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In my Cholesterol Podcast on the Livin' La Vida Low-Carb Show with Jimmy Moore, I offered the view that atherosclerosis and many other degenerative diseases can be seen as a process of oxidative damage wherein polyunsaturated fatty acids (PUFAs) get damaged by toxins, heavy metals, and byproducts of normal metabolism, break into pieces, and then continue to damage other molecules. I suggested thinking of this as breaking a glass on the floor — the glass breaks into shards, and then becomes dangerous. Step on the shards, and your foot will bleed. Likewise, when proteins, DNA, and other important molecules come into contact with “the pieces of broken PUFAs” they get seriously hurt.

PUFAs are not the only molecules subject to this type of damage. “Oxidative stress” is very similar to and very related to “nitrative stress” and “carbonyl stress.” “Carbonyl stress” involves the breakdown products of sugars.When our bodies metabolize sugar, we first do two things to it: first, we add some phosphate to it in order to trap it in the cell, target it through a specific series of reactions, and provide some of the energy necessary for those reactions; second, we split it in half. The technical term for this process is “glycolysis.”


A small percentage of the resulting half-sugar will spontaneously lose its phosphate and degenerate into a compound called “methylglyoxal.”


The next few paragraphs might make your eyes glaze over if you aren't in love with biochemistry. If that happens, you can skip to the last two paragraphs when the plain English will resume.

In the picture of methylglyoxal above, “C” represents carbon, “O” represents oxygen, “H” represents hydrogen, and the lines represent chemical bonds. The carbons double-bonded to oxygens are called “carbonyl groups.” These carbonyl groups are highly reactive. They especially love to react with nitrogens from the “amino groups” of other molecules and form what's called an imidazole ring.In the picture of the imidazole ring above, “N” represents nitrogen and each corner of the ring structure represents a carbon bonded to a hydrogen. The circle in the middle indicates that some of the electrons travel around continuously through the ring rather than sticking with particular atoms. Imidazole rings are naturally present in the amino acid histidine, but methylglyoxal can form them by spontaneously reacting with the free amino groups of the amino acids lysine and arginine. In doing so, it can damage the structure and function of the proteins these amino acids are part of

Every amino acid has a nitrogen-containing amino group, but on most amino acids this amino group would be bound to other amino acids and tucked away safely within a protein. In the two pictures that follow, this “safe” amino group is the one on the far right. The “side chains” of the amino acids are not always tucked away and are thus not always safe. In the two pictures that follow, the side chains proceed to the left.

The side chain of arginine has two nitrogens, and can thus provide the two nitrogens necessary to form an imidazole ring:

The side chain of lysine has only one nitrogen, so two lysines are necessary to form an imidazole ring:
Consequently, methylglyoxal reacts more often with arginine, by simply creating an imidazole ring in its sidechain that does not belong. This deranged form of arginine accumulates in the body with age and has been found in high amounts in human lens tissue.

When methylglyoxal reacts with lysine, however, it does something more dramatic. Since two lysines need to participate to form an imidazole ring, lysines that would ordinarily be distant from each other within a protein, or even lysines from two completely independent proteins, can get stuck together. In the first case the shape of the protein could get damaged and in the second case the protein would get stuck to another protein. Think “bumper cars.” It's hard to drive your car when its stuck up against another car — makes a fun game from time to time but if you're playing “bumper cars” on the way to work you're going to get a ticket, your boss isn't going to be happy when you arrive late, and you could get seriously hurt.As you can see in the following picture, two lysines supply “amino” (NH2) groups that interact with the “carbonyl” (C=O) groups of methylglyoxal. The hydrogens (H) and oxygens (O) leave the scene as water. An imidazole ring is formed, leading to an “imidazolium” crosslink between two lysines, whether of the same protein or of two wholly different proteins. The resulting advance glycation endproduct (AGE) is not so affectionately termed “MOLD,” (MethylglyOxal-Lysine Dimer).

And now, returning to plain English…

Like PUFAs, sugars can be broken into harmful pieces, and like shards of glass, they too can damage other molecules. Some authors have suggested that methylglyoxal can, in small amounts, play important physiological functions. Most look at its ability to damage proteins and cause crosslinks within and between proteins and see a molecule running awry, contributing to “carbonyl stress” just like oxidizing compounds contribute to “oxidative stress.”

Over the next several months, I will be performing several experiments to determine what type of dietary factors inrease and decrease the formation of methylglyoxal. I will also be reviewing the literature to better understand what kind of harm, and perhaps, what kind of good, it might do in the body. I will be sure to update you here, so stay tuned!

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  1. There are certainly some risks when it comes to ketogenic (low carb) type of nutrition, but it has effectively been used to treat various conditions, even epilepsy, so this should also be considered.

  2. Sorry to hijack the comment section, but I've got to ask:

    Aaron, how do you make the sweet potato fries crispy without dusting them with flour?

  3. Nigel,

    Thanks for your response. MG can be formed from the enzymatic oxidation of acetone, but this does not show that MG is an "end product" of anything but could simply be an intermediate in acetone production. No one to my knowledge has shown that the methylglyoxal synthase that exists in E. coli and some other species, which makes methylglyoxal as an endproduct of glycolytic intermediates exists in humans. The current view is that MG forms at rates of 0.1-0.4% from the spontaneous dephosphorylation of the enediol intermediate between DHAP and G3P, not enzymatically.

    Maybe the enzyme exists in humans, but that is not the current view and I don't think anyone has shown this.

    I understand the usefulness of inhibiting glycolysis on a ketogenic diet, but there are non-toxic ways of regulating glycolysis, and, on a ketogenic diet, there isn't a whole lot of glucose, so substrate deprivation should be sufficient anyway. Conditions that favor gluconeogenesis always favor suppression of glycolysis, so glycolysis essentially occurs in the presence of dietary glucose.

    MG may be less toxic than anticarcinogenic drugs, but that doesn't mean that its spontaneous formation doesn't play a role in the pathogenesis of degenerative diseases.


  4. Great post, thanks.

    I have just read a very insightful post on the Paleo Clinic blog, somewhat related to your post:

    I think we need a better understanding of the link between evolutionary pressures and paleo nutrition. Not everything is as simple as it looks, as shown by that post.

    The post discusses a brain response to glucose that may indeed be an adaptation that, while not very good for an individual human ancestor’s health in the long term, might have actually improved that ancestor’s reproductive success in the short term.

    That is, the response, displayed by modern humans, may be an evolved handicap, or costly trait.

    Coincidentally, I have just posted on this topic, and its relationship to strict paleo dieting.

    Take care, Ned

  5. Chris,

    As an ex-Engineer, I honestly don't know! My knowledge of biochemistry comes from textbooks. I can only guess that inhibiting glycolysis regulates the level of some end-product of glycolysis.

    The study in Peter's blog states that there is increased MG production in humans on a ketogenic diet. This suggests that it's synthesised somehow.

    On a low-carb/keto diet, it's beneficial to inhibit glycolysis as this minimises the usage of blood glucose and maximises the beta-oxidation of fatty acids.

    Ray's group are suggesting that MG is much less toxic than other anticarcinogenics as it can be detoxified.


  6. Dr. Cynthia,

    Methylglyoxal can be detoxified in the cell by the glutathione- and zinc-dependent glyoxalase system. Advanced glycation endproducts and reactive carbonyls are also normally excreted by the kidney, and increase dramatically during renal failure. I'm sure there is also more to the picture than what I and what we collectively know.


  7. Nigel,

    Peter's argument is interesting, but hardly complete. Does a dose of sugar increase methylglyoxal over fasting levels, as would be predicted according to the mainstream view that most methylglyoxal is generated spontaneously from the intermediate between DHAP and G3P in glycolysis? If so, how is it helpful to inhibit glycolysis in this scenario?

    Methylglyoxal has anticarcinogenic effects, but so do many toxic chemotherapeutics. It does more than inhibit glycolysis and kill cancer cells.


  8. I'd prefer that you not be influenced by the glucose-lovers and do your analysis as you believe is best! Most systems in the body have a way of correcting mis-metabolized or damaged compounds, so they can be detoxed or excreted. I suspect there is a similar control system here, but whether it's been discovered or not I don't know. I'll look forward to reading your posts about it.


  9. Matt, your analysis sounds like an exact parallel with the argument for eating cholesterol. I'm going to be watchiing closely how this all turns out. I love my saturated fats, and I love my potatoes and squash. I make killer sweat potato fries in lard, ghee, bacon drippings, duck fat, or coconut oil–and I ain't going to give them up. Don Matesz has made an excellent case for starch from tubors etc. being an important part of the human paleolithic diet.

  10. Well, whatever you do, don't turn your back on glucose. The answer is to find ways to improve the body's metabolization of it. Too many intelligent people have been overly eager to cast condemnation against glucose. Glucose is one of the most important assets for human health. Too much glucose, and problems arise – but that's not necessarily a simple result of eating too much glucose. As I've found, eating more glucose can be synonymous with less glucose in the blood – both fasting and postprandial levels.

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