protein folding disease

Protein, Protein Folding, and Enzyme Activity

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As everybody knows, organic food consists of proteins, fats and carbohydrates. In this post I am going to indicate how protein is used to create enzymes. There are animal and vegetable proteins in food. The first thing that happens when one of these proteins is ingested is that digestion breaks it down into a range of chemical substances known as amino acids. They are absorbed and circulate in the blood stream. If they are not used, they are excreted in the urine. The ones chosen to construct enzymes are then reconstituted into these biologically active proteins. As most people know, the body uses enzymes in much the same way as a complex man made machine uses cogwheels. They connect the power to the action and are essentially the “workhorses” of the body.

How Enzymes Work

In order to understand some of the principles, I am going to take an enzyme known as pyruvic dehydrogenase as an example. This enzyme initiates energy production by stimulating the metabolism of glucose, the sugar that is used in the body as fuel for its cells, particularly those in the brain. The combustion of glucose is achieved by its combination with oxygen, the principle of all forms of combustion. We have many different names for this process, depending on the speed of the reaction. Singeing, fire and explosion represent the different speeds of combustion and it must be emphasized that it is never complete. There is always ash.

However, in the body this is a very unique process. The combination of glucose with oxygen begins the complex process of energy production. The “ash” is carbon dioxide and water. The enzyme functions by bringing the oxygen and glucose together but the combustion, known as “oxidation” can only be achieved in the presence of vitamin B1 (thiamine) and magnesium. These are known as cofactors to the enzyme and are supplied in the organic food which we are designed to consume. It is important to understand that this is the gateway to the production of energy which enables us to function and explains why thiamine and magnesium are essential ingredients of health through diet. Without their sufficiency, energy production suffers and an incomplete supply of energy interferes with normal activity of the entire body and brain. This oxidation initiates action in the citric acid cycle, essentially the “engine” in each of our cells. It is a complicated process that I do not need to discuss here, but it leads to the production of a chemical substance known as adenosine triphosphate (ATP). This substance stores energy and the nearest comparison is a battery. For this reason, it is sometimes referred to as “energy currency”.

An Enzyme Is a Protein

I pointed out above that the protein in food is broken down to amino acids that are absorbed into the body and reconstituted to form the biologically useful proteins known as enzymes. An enzyme is created by collecting a group of amino acids together in a bunch to form a chain. The electrical properties of the atoms and molecules in these amino acids enable the chain to be created by what is essentially a magnetic action between its ingredients.

The next thing that happens is absolutely vital to the biochemical action of the protein/enzyme. The protein has to be folded for storage and unfolded for action. The action of folding is repetitively unique to the enzyme. Research that is going on concerning this process is essential to a better understanding of an associated disease process. Mother Nature dictates the folding process which is exquisitely complex. In order to understand how this automatic process takes place, we need to know the exact design and electrical properties of the chain, facts that are still hidden in mystery. What we do know is that there is a whole series of diseases where the enzymes are misfolded or even completely unfolded. Unlocking the exact method by which folding and unfolding takes place leads to an understanding of the basic cause of the respective disease in which this mechanism has failed. There are about 50 different diseases in which this mechanism is responsible. As a group, the respective diseases are known as proteopathies. Alzheimer’s and Parkinson’s diseases are both known as examples of proteopathies and their solution depends on our understanding of this folding and unfolding process. A review of this field of science refers to the advances that have been made over the last decade in our understanding of the fundamental nature and consequences involved.

The Role of Thiamine in Protein Folding

It has long been known that thiamine is involved in the metabolism of Alzheimer’s disease and some attempts have been made to use megadoses of thiamine in its treatment. In fact, the earliest and perhaps best example of an interaction between nutrition and dementia is related to thiamine. Throughout the last century, research showed that thiamine deficiency is associated with neurological problems including cognitive deficits and encephalopathy. Multiple similarities exist between classical thiamine deficiency and Alzheimer’s disease. Benfotiamine, a derivative of thiamine ameliorated the clinical and biological pathologies that define Alzheimer’s disease. A 12-month treatment with this agent tested whether clinical decline would be delayed in the treated group compared to a placebo group. There was a “nearly statistically significant improvement” in the treated group, a fact that the authors have concluded that they need to repeat the study. A huge number of proteins that occur in the body have to be folded into a specific shape in order to become functional. Because of the known involvement of thiamine, it has been hypothesized that it plays an important part in the folding and unfolding mechanism of the respective proteins.

Prevention Is Better Than Cure

We have hypothesized that thiamine deficiency disease is common in America because of what we have called high calorie malnutrition. It has suggested that this common form of diet acts as a forerunner to one of these proteopathies because of the prolongation of the deficiency. We have suggested that the symptoms caused by high calorie malnutrition are those that collectively give rise to “the walking sick”, the individuals that are haunting the offices of physicians and who are being so frequently diagnosed as psychosomatic disease. Many of these patients have done their own research work and have concluded that the symptoms are arising from vitamin deficiency disease. Many have learned this from the posts on this website. When they go back to their physicians, claiming the true cause of their symptoms, they are almost invariably ignored and often considered to be psychiatric cases. Without a proper discussion concerning diet, many of these individuals continue with the symptoms indefinitely, concluding that they have untreatable disease. Perhaps they are not particularly surprised and may even be a little relieved when new symptoms have appeared and are diagnosed as a recognizable neuropathy such as Parkinson’s or Alzheimer’s disease. That is why it has been hypothesized that thiamine and magnesium are “keys to disease“.

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This article was published originally on February 17, 2021.

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Mitochondrial Energy, Not Genetics, Underlies Health and Disease

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Over the course of writing our book, Thiamine Deficiency Disease, Dysautonomia, and High Calorie Malnutrition, I had the privilege of reading hundreds of Dr. Lonsdale’s case studies, a treasure trove of clinical insight. One in particular has become incredibly important and may shake the very foundation of the current genetic paradigm. The case involved an 8 year old girl who suffered from severe asthma and bronchitis brought on, presumably, by a genetic mutation in a protein that controls the folding of other proteins, called alpha antitrypsin (AAT). The deficiency in AAT that ensues causes an accumulation of misfolded proteins that wreak havoc on the liver and on the lungs.

Dr. Lonsdale reported the details here on our blog, and of course, in the book. What was most striking about her case was not that thiamine proved beneficial. Thiamine sits atop the mitochondrial energy production machinery acting as gatekeeper of sorts and so this alone makes thiamine critical to health. That is not why this case is important, however. Nor is it because her case demonstrated how a series of what are essentially vitamin treatments effectively quelled what is usually a lifelong condition. Except for two episodes, she has been asthma free for 30 years. Those findings are impressive enough by themselves, but they pale in comparison to the discoveries her case has motivated; namely, that genetics can be altered by nutrients, or more specifically, that mitochondrial bioenergetics may determine whether and how genetic disorders are expressed. Sit with that one for a moment. Energy, not genetics, may be the most fundamental component of health or disease. Energy. Simple. Uncomplicated. Energy.

Why we have not considered energy availability in the initiation or maintenance of disease boggles the mind. Maybe it’s just too obvious. While I was in graduate school, mitochondrial energy production was not considered in any depth. Barring outright starvation or what were believed to be rare genetic aberrations of mitochondrial DNA, it was assumed that mitochondria would forever and always, no matter the circumstances, produce sufficient ATP to power all cellular function. Nary was a thought given to the possibility that energy production could be absconded by environmental or pharmaceutical toxicants or that mitochondria require micronutrients, vitamins and minerals, to turn macronutrients into fuel. This stuff just happened, magically I expect. And Warburg, well his work was no more than a historical footnote, something medical science had progressed beyond. For all intents and purposes, mitochondria were just there, doing their thing. Period. No need to consider otherwise. I suspect had I continued on the more traditional academic trajectory, I might not have ever considered the importance of mitochondria.

