Question

In humans, most NADPH is produced by the following reaction (not discussed in this course):

Glucose 6-phosphate + H₂O + NADP⁺à 6-phosphogluconate +NADPH +H⁺. This reaction is catalyzed by an enzyme called glucose 6-phosphate dehydrogenase.

Could inhibiting glucose 6-phosphate dehydrogenase be a useful strategy for lowering high cholesterol? Explain, and note any possible complications.

Answer 1

Answer: No, it is not an effective strategy.

Solution: As given in the question, the enzyme G6PD catalyzes the first step in the pentose phosphate pathway. The reaction produces NADPH. NADPH serves as a reductant and is required for several anabolic processes occurring in the cells. In addition, NADPH also protects cells from oxidative damage. NAPDH protects the cellular structures and molecules against the oxidative damage by hydrogen peroxide (H2O2) and superoxide free radicals. H2O2 and superoxide are the highly reactive oxidants and are produced in several metabolic processes. Detoxification of H2O2 includes its conversion into H2O by reduced glutathione and glutathione peroxidase. The oxidized glutathione is converted back to the reduced form by glutathione reductase and NADPH. Likewise, H2O2 is scavenged into H2O and O2 by the enzyme catalase. Catalase enzyme also requires NADPH. Deficiency or inactive G6PD would result in reduced production of NADPH and the detoxification of H2O2 would be inhibited. These reactive species would damage the erythrocyte membranes and oxidize proteins and DNA.