Biochemistry 401 Lecture 25 Today we’re going to talk about the pentose phosphate pathway. This is abbreviated PPP. We’re going to start with an overview of the pathway, and then we’re going to discuss the differences between NADH and NADPH. We’re then are going to discuss the pentose phosphate pathway in depth, the reactions, and the function of the pathway overall. Now the pentose phosphate pathway is a very important pathway that is found in the cytosol. It has many purposes. It has two phases, the oxidative phase that is shown in white, and the non-oxidative phase that’s highlighted in yellow. The oxidative phase is mainly concerned with the production of NADPH, whereas the non-oxidative phase is involved with the inter-conversion of sugars. The products of the pentose phosphate pathway are NADPH for reductions, and ribose for nucleotide synthesis, and glycolytic intermediates. These intermediates can go on through the rest of the glycolytic pathway to form pyruvate for ATP production, or these intermediates can be sent back through gluconeogenesis to form glucose again, and so this pathway is very versatile and we’ll see that it serves many functions. In this slide, we see NAD+ on the left in an NADP+ on the right, and these two are different both structurally and functionally. NAD+ has an OH at the two prime position in the adenine. In NADP+ there is a phosphate group there at the two prime position in adenine. That's the structural difference. Now functionally, they’re quite different. The ratios in the cell of NADH and NAD+ favor NAD+. There's more NAD+ than there is NADH in the cell, and so NAD+ is used to oxidize substrates in catabolic pathways. With NADP+ is very different. The ratios of NADPH to NADP+ favors NADPH, and therefore NADPH is going to reduce substrates, and it does so in reductive synthetic reactions that occur in anabolic pathways. Now another thing that NADPH does is it reactivates glutathione, and so it's a very important molecule to have in sufficient quantities. And so these two electron carriers serve different purposes. For instance, in the mitochondrial matrix, NAD+ oxidizes substrates to produce reducing equivalents, NADH. This happens in the citric acid cycle, in fatty acid oxidation, and also, as we saw, in the pyruvate dehydrogenase complex. Then this NADH reduces electron carriers in order to power ATP synthesis. This happens in the electron 1transport chain. In the cytoplasm, NADPH reduces substrates in reductive synthetic reactions. These include fatty acid synthesis, cholesterol synthesis, nucleotide synthesis, and neurotransmitter synthesis. Now NADPH is a very important electron carrier, and it serves many purposes. It's used for reducing equivalents in biosynthesis as we saw just previously, but it also combats infection, and it does so, because it's used in neutrophils for the synthesis of reactive oxygen species, to make superoxide to peroxides from oxygen, in order to kill microbes. Neutrophils are our body's first line of defense incombating infections. You’ll often find neutrophils there first, and these white blood cells synthesize superoxide and peroxides from molecular oxygen. NADPHalso is important in the synthesis of nitric oxide. Now nitric oxide is a short-range hormone that also serves many purposes. It can act as a vasodilator, by increasing the diameter of blood vessels to allow greater blood flow. It's also usedin the synthesis of reactive nitrogen species, and these also will kill bacteria. NADPH is also used to reduce, and thereby reactivate, glutathione, and this is a very potent antioxidant. Let’s take a look at this. Here is glutathione in its reduced state. This is actually a tripeptide that's made up of glycine, cysteine, and glutamate. This tripeptide protects against oxidative stress, by reducing oxidized components in the cell. But the thing is, when this happens, glutathione forms disulfide bonds, so you’ll have two glutathiones that are bonded to one another through the cysteines, and this is a problem. We have to get rid of that disulfide bond in order to regenerate the two glutathione's that are independent of one another, and so NADPH can be used as reductant in order to reduce these disulfide bonds and release these two glutathiones from one another. And so it's important to have sufficient levels of NADPH to keep our cells safe, by reactivating glutathione. And this is especially important in red blood cells. Red blood cells do not have mitochondria, and therefore they rely on NADPH, because they rely on the pentose phosphate pathway for most of their reducing power. Glutathione is important as a sulfhydryl buffer, to keep important cysteine residues in hemoglobin and other molecules in the red blood cell reduced. Glutathione is also important for reducing peroxides and other reactive oxygen species that can damage membranes and other cellular structures within the cell. In this figure to the right, we see Heinz bodies. Now Heinz bodies are clumps of denatured 2hemoglobin that adhere to the membrane. These Heinz bodies are actually a hallmark of oxidative destruction, and so when red blood cells are confronted withoxidative stress, this is what can happen if there isn’t sufficient NADPH to reduce glutathione. Red blood cells are especially vulnerable to oxidative stress, and if there is insufficient NADPH available to reduce glutathione disulfide, to form independent glutathione molecules, then oxidative stress can have a profound effect on red blood cells, and so glutathione is important as a sulfhydryl buffer in order to keep important cysteine residues in hemoglobin and other molecules in the red blood cell reduced. Glutathione is also important for reducing peroxides and other reactive oxygen species within the cell that can damage membranes and other cellular structures. This is a list of tissues that have active pentose phosphate pathways. The pentose phosphate pathway is most active in the adrenal glands, in the liver, and testes, and adipose tissues, in the ovary, and mammary glands, and in red blood cells. In many of these tissue types, the reason that the activity of the pentose phosphate pathway is so high is because these tissues produce steroid hormones. The liver produces a sterol, cholesterol. In addition some of these tissues produce fatty acids and the production of fatty acids requires NADPH. Red blood cells rely on the production of NADPH for the maintenance of
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