Fortunately, circumstance intervened, plans changed, and over the last several years I have been privileged to learn from Dr. Lonsdale and to interact with thousands of chronically ill patients via my work on Hormones Matter. Their illnesses were refractory to modern medicine, and I would argue, sometimes initiated, and almost always, worsened by conventional therapeutics. Their illnesses demanded I look for other solutions and this led me to the mitochondria. What if the mitochondria were not the magical black boxes we thought them to be? What if we needed more than just calories to make cellular fuel? And what happens when we have more calories than actual nutrients? Does the machinery work just as well or do we start seeing decrements in energy production that underpin many of complex disease process of modernity? Unfortunately, as the obesity and chronic illness epidemics suggest, it is definitely the latter.

From Food to Fuel

Mitochondria convert the food we eat into the cellular energy our bodies require. To perform this magic they require a sufficient supply of both macro and micronutrients. For far too long we have paid heed only to macronutrients, the carbohydrates, fats, and proteins, while completely ignoring the micronutrients, the vitamins and minerals that power machinery that makes the whole operation possible. Indeed, the literature is rife terms like ‘overnutrition’ an absolutely ludicrous proposition that not only errantly equates the ingestion simple calories with vitamins and minerals but suggests that somehow we all suffer from nutritional overload i.e. we get too many nutrients from the modern American diet. How’s that for magical thinking? Imagine the dissonance required to argue that the Big Mac provides too many nutrients; empty calories, and chemicals, yes, but too many nutrients? That is what the concept of overnutrition implies.

Ignoring the absurdity of this proposition for a moment, let us consider the mitochondrial black box. In addition to a ready supply of molecular oxygen, (which, interestingly enough, is also thiamine dependent), it takes 22 vitamins and minerals to power the mitochondrial enzymes that convert food into ATP, cellular energy. (We have a fantastic graphic detailing the mitochondrial vitamins and minerals in chapter 3 of our book). Deficiencies in any one of these nutrients throws a monkey wrench in the machinery, things back up, compensatory reactions begin, and no matter how many raw materials (carbohydrates, fats, proteins) are waiting to be converted into product (ATP/energy), without fully operational enzymes, those raw materials will sit idle, or more specifically, they will back up at the factory gates and eventually be shuttled into storage (fat) for use at another time. (Yes, fat storage is a protective mechanism). For all its complexity, it’s quite simple, without micronutrients, the mitochondria begin to fail and when they do, all sorts of complicated reactions begin, reactions that can be mapped quite easily, but vary considerably in their individual expression owing to the individual’s unique constitution of genetic and environmental tolerances. Invariably though, the organ systems hardest hit are those that require the most energy, the brain, heart, GI, musculature. (Yes, nutrient deficiencies affect brain function, quite severely in fact, a concept many are loathe to admit.)

Insufficient nutrients equals insufficient bioenergy, or ATP, which in turn equals disease. When evaluating health and disease, the question we should be asking is do the mitochondria have the components to make energy? If yes, then the individual can withstand all sorts of toxic insults for long periods of time before finally succumbing. If no, then downward trajectory of complex illness begins, sooner. In some cases, before birth.

Why Do We Ignore Energy?

If it’s really that simple, why do we ignore bioenergetics in health and disease? The answer is as much about philosophy and world view as it is about science with equal parts economics and self-interest thrown in for good measure. The cynic in me thinks that we ignore energy because it affords far too few opportunities to pray at the altar of pharmaceutical science. After all, if energy availability is at the foundation of health and it absence evokes disease, then maintaining or restoring health boils down to nothing more than a ready supply of sufficient micro and macronutrients to meet the needs of the organism. Nothing sexy there and certainly not a lot of profit with the ‘eat well and live healthy’ message.

