Glucose-6-Phosphate Dehydrogenase Deficiency

Bulletin of the World Health Organization, November-December 1989 | Go to article overview

Glucose-6-Phosphate Dehydrogenase Deficiency


Glucose-6-phosphate dehydrogenase deficiency*

WHO Working Group

Introduction

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the commonest disease-producing enzyme disorder of human beings. More than 300 variants of G6PD characterized by standard methods are now known, and the recent isolation of the Gd gene promises important fundamental advances in the understanding of enzyme structure and function.

Since comprehensive reviews already exist [1-3], this article deals with recent developments in the methodology for characterizing G6PD deficiency, its epidemiology and the factors that can cause haemolysis, re-evaluation of its relevance for public health, community approaches for prevention of haemolytic crises and neonatal jaundice, and the implications of recent advances at the DNA level.

Role of the enzyme

Glucose-6-phosphate dehydrogenase is a "housekeeping" enzyme, vital for the life of every cell. Complete absence of the enzyme is unknown in the human species. Within the restricted metabolism of the red cell, G6PD occupies a particularly important place. It catalyses the first step in the hexose monophosphate pathway, converting glucose-6-phosphate to 6-phosphogluconolactone and reducing the co-factor nicotinamide-adenine dinucleotide phosphate (NADP) to NADPH. The second enzymic step in the pathway is also associated with the reduction of NADP to NADPH.

In the red cell this pathway is the only source of NADPH, which is necessary to protect the cell and its haemoglobin from oxidation in view of their role in oxygen transport. The --SH groups of several enzymes and of the [beta]-chain of haemoglobin are particularly vulnerable to oxidation, with potentially serious consequences. Protection against oxidation is mediated by glutathione which is actively synthesized and is present in high concentration in red cells, almost entirely in the reduced form (GSH) (Fig. 1). The latter can restore oxidized --SH groups, and reacts with peroxides via glutathione peroxidase, becoming itself oxidized (to GSSG) in the process. NADPH is required for regeneration of GSH by the enzyme glutathione reductase; this is considered to be the most important function of NADPH in the red cell.

Though G6PD deficiency affects every cell in the body, its primary effects are haematological because the red cell has no alternative source of NADPH. Other more complex types of cells are protected by additional enzyme systems (such as the less specific hexose-6-phosphate dehydrogenase) that can generate NADPH in the absence of adequate G6PD activity.

In normal intact red cells NADP is mostly in the reduced form NADPH, and G6PD operates at only about 2% of its theoretical maximum rate. This is because, under normal circumstances, (1) the quantities of glