Unlocking The Lock And Key Mechanism That Governs Our Body’s Cellular Functions.
The idea of a lock and key mechanism was borne out of a need for security. We have valuables to safeguard. We have private issues that we don’t want to make public. We keep them locked up and hidden away. However, we do have keys to unlock those locks and gain access to our private stashes.
In the same way, a lot of the cells in our body communicate on a lock and key mechanism, which we can collectively term as “cell signalling”. Our cells have receptors on their surfaces, and specific biochemicals can bind to those receptors to signal them to do something.
For example, our cells possess insulin receptors. Insulin is produced by the beta cells in the pancreas when we consume food, and it then binds to the insulin receptor on the cell to signal the cell to take in glucose from the blood. In this situation, the presence of insulin unlocks the cell’s ability to take in glucose from the blood. Insulin stays in the insulin receptor for a specific period of time, which we call the residence time. After that period of residence, it disassociates from the receptor, which then reduces the cell’s ability to take in any more glucose from the blood.
Some enzymes also function on the lock and key mechanism. The enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (HMGCR), for instance, converts HMG-CoA into mevalonate, which is an important step in the biosynthesis of cholesterol in the body. In this case, HMG-CoA unlocks the activity of HMGCR, which then converts the HMG-CoA into mevalonate, and the mevalonate further unlocks other enzymes in the process for its conversion into cholesterol.
It is important to note that there can be different keys that can bind onto the lock receptor, much like how a thief can use a safety pin to unlock a car’s or house’s doors to steal valuables from the car or house. However, even though different things can fit into the lock, only some will be able to truly unlock the biochemical process that is contained within. Others will stay within the lock and prevent a biochemical process from occurring, which is what happens in drug development and discovery.
Chirality and Racemic Mixtures
Most biomolecules in our body are chiral in nature. They have similar chemical compositions, but their structural arrangements are different. For more information on chirality, this Youtube video serves as a good explanation:
Broadly speaking, we can classify simple chiral molecules as levorotatory (L, or rotating a plane of light leftwards) or dextrorotatory (D, or rotating a plane of light rightwards).
A normal chemical synthesis of these molecules results in a racemic mixture (approximately 50–50) of the L and D isomers, which are also known as stereoisomers or enantiomers.
To complicate matters further, these stereoisomers can also be classified as R (rectus) or S (sinister) molecules, which illustrates the configuration of the functional groups on the molecule instead of the direction of light rotation. This is especially more convenient for describing molecules that have more than 1 chiral centre.
Ibuprofen, for example, is marketed as a non-steroidal anti-inflammatory drug. The R-enantiomer is pharmacologically inactive, while the S-enantiomer is the one that inhibits the cyclooxygenase enzymes from proceeding with their pro-inflammatory biochemical pathways. Therefore, the S enantiomer fits into the cyclooxygenase enzyme lock, while the R doesn’t really do squat with the cyclooxygenase enzymes. The chirality of the molecule also plays a big role in the lock and key mechanism.
Cell signalling processes are highly regulated in a healthy human body. What happens when they fail?
In Type 1 diabetes, for instance, the beta cell population is mistakenly diagnosed by the immune system to be a dangerous invader and is killed off by the immune system. The surviving beta cells do not have enough insulin production capacity and are underproducing insulin. When there are insufficient keys to unlock all the locks, most cells will end up taking in less glucose than they are supposed to be taking in, leaving the leftover glucose to accumulate in the blood, which leads to diabetes over time.
Because the problem here is an underproduction of insulin, there are 2 ways to go about solving the problem:
- Rejig the immune system to not misdiagnose the beta cells as foreign invaders (which is next to impossible).
- Introduce constant insulin injections to bump up blood insulin levels (which is a more sane option as compared to Point 1). This is the usual style of managing Type 1 diabetes.
What do drugs do to the cell signalling process? (And what do they not do?)
I will highlight 3 different examples here:
- Statin treatment for cholesterol management.
