1. Pentose phosphate pathway

Last updated on November 19, 2018 at 17:16

Summary:

  • Starts with glucose 6-phosphate (G6P)
  • Produces NADPH, an important molecule for reducing other molecules
  • Produces pentoses (sugar-molecules with 5 carbons), that are used in nucleotide synthesis
  • Has two phases: oxidative phase first, then the non-oxidative phase
  • Takes place in the cytosol

Oxidative phase

During the oxidative phase, molecules of G6P are oxidized to ribose 5-phosphate. This phase produces 2 NADPH. The enzymes in this phase that convert NADP+ to NADPH are glucose 6-phosphate dehydrogenase and 6-phopshogluconate dehydrogenase, which each yield 1 NADPH.

In some tissues, that need both NADPH and pentoses for nucleotide synthesis, the pathway stops here. However, there are tissues that only need NADPH and would rather use the pentoses for energy. That’s when the non-oxidative phase begins.

The non-oxidative phase of the pentose phosphate pathway. Note that transketolase can catalyse two similar, but different reactions. Check the MRTs.

Non-oxidative phase

During the non-oxidative phase, 2 molecules of ribose 5-phosphate (one of the products of the oxidative phase) go through a series of reactions to be converted to glucose 6-phosphate, which can be used for energy. The non-oxidative phases use multiple enzymes, two of which are exclusive to this pathway. Those are transketolase and transaldolase. The others are enzymes also used in gluconeogenetic or glycolytic pathways.

Transketolase and transaldolase both function by basically moving groups of H – C – OH between sugar molecules. See the MRTs for more details. Note that transketolase uses TPP as a cofactor and transaldolase doesn’t.

Some tissues don’t need NADPH, and just needs pentoses. They can produce pentoses without NADPH through other pathways.

Regulation

The pentose phosphate pathway is regulated by the ratio of NADP+ to NADPH. If the ratio is high (there is a lot of NADP+ but not much NADPH), then glucose 6-phosphate dehydrogenase will be allosterically activated by NADP+.

What is NADPH used for?

  • Reduction of glutathione, which is used to protect the cell from oxidative stress
  • Fatty acid synthesis
  • Cholesterol synthesis
  • Production of NO, a neurotransmitter and vasodilator
  • Nucleotide biosynthesis
  • Cytochrome P450 monooxygenases, which detoxify substances in the liver.

What are pentoses needed for?

  • RNA synthesis
  • DNA synthesis
  • ATP synthesis
  • NADH
  • FADH2
  • CoA

Clinically

G6P dehydrogenase deficiency is a genetic condition in which the body has reduced capacity to produce NADPH. Cells of people with this condition are more vulnerable to oxidative stress than healthy people. In periods of high oxidative stress, the haemoglobin in RBC’s can be degraded into so-called Heinz-bodies. However, most cases of G6PD are asymptomatic until drugs, toxins or certain foods are ingested. This condition is common in places where malaria is prevalent. This is because G6PD has malaria resistance as a side effect. This is because cells that are infected by malaria are exposed to heavy oxidative stress, which kills the cells, as G6PD patients’ cells cannot handle this stress. This coincidentally makes the malaria unable to spread.

Wernice-Korsakoff syndrome is a disorder caused by severe thiamine (vitamin B1) deficiency. TPP is derived from thiamine. A defect in the gene for transketolase, which requires TPP to work, can give the enzyme a much lower affinity for TPP than normal. This defect makes patients much more sensitive to thiamine deficiency. Patients with this defect cannot tolerate even mild thiamine deficiencies, that healthy people could tolerate.


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2. Gluconeogenesis

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