If we were to recognize that health depends upon mitochondrial energetics, then we’d have to admit to all the products and processes in modern living that derail energetics, like the industrial, agricultural, or pharmaceutical chemicals that not only directly damage the mitochondria, our endogenous energy factories, but simultaneously demand of those factories more energy for detoxification and survival. We’d have to admit to ourselves that food-like substances we crave fail to provide sufficient micronutrients, the micronutrients required to power the mitochondria and produce injury, something few of us are willing to accept. If we looked at energetics as a basis for health or disease, we’d have to look seriously at vitamins and minerals, and that’s just not sexy. Basic nutrition, the kind most of our grandmothers preached, is not interesting. It’s not profitable (imagine all the industries that would collapse) and it’s just too damned obvious to be real. Or is it?

Mitochondria, Energy and Misfolded Proteins

If we return to Dr. Lonsdale’s patient, the little girl with a genetic disorder that causes misfolded proteins that preferentially affect the lungs and liver and consider how in the world something as simple as thiamine resolved her disease process, we come back to energy. The thiamine provided her mitochondria with the fuel they needed to produce energy, energy that could be used to overcome the misfolded proteins that were damaging her lungs. It’s that simple.

Protein folding is an energy dependent process, one with many correction or protection points where, when errors occur, when proteins are misfolded, the body initiates its built-in mechanisms to either correctly refold the protein or sequester it, thus removing the possibility of causing harm. These functions are energy dependent too. No energy, no corrections or protections. The errors continue, the damage builds, until the entire system is compromised. The simple act of supplying the body with the necessary substrates to create cellular energy allows it to overcome all manner of disease processes. Conversely, depriving the body of those same substrates, initiates and exacerbates disease.

In the case of AAT deficiency, research suggests that up to 50% of folks with these mutations are thiamine deficient, whether by cause or consequence is unknown, however. But it doesn’t matter. If we recognize the energy is important for health, and that certain vitamins and minerals are necessary to create that energy, then the roots of many diseases processes become clear. Think about how many neurodegenerative disorders involve misfolded proteins, Alzheimer’s and Parkinson’s to name but two. Is energy availability at the foundation of these processes? And if so, can they be prevented? Possibly.

If energy, or more specifically, the nutrients required to produce energy, lay at the foundation of health, shouldn’t all medical evaluations begin with two fundamental questions: 1) what does the patient require to achieve health and 2) is he/she meeting those requirements? I think they should, and yet, when is the last time a physician tested or even inquired about your diet and nutrient status? And if we’re honest with ourselves, when is the last time we considered addressing our own nutrient deficiencies or dietary issues? Chances are, most of us do not look seriously to nutrients unless or until all else fails; until we are absolutely desperate to find a solution, any solution, to the chronic pain of illness. The place we should look first, we look last. I told you vitamins and minerals weren’t sexy. Heck, most do not even consider them ‘real medicine’.

The notion that nutrients do not matter and have no role in medicine is so pervasive that even when a physician runs the most basic of nutrient panels and finds significant deficiency, both the physician and the patient proceed as if the labs were normal, because after all, there was no ‘real’ problem identified. I cannot tell you how many times patients communicate with us how their labs were completely normal, dismissing severe nutrient deficiencies outright.

When we are deficient in critical nutrients, no matter the diagnosis or even the origins of the illness and no matter what treatment is offered, it will fail, unless and until those basic energetic requirements are met. Period. Energy is required to sustain life. The mitochondria simply do not work very well absent critical nutrients. And when the mitochondria fail, so too does everything else, maybe not quickly, but inevitably. Don’t believe me? Look it up; or at the very least, ask yourself honestly if your current medical treatments are working. My guess, if you are reading this, things are not going so well.

The bottom line is that the body can overcome all manner of genetic and environmental insults provided it has the energy to do so. Energy production requires vitamins and minerals. Absent those nutrients, health is impossible.

We Need Your Help

More people than ever are reading Hormones Matter, a testament to the need for independent voices in health and medicine. We are not funded and accept limited advertising. Unlike many health sites, we don’t force you to purchase a subscription. We believe health information should be open to all. If you read Hormones Matter, like it, please help support it. Contribute now.

Yes, I would like to support Hormones Matter. 

This article was published originally on October 17, 2017. 

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