- Antihistamines for runny noses and allergic reactions.
- Novel biologics drugs (such as monoclonal antibodies) that treat autoimmune disease flare ups.
Statin treatment for cholesterol management
Statins are a class of drugs that are used for treating people who are experiencing high cholesterol levels. What they do is that they can bind to the HMGCR receptor site, but they bind onto the HMGCR enzyme as a dead weight. They do not participate in any biochemical reaction.
However, the binding of the statin molecule to the HMGCR prevents HMG-CoA from binding to HMGCR and being converted into mevalonate. In this way, the synthesis of new cholesterol is prevented.
However, as mevalonate synthesis is also crucial for the synthesis of Coenzyme Q10 (CoQ10), blocking the mevalonate synthesis pathway not only reduces the synthesis rate of new cholesterol, it also reduces the synthesis rate of CoQ10. As a result, people taking statin drugs would also face side effects related to a decreased cellular level of CoQ10.
Also, statins only focus on the synthesis of fresh cholesterol. They don’t focus on how the body excretes cholesterol. Cholesterol is processed by the liver into bile salts, and these bile salts are dumped into the intestines for excretion. A portion of these bile salts will be reabsorbed back into the blood from the intestines.
So what do you think happens when one is facing constipation problems or problems with their liver function? Would statins alone help with their high blood cholesterol?
Antihistamines for runny noses and allergic reactions.
We know that histamines cause runny noses. Its mechanism of causing a runny nose, though, is also based on a lock and key situation. The histamine molecule binds to a histamine receptor in our nasal region, which then signals the nose to produce excessive amounts of mucus (hypersecretion). In fact, it’s not just mucus hypersecretion, but an allergic reaction, according to the University of Texas,
activates a series of events leading to increased vascular permeability and dilation, stimulation of nerve fibers and initiation of inflammatory cascades that are collectively responsible for the signs and symptoms of immediate hypersensitivity — itching, sneezing, increased mucus secretion (i.e. rhinorrhea, etc.), bronchospasm and, if enough vascular tissue is involved, hypotension.
An antihistamine is a molecule that mimics the shape of the histamine key and binds to the histamine receptor without triggering the mucus hypersecretion process.
In that way, we can consume antihistamines during a allergic reaction and be lulled into a false sense of security because the symptoms of the allergic reaction have been calmed down by blocking the histamine signalling process at the histamine receptors.
But no, once the antihistamine has unbound itself from the histamine receptor… If there are still histamines being produced from a triggering stimulus, then the runny nose/allergic reaction will rear its ugly head once again.
In an allergic reaction, what we do need to understand is the presence of mast cells. These cells contain many granules that are rich in histamines and interleukin cytokines. When allergens bind to the Immunoglobulin E (IgE) antibodies present on the surface of the mast cell, the mast cell releases its payload of histamines and interleukins to set off the allergic reaction.
However, even before that happens, we do see the effect of an increased activity in the IgE-producing B cells, which stem from an increased activity of the T helper 2 (Th2) cells. Certain interleukins that are released by the mast cell payload also do trigger the B cells to produce more IgE for a more pronounced allergic reaction the next time round. It’s a vicious positive feedback amplification loop that we’re looking at here.
In the background, there can be something wrong with the activity of the Th2 cells, the B cells, or the mast cells. The antihistamine drug does not interfere with or support any of their activities, but it focuses squarely on blocking the histamine receptor’s biological activity.
Now, is that why some people have such severe allergic reactions? Tiny amounts of peanuts are enough to cause death in small children. Would that be considered a cytokine storm? The jury is still out on that.
Novel biologics drugs such as monoclonal antibodies (MABs)
The MABs are an emergent player in the biologics drug markets these days. Adalimumab (marketed as Humira) is a MAB that is prescribed for the treatment of psoriasis, and the use of it for a year’s worth of treatment cost a psoriasis patient US$38,000 (2018 prices).
The pro-inflammatory cytokine tumour necrosis factor alpha (TNF-α) is one of the main biochemical agents in the body that contribute to the symptom of excessive skin cell (keratinocyte) growth. It does so by binding to a TNF-α receptor on the dendritic cell (a type of immune cell), which signals it to express an interleukin cytokine (IL-23) that accelerates the growth rate of keratinocytes. In fact, the dendritic cell also expresses IL-20, another interleukin cytokine that stimulates the activity of the T helper 17 (Th17) cell. The increased Th17 cell activity allows them to produce more interleukins (IL-17 and IL-22), which also aid in the acceleration of keratinocyte growth. In fact, the dendritic cell itself also produces its own TNF-α.
As excessive Th17 activity contributes to the development of autoimmune disorders, psoriasis can be considered to be an autoimmune disorder too.
Humira is an anti-TNF-α agent. It binds to the TNF-α receptor but does not trigger the dendritic cell to release the IL-20 or IL-23.
However, it does not deal with the question of why there is that much TNF-α present, and more worryingly — what else can that TNF-α do elsewhere?
TNF-α is produced by various immune cells such as an inflammatory signal to indicate that something is wrong somewhere. When there isn’t any problem, the blood concentration of TNF-α ought to be low. However, there are situations when TNF-α levels are elevated, such as in the case of an infection or an injury. The symptoms of swelling, pain and discomfort in a sprained ankle, for instance, can be pinpointed to the elevated concentrations of TNF-α in our blood. When the sprained ankle is healed, the blood concentration of TNF-α ought to go back to its original low levels.
The problem, then, is that our poor lifestyle choices can mess with the levels of TNF-α in our blood, which I do highlight in Four Ways That Our Lifestyle Affects Our Immune System. A mildly elevated level of TNF-α in our blood, when kept constant, can activate the pro-inflammatory nuclear factor kappa B (NF-κB) transcription pathway in our cells to express even more pro-inflammatory cytokines, such as interleukin 1-beta (IL-1β).
And as I have shown in other articles, excessive IL-1β production can contribute to the development of symptoms such as:
- Insulin resistance (Type 2 Diabetes — A Case of The Immune System Gone Bad, Too?)
- Osteoporosis (Why Does Osteoporosis Affect Post-Menopausal Women More Significantly Than Other People?)
- Cardiovascular disease (Now Seriously, What’s So Tricky About Cholesterol?)
These anti-inflammatory drugs (whether biologics such as Humira or off-the-counter non-steroidal anti-inflammatory drugs, or NSAIDs) deal with the inflammation signal but not the source of the TNF-α. They may block the TNF-α from binding to the TNF-α receptor, but they don’t address the problem of why there is more TNF-α being produced than usual. Constantly elevated TNF-α levels will pose a problem elsewhere too.
Because the cells in our body operate on a complicated, intricate tangle of signalling processes, it is difficult to pinpoint where the problem comes from, and what brings temporary relief to the problem that causes the symptom.
However, being able to get the 38 trillion cells in our body humming along in sync is much better, though that can be a tall challenge.
Getting the right key into the right lock at the right intensity matters. Unfortunately, years of mutation and poor maintenance can lead into a breakdown of the signalling processes in the body, and some of the breakdowns can be genetically passed on to future generations, for which there may be no cure, which I explore in On The Concept of Genetics, And What It Entails In Our Lives.
And that’s a detailed explanation for why our bodies seem to develop more and more health complications as we age, but also why our children seem to be having more health problems that didn’t seem to be a problem for us, either.
Joel Yong, PhD, is a biochemical engineer/scientist, an educator and a writer. He has authored 4 ebooks (available on Amazon.com in Kindle format) and co-authored 6 journal articles in internationally peer-reviewed scientific journals. His main focus is on finding out the fundamentals of biochemical mechanisms in the body that the doctors don’t educate the lay people about, and will then proceed to deconstruct them for your understanding — as an educator should.
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