Pentose phosphate pathway and G6PD deficiency haemolysis
The pentose phosphate pathway, a side route off glycolysis, makes NADPH (a carrier of high-energy electrons), which protects red cells against damaging oxygen-containing molecules.
Remember
Red cells make NADPH mainly through the pentose phosphate pathway, and NADPH keeps glutathione (the red cell's main antioxidant, which neutralises damaging oxygen-containing molecules) in its active form; without enough NADPH, when an oxidant (something that produces damaging oxygen-containing molecules) arrives, for example from a drug or an infection, haemoglobin is damaged and premature destruction of the red cells follows.
The pentose phosphate pathway is a side route that branches off glucose-6-phosphate (the molecule formed in the first step of glycolysis). It makes five-carbon sugars and NADPH, a molecule that carries electrons and so supplies "reducing power". Mature red cells have no nucleus and no mitochondria, and in them the main job of this pathway is to make NADPH.
Red cells face constant exposure to reactive oxygen species (unstable oxygen-containing molecules that damage proteins and membranes), because they carry large amounts of iron and pass through highly oxygenated tissues. Their main defence is glutathione, an antioxidant that neutralises these molecules by donating electrons. Each time it does so, it is oxidised and no longer active, and NADPH is needed to restore it to its active, reduced form. Picture NADPH as a battery that recharges glutathione.
The first enzyme of the pathway is glucose-6-phosphate dehydrogenase (G6PD). In G6PD deficiency, NADPH production is impaired, so when an oxidant arrives, for example from a drug or an infection, it can overwhelm the red cell's defences against reactive oxygen species. Haemoglobin loses its folded shape (it is denatured) and clumps into Heinz bodies, which special stains show. The spleen removes the damaged cells. This haemolysis (premature destruction of red cells) causes anaemia, jaundice (yellowing of the skin and eyes from bilirubin, a pigment made when haemoglobin is broken down) and dark urine.
Key facts
- Two outputs
- the pentose phosphate pathway makes NADPH, which gives protection, and five-carbon sugar phosphates such as ribose-5-phosphate, which are building blocks for DNA and RNA.
- Two pathways, two jobs
- glycolysis gives red cells ATP for energy, whereas the pentose phosphate pathway gives them NADPH for antioxidant protection.
- The chain
- G6PD makes NADPH, NADPH recharges glutathione, and reduced glutathione protects haemoglobin from reactive oxygen species.
- Heinz bodies
- clumps of denatured haemoglobin that special stains (supravital staining, which is staining of living cells) show, with the damaged cells removed by the spleen.
- Triggers
- oxidant drugs such as primaquine (an antimalarial), and also infection, can provoke haemolysis in G6PD deficiency.
- Presentation
- anaemia, fatigue, jaundice and dark urine after exposure to an oxidant drug or infection.
Exam traps
- Failed ATP production from glycolysis would harm the pumps and shape of a red cell, but it does not explain Heinz bodies, which are caused by oxidant damage to haemoglobin.
- The five-carbon sugars made by the pentose phosphate pathway are building blocks for DNA and RNA, not antioxidants. Protection comes from glutathione, so the pathway helps only indirectly, through its NADPH.
- A shortage of ribose-5-phosphate (a five-carbon sugar phosphate used for building DNA) would not damage circulating red cells, because mature red cells have no nucleus and do not replicate DNA.
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