PPP and glucose switch

Glycolysis and Pentose Phosphate Pathway.

I just started to dig into how exactly these are regulated and it seems these pathways are competing for glucose.

At first I thought they run in parallel, PPP providing NADPH for GSH recycling, but then I found studies that propose a “metabolic switch” - when glucose is directed towards one or another depending on, for example, availability of oxygen.

Then I found that Nitric Oxide upregulates G6PD (a rate-limiting enzyme of PPP).

In a condition of GSH depletion, the recycler (GSR) will be activated and the process of restoring GSH from GSSG will consume NADPH.

Lowered level of NADPH will unblock the rate-limiting enzyme G5PD and that will literally steal glucose from glycolysis, which results in less pyruvate.

This is all good and right when oxidative stress is normal and caused by normal respiration.

Now imagine that GSH is depleted by something else: toxic metals (even the ones that are normal, but in elevated amounts - copper, iron, etc), toxic metabolites that bind to GSH for elimination.

This attempt to get rid of toxic things via glutathione will divert glucose from energy making into PPP to make more NADPH.

I now wonder how people with GSH depletion are feeling on Keto diet?
And what about poor kids that are put on low-carbs diet and on detox protocols at the same time.

I know we are constantly making glucose from protein, but that also has side effects - e.g. elevated ammonia production which requires more efforts for elimination.

Or it is not as dramatic as I wrote here. Looking closer at the chart (and reading the article):

“Through ultra-short 13C labeling experiments, we provide evidence for multiple cycling of carbon backbones in the oxidative PPP, potentially maximizing NADPH reduction.” (R1)

PPP feeds into Glycolysis as a cycle, so this doesn’t actually steal lots of glucose, bu rather organises a loop.

And you know what enzyme provides that connection?

Transketolase. The one that depends on Thiamine.

So, thiamine deficiency is responsible for inefficient NADPH generation, which ultimately leads to GSH depletion.

Boom.