Nicotinamide adenine dinucleotide phosphate

And that requires an enzyme called glutathione reductase.

And glutathione reductase requires NADPH, which is a source of reducing power.

And so now there's another layer here where you need to be able to make, number one, make glutathione, number two, use it, number three, regenerate it, and then number four, continue producing the cellular reducing power required to keep that whole system running.

And a lot of people can't do that, again, because of antioxidant deficiencies and stuff.

So this is why antioxidant biology is way more sophisticated than simply taking an antioxidant supplement.

So where does NADPH come from and how do we get it so we can make this whole pathway run? Well, one important source is pentose phosphate pathway.

This pathway is really major and one of the major inputs into this pathway is glucose.

This is an important nuance.

It can enter the glycolytic pathway, ultimately being finally oxidized all the way down to pyruvic acid or lactate, all in the cytoplasm.

or it can enter the axis of pentose phosphorescent, where it can be initially oxidized, and there'll be two oxidations, and those two oxidations will allow for the reduction of NADP to NADPH.

That will give you reducing power for many other events downstream, postprandially, you see.

And of course, that remaining glucose will have been decarboxylated, so now that it will become a pentose sugar, not a hexose.

And after ribulose is made, of course, via one other reaction, ribose will be generated, ribose 5-phosphate, and that can be used directly for nascent nucleotide biosynthesis.

So moving through the acts that pentose phosphate's shown, gives NADPH and ribose 5-phosphate.

Those are very absolutely necessary components, metabolites, for example, for cell cycle to progress, because all of that reducing power will be necessary for reproducing the genome.

because you need to replicate the genome before cell division at cell cycle.

That rapidly splits into two shorter chains containing three carbons each and called phosphoglycerates, or PGAs for short.

Enter ATP and another chemical called nicotinamide adenine dinucleotide phosphate, or just NADPH.

ATP, working like a lubricant, delivers energy, while NADPH affixes one hydrogen to each of the PGA chains, changing them into molecules called glyceraldehyde 3-phosphates, or G3Ps.

Glucose needs six carbons to form, made from two molecules of G3P, which incidentally have six carbons between them.

So sugar has just been manufactured, right? Not quite.

Next on the metabolic list is glucose-6-phosphate dehydrogenase deficiency or G6PD.

G6PD.G6PD is an enzyme vital for the pentose phosphate pathway, which generates NADPH.

NADPH is necessary to keep glutathione in its reduced state, which protects the red blood cell from oxidative stress.

If a patient with G6PD deficiency is exposed to massive oxidative stress, the hemoglobin denatures, precipitates as Heinz bodies, and the cells are destroyed.

We know these flares are triggered by specific events, severe infections, certain drugs like benzocaine or antimalarials, and the classic board question favorite, fava beans.

of oxidative metabolism.

This, of course, includes glutathione synthesis, NADPH production in the oxidative pentose phosphate shunt and from malic enzyme, and then all the other defenses that are typically raised against oxidative damage.

And again, reiterating what I just said, iatrogenic that is treatment therapy applied at a clinic, is often then employed, but unfortunately overlooked as a source of potentially increasing disease severity and complexity, especially when there is a lack of knowledge of integration.

of membrane lipid signaling, intermediary metabolism, especially associated with epigenetic alteration of immune cell gene expression that indeed normally naturally alerts and defends against all these stress responses, even after pain or other signs and symptoms have fully manifested.

The most strong, significant oxygen.

It has a very short half-life.

Rather than having that kind of intense oxidative stress, Often what happens, superoxide is generated from, for example, the NOX enzymes, the NADPH oxidases, or from succinate dehydrogenase in the electron transport chain complex 2, the mitochondrion.

Now that superoxide will be dismutased to H2O2.

But it doesn't mean it's a linear event.

Nevertheless, What happens during senescence is an increase initially, remember, of reactive oxygen species coming from the mitochondria and from the NADPH oxidase systems, the NOx enzymes, which can be found in the plasma membrane.

Remember, those systems, the NOx systems, are also involved in, they generate superoxide, but they're also involved in maintaining NADPH levels and carrying out upstream and downstream regulation of the removal of reactive oxygen.

For example, superoxide can quickly be dismutase to hydrogen peroxide, which is still an oxidizing reactive oxygen.

but it's no longer a free radical.

Nevertheless, it has to be removed by catalase.

So that then associates back with NADPH and with glutathione, glutathione reductase, and then the activities of ascorbic acid and tocopherol.

So all of the normal descriptive antioxidant pathways then are playing a significant role.

If you are G6PD deficient, your red cells are much more sensitive to oxidative damage.

The lack of G6PD means that NADPH plus cannot be reduced to NADPH, which helps prevent oxidative damage.

Around 400 million people worldwide have G6PD deficiency, so that's about 5% of the world's population.

And interestingly, it is more common in places where malaria has been endemic.