Pentose Phosphate Enzymes, ATP, and B Vitamins | Masterclass With Masterjohn 1.11

By: Chris Masterjohn, PhD

Hi. I'm Dr. Chris Masterjohn of, and you are watching Masterclass with Masterjohn. And today we're in our eleventh in a series of lessons on the antioxidant defense system. In the last lesson we talked about how the pentose phosphate pathway is what produces NADPH.

And NADPH is an energy carrier that is derived from the B vitamin niacin that takes energy from glucose, transfers it with the help of the enzyme glutathione reductase, dependent on the other B vitamin riboflavin, which is vitamin B2, takes that energy that originally came from glucose and donates it to glutathione so that glutathione can then use it in the antioxidant defense system. And what we're going to do today is round off our discussion of the ways in which B vitamins and the system of energy metabolism support antioxidant defense. And this lesson is not the end of the series, but it's the last lesson that actually carves out components of the system. So shown on the screen is the simplified version of the pentose phosphate pathway that we looked at last time. We can see that you have a shunt that goes out of glycolysis to make pentose phosphates, that's where you get NADPH, those pentose phosphates can be the source of many different uses of five-carbon sugars; and if you need those great, but if you don't you can return them to glycolysis and your need for NADPH is almost always going to be in great excess of your need for five-carbon sugars so operating this as a shunt that can go back and forth is what allows you to get the NADPH that you need. So let's look at a couple things that can contribute to variations in people's ability to use this pathway for that purpose. The first thing we're going to do is zero in on this first step where we actually make the NADPH when we go from hexose phosphates to pentose phosphates.

This first step in the pathway is actually taking glucose 6-phosphate and turning it into ribose 5-phosphate, making NADPH in the process, and the enzyme that catalyzes that is called glucose-6-phosphate dehydrogenase. The name straightforwardly follows from the fact that glucose 6-phosphate is having its hydrogens taken away, along with electrons, and those, it's being dehydrogenated so that NADP+ can be hydrogenated to make that NADPH. The single most common enzymatic defect in the entire world is glucose-6-phosphate dehydrogenase deficiency. It affects 400 million people worldwide. And shown on the screen is a map of the global prevalence. Now you can certainly see that there are areas that are white, which are areas where this hasn't been measured, so it hasn't been studied completely, but you can also tell that there's so much data that is synthesized in this figure you can clearly tell from that that this has been viewed as super important and has been studied a lot. If you look at the United States, you can see that four to seven percent of people in the United States have this. It's lower in Mexico and it's very high in a spotting of other countries, it's higher in India, it's higher in the Middle East.

But where it's really high is in Sub-Saharan Africa. And to some degree because there's so many African countries that aren't measured and are shown in white, that is, if you can just imagine that this dark brown is probably continuous down here, then you can see that the prevalence is very great there. And it's thought the reason that the prevalence is so great in Sub-Saharan Africa, is that that has historically been where malaria has been a problem. And the malaria actually parasitizes the glutathione pool and other products in the pentose phosphate pathway. So if you can starve malaria of glutathione, unfortunately you have to starve yourself of glutathione in the process, but hey if the malaria can't get your NADPH and your glutathione then that's kind of good for you because the malaria are going to have a lot tougher time surviving.

Pentose Phosphate Enzymes, ATP, and B Vitamins | Masterclass With Masterjohn 1.11

Now the figures for the United States is an average across the country; if you look within people in the country, then you're going to see the highest rates among African Americans. So in African Americans there are, there is an 11 percent prevalence, and that reflects their ancestry from regions in Africa where malaria has been a problem. If you imagine however that malaria isn't a problem suddenly that's not a survival advantage that's a survival deficit because it's not protecting you against any parasite and now it's compromising your ability to support antioxidant defense. Glucose-6-phosphate dehydrogenase activity is also very well known as a cause of favism, which is an inability to tolerate fava beans because they have an oxidative toxin in them that most of us can handle perfectly well if we have good antioxidant status, but if you have glucose-6-phosphate dehydrogenase deficiency, you have a lot of trouble maintaining normal antioxidant status. Fortunately it is incredibly easy to find out what your glucose-6-phosphate dehydrogenase activity is because Labcorp offers it, Quest offers it.

It would be very easy if you're a doctor to order, it would be very easy for you to ask your doctor to order it, it's even easy to use something like Direct Labs to order it yourself. Now if we come back to the pentose phosphate pathway we are now going to zero in on the ability to return pentose phosphates back to glycolysis. And in order to do that we need to rearrange them into hexose phosphates, and triose phosphates because there aren't any pentose phosphates in the glycolytic pathway.

And so what this pathway is summarizing is the need to rearrange those pentoses to send them back. Sending those pentoses back actually requires a bunch of steps, but the critical one that we're going to talk about in this lesson is a step catalyzed by the enzyme transketolase. Transketolase is shown on the screen as TK and it uses a cofactor, thiamine pyrophosphate, TPP, which is derived from the B vitamin, thiamine, also known as vitamin B1. Its role is to take a two-carbon unit away from a pentose phosphate and add it to another pentose phosphate. In the process you get a septose phosphate which is a seven-carbon sugar, and a triose phosphate which is a three-carbon sugar. That triose phosphate is now ready to get sent back to glycolysis, the septose phosphate is not, it's going to undergo other steps of metabolism and we're not going to talk about all of them because the point here isn't to look at the pathway comprehensively, but this part of the pathway is the other key step that can be affected by nutrition, and lifestyle, and related factors like that.

In a few minutes we'll talk more about what can affect thiamine status. However there are other things that affect transketolase activity as well. This is best known about in the context of something called Wernicke's encephalopathy, which is generally associated with thiamine deficiency, plus alcoholism, plus either a genetic or epigenetic basis that affects the enzyme transketolase.

To this day we don't really know the details. Many years ago it was thought that this was genetic. Current thinking with current evidence is that it's actually epigenetic, but the exact basis we don't really know.

What we know is that some people who are vulnerable to Wernicke's encephalopathy, you can take their cells and you can measure their transketolase activity, and it will be low even if you try to restore the thiamine to the cells. And if you culture cells from those cells and reproduce the cells that defect continues on. So there seems to be some kind of modification to the enzyme that is independent of thiamine status.

Unfortunately, I cannot find a commercial lab in the United States that will measure erythrocyte transketolase activity, that's the transketolase activity in red blood cells, even though all thiamine experts recognize that that's the best marker for thiamine status. There are labs that offer plasma thiamine even though that's well recognized as only a marker recent thiamine intake and not a true marker of thiamine status. If there is anyone who works at a laboratory who would have control over this, I implore you to try to offer transketolase activity. Because it's important, not only because it's a very good marker of thiamine status, it's also important because we know that there are poorly understood things independent of thiamine status that lower people's transketolase activity.

And we don't know how prevalent they are, but if we find oxidative stress in someone that we can't figure out it makes complete sense to measure their transketolase activity and right now that's very difficult to do for the average person or the average health care practitioner. Now the B vitamins involved in energy metabolism aren't only impacting the antioxidant system through the pentose phosphate pathway. Energy itself in the form of ATP is critical to antioxidant defense.

Shown on the screen is only one example of that. Both steps in glutathione synthesis: the first step catalyzed by glutamate cysteine ligase, and the second step catalyzed by glutathione synthetase, both of them require energy from ATP. Although not shown on the screen, everything in the entire body that uses ATP uses ATP as a magnesium chelate because magnesium is needed to stabilize the ATP molecule therefore both of these steps are dependent on magnesium. With that said, magnesium is also necessary for the production of every single protein in the body.

So when we're looking at the antioxidant defense system, we have a bunch of enzymes those enzymes are proteins; synthesizing proteins also requires energy, also requires magnesium, and also requires dietary protein. But let's just take the synthesis of glutathione as an example. If we have a poor rate of glutathione synthesis it could be for all the reasons that we talked about before involved in the regulation, or it could just be that we don't have enough energy and there are metabolic and hormonal factors that are going to affect energy status not just micronutrients. However as indicated on the screen, there are three B vitamins that are critical to energy metabolism. Thiamine, which is also known as vitamin B1, riboflavin also known as vitamin B2, and niacin also known as vitamin B3.

Pantothenic acid, also known as vitamin B5, is just as universally important to energy metabolism and these three, but these three are more likely to be deficient for reasons that we will briefly discuss later. Fully discussing these nutrients is beyond the scope of a series on the antioxidant system. We're really now reaching into the depths of energy metabolism and so it makes sense to cover these vitamins in detail in another series on energy metabolism itself. But for the purposes of rounding out our understanding of the antioxidant defense system, let's just talk very briefly about some of the key factors that affect our nutritional status of these B vitamins. And the first one is noted on the screen which is that carbohydrate requires twice as much thiamine as fat when we're burning it for energy. So one thing to note is that carbohydrate increases the requirement for thiamine. If we look across B vitamins, we could say a handful of things; that most natural foods, whether it is meat or milk, or eggs or whole grains or seeds or nuts or vegetables, most whole foods contain decent amounts of B vitamins and are going to make some contribution to nutritional status. And nutritional yeast is widely recognized as one of the best sources, it's not something people usually eat, but it's often used as a supplement because it's so rich in B vitamins.

Now the refining of foods, at the beginning of the 20th century removed the B vitamins from those foods and the classical deficiencies that were studied at that time became rampant. Now to try to counteract those historical deficiencies we've added niacin, riboflavin, and thiamine to things like enriched rice and enriched white flour. This is not to reconstruct the original nutritional composition of the flour, and one of, that causes some problems of its own, but what it is is a way of managing a public health policy to recognize that historically those deficiencies were so prevalent and now they're virtually eradicated because people can continue to eat refined foods, and although that might not be the healthiest options for them, it's not causing overt deficiencies of these vitamins. So what could cause a thiamine deficiency? Well, out of all these B vitamins, thiamine is the one that's most sensitive to heat. Even pasteurization of milk destroys 20-percent, typical baking causes twenty to thirty percent losses, and pet food processing causes ninety percent losses. It's almost baffling to think about how pet food is made with respect to thiamine. What they do is that they add ten times more thiamine than they want to the food because they know that ninety percent of it is going to be destroyed, and then they obliterate it and there's just enough left over to satisfy the animals nutritional requirements.

The interesting thing about thiamine is that the most likely causes of deficiency aren't low thiamine intakes, they're low thiamine intakes compared with other factors that antagonize thiamine status. One of those is thiaminases, enzymes that break down thiamine that can be found in raw fish. Now clearly the consumption of raw fish is associated with good health in a variety of cultures. However, if you were to eat mostly raw fish as your main source of calories, that could put you at risk of thiamine deficiency. This was originally discovered in North America during attempts to domesticate or semi-domesticate wolves, and feed them exclusively on raw fish.

That caused overt thiamine deficiency in the wolves, and that's how it originally became studied. Now there are other cases where for example, in the rumen of a ruminant, you may have overgrowth of bacteria that produce thiaminases or thiamine antagonists; and in fact in humans there can be a bacterium in the gut that was a long time ago called Clostridium thiominolyticus and is now called Paenibacillus thiominolyticus. And I don't know how prevalent that is, but and I also don't know if it's the only example of a gut bug that can destroy thiamine. However, there is a possibility that some people could have overgrowth of bacteria in the intestines that degrade thiamine or otherwise antagonize it. There are also regional outbreaks of thiamine deficiency among animals.

For example, in dead zones around the Baltic Sea. And in these cases what you find is birds that will have thiamine deficiency so intense that they have seizures or they're paralyzed. And if they have a more moderate deficiency they produce eggs that have much lower levels of thiamine and then other animals eat those eggs and the deficiency spreads thoough the food chain.

The exact causes of these outbreaks aren't known, but it's thought to be thiamine antagonists that are synthesized by algae in the dead zones. There are also some traditional foods and one example is in southwestern Nigeria, there is a moth whose larvae is eaten in the rainy season, July to October, and it has heat resistant thiaminases that cause thiamine deficiency in this population. And the picture on the screen is of a different moth.

I couldn't find one of the anaphe venata, I have no idea if I'm pronouncing these things right. But, anyway that particular moth, its larvae has been associated with thiamine deficiency. Part of the problem is that it's eaten in the context of a very high carbohydrate meal and the high carbohydrate meal is increasing the need for thiamine. Meanwhile, the population has a general background low intake of thiamine. So when you combine low thiamine intake with high carbohydrate, which increases the need for thiamine, with thiamine antagonists produced in these larvae, then you can wind up with serious thiamine deficiencies. The most likely cause of riboflavin deficiency is going to be destruction of rivboflavin in foods due to exposure to light. Riboflavin is incredibly sensitive to light.

And one of the issues with using clear bottles on the shelves of stores, was that the light in the store would destroy the riboflavin in the milk. So there were two adaptations to this; one was the shift to paper cartons, and the other was to set up shields in the store that would block the wavelengths of light and stop them from hitting the milk on the shelf. Now you can imagine though that do you take the same protection at home, does every milk producer take the same protections during the transport of the milk? If you are buying milk from a farmer's market, do they keep it in a dark place during the transport and when they're there? These are all important considerations to make sure that we maintain good riboflavin content in our foods.

A deficiency of niacin is extremely unlikely because we can make our own niacin. However there are a few possible causes. First of all when we make niacin we do so by taking tryptophan, an amino acid found in dietary protein, with the help of vitamin B6 and iron, we make niacin.

So if we're anemic or if we're deficient in vitamin B6, or we're deficient in protein, that's going to set the stage for niacin deficiency. However, even still we're going to have one of those things plus a very low intake of niacin. One of the ways that that was achieved historically was when Europeans came to America they took corn which was domesticated by the Mexican natives with a process called nixtamalization, which processed the corn with alkali and freed up niacin from proteins to which it is otherwise bound, that prevents its bioavailability. But European Americans took the idea of corn without taking the idea of nixtamalization, and eventually many parts of the United States were eating diets that were mostly corn. So the corn was not processed with alkali, the niacin was very poorly bioavailable and the diet didn't contain enough tryptophan from protein, and maybe other nutrients as well like iron and vitamin B6, so endogenous synthesis of niacin was also very low and all of those things conspired together to produce true niacin deficiency. One of the nutrients that I didn't really focus on in this lesson is pantothenic acid.

Pantothenic acid is a component of coenzyme A. Coenzyme A is universally found all over energy metabolism as a carrier of fatty acids, of two-carbon units, and of many other molecules that allow us to break things down and derive energy from them. Pantothenic acid derives its name from the greek word, Pantos, which means any, all, everything, everywhere, because pantothenic acid is so common in foods that it has been almost impossible to observe a true overt deficiency of it, except in concentration camps during the war and experimental animals.

Now, that's not to say that there's no place for discussion about whether variations in pantothenic acid intake could affect our health status, but looking at these in detail really truly belongs in a series of lessons on energy metabolism itself. Alright, there we have it. This discussion basically rounds out how the system of energy metabolism supports the antioxidant system and completes our discussion of the individual components of that system.

All right, I hope you found this useful and enjoyable. Signing off, this is Chris Masterjohn of You have been watching Masterclass with Masterjohn and I'll see you in the next video.

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