The pentose phosphate pathway in red blood cells favism

The pentose phosphate pathway is also important in the red blood cell, where NADPH is required to maintain an adequate pool of reduced glutathione, which is used to remove hydrogen peroxide.

As shown in Figure 5.15, the tripeptide glutathione (y-glutamyl-cysteinyl-glycine) is the reducing agent for glutathione peroxidase, which reduces H2O2 to H2O and O2. (Glutathione peroxidase is a selenium-dependent enzyme (section 11.15.2.5), and this explains the antioxidant action of selenium.)

Oxidized glutathione (GSSG) is reduced back to active GSH by glutathione reductase, which uses NADPH as the reducing agent. Glutathione reductase is a flavin-dependent enzyme, and its activity, or its activation after incubation with FAD, can be used as an index of vitamin B2 status (section 11.7.4.1), in the same way as activation of transketolase by thiamin diphosphate can be used as an index of thiamin status (section 11.6.4.1).

Partial or total lack of glucose 6-phosphate dehydrogenase (and hence impaired activity of the pentose phosphate pathway) is the cause of favism, an acute haemolytic anaemia with fever and haemoglobinuria, precipitated in genetically susceptible people by the consumption of broad beans (fava beans) and a variety of drugs, all of which, like the toxins in fava beans, undergo redox cycling, producing hydrogen peroxide.

Figure 5.15 The reaction of glutathione peroxidase.

Infection can also precipitate an attack as a result of the increased production of oxygen radicals as part of the macrophage respiratory burst (section 7.4.2.2).

Because of the low activity of the pentose phosphate pathway in affected people, there is a lack of NADPH in red blood cells, and hence an impaired ability to remove hydrogen peroxide, which causes oxidative damage to the cell membrane lipids, leading to haemolysis. Other tissues are unaffected in favism because there are mitochondrial enzymes that can provide a supply of NADPH; red blood cells have no mitochondria.

Favism is one of the commonest genetic defects; an estimated 200 million people world-wide are affected. It is an X-linked condition, and female carriers are resistant to malaria; this advantage presumably explains why defects in the gene are so widespread. A large number of variant forms of the glucose 6-phosphate dehydrogenase gene are known; some have no effect on the activity of the enzyme, whereas others result in favism. There are two main types of favism:

A moderately severe form, in which there is between 10% and 50% of the normal activity of glucose 6-phosphate dehydrogenase in red blood cells. The abnormal enzyme is unstable, so that older red blood cells have low activity but younger cells have nearly normal activity. This means that the haemolytic crisis is self-limiting, as only older red blood cells are lysed. This is the form of favism found among people of Afro-Caribbean descent, and crises are rarely precipitated by consumption of fava beans.

A severe form, in which there is less than 10% of normal activity of glucose 6-phosphate dehydrogenase in red blood cells. In this case the problem is that the enzyme has low catalytic activity or an abnormally high K for NADP+. In especially severe cases, haemolytic crises can be occur without the stress of toxin or infection. This is the form of favism found among people of Mediterranean descent.