FAD molecule*.
The main activity of MAO-B is driven by the oxidation of the FAD molecule, and its reactions with the substrate, which in this case, would be dopamine. The FAD reacts with the dopamine and allows for the breakdown of the subsequent breakdown of the neurotransmitter.
MAO-B’s structure allows for a close interaction between FAD and the substrate, which is known as the aromatic cage.
An enzyme inhibitor, such as that of the MAO-B inhibitor, is a molecule that disrupts the normal reaction pathway between an enzyme and a substrate. Enzyme inhibitors can either be competitive or non-competitive, depending on their method of action. In this case, the MAO-B inhibitor is a competitive inhibitor. This means that the inhibitor itself has a similar shape to the substrate, meaning that it is capable of binding to the active site of the enzyme as it is complementary to it. Therefore, fewer substrate molecules bind to the enzyme, so fewer enzyme-substrate complexes can form.
In the case of MAO-B, this infers that the MAO-B inhibitors have a similar shape to the dopamine which can bond to the MAO-B and restrict less dopamine from reacting with MAO-B, restricting the neurotransmitter from breaking down at the higher rate that it was originally being broken down.
The MOAB inhibitor will covalently bind to the FAD molecule and prevent its ability to transfer electrons from substrate to itself, which in turn prevent reactive oxygen species from being produced, and dopamine from being depleted and shuts down the catalytic activity of MAO-B.
The MAO-B inhibitors (MAOI’s) are usually taken either at early stages of Parkinson’s Disease, as well as with other drugs at any later stage. By inhibiting the amount of dopamine, which is converted, allowing for a larger amount of the neurotransmitter to remain in the patient’s system, it reduces the frequency of un-intended movements and allows the patient to feel more frequent emotions of happiness and relief.
The fluctuation of popularity for MAOI’s was primarily in early stages of producing treatments for Parkinson’s Disease, as the medicine was considered as the first real and effective antidepressant. While there was an influx in number of patients that was using such treatment in the past, other antidepressants are now highly preferred in our generation as the risks are simply too high.
Some food that we consume contains tyramine, another neurotransmitter which the MOAI’s also produce as a product of their metabolic process. Therefore, if one takes an MAOI and eats high-tyramine foods such as bananas, meat, cheese or beer, tyramine can quickly reach dangerous levels and cause a serious spike in blood pressure. This could consequently lead to the requirement of emergency treatment. As tyramine is found very easily in a large range of food and cannot be prevented by cooking such food in a specific way, MAOI’s became less and less popular, as the risks of a slight slip in diet while taking the medication was too dangerous of a threat.
Additionally, elderly patients with Parkinson’s Disease can lead to confusion and hallucinations, which can be extremely dangerous especially for a patient at an older age that stereotypically does not have the mental stability to be able to rationalize themselves out of such an impacting and terrifying experience.
Overall, while Parkinson’s Disease does initially sound overwhelming, having a basic understanding on the scientific processes behind the disease itself and on the mechanisms attempting to help patients carrying the disease allows our society to close this large gap between the “sick” and the “normal”. The science puts into perspective how this is truly not something that a patient should be judged about, as they cannot control what is going on in their heads.
MAO-B inhibitors are currently being used by numerous hospitals around the world for patients with Parkinson’s Disease, and while it might soon go out of date due to the advancements of more technologically developed cures, it is currently allowing patients to live more bearable lives. Despite the controversies that have to do with the side effects of the treatment, the inhibitors have been one of the most trustworthy, longstanding solutions to helping those with Parkinson’s Disease, and many lives would not have been saved without it.
Terms for Clarification:
FAD: redox-active coenzyme associated with various proteins, prosthetic group
Substrate: A molecule that an enzyme reacts with
Active site: The specific region of an enzyme where a substrate binds to, and a chemical reaction between the two occurs.
Image Source:
Unknown. “Monoamine Oxidase.” BOC Sciences, www.bocsci.com/tag/monoamine-oxidase-247.html. Accessed 27 Nov. 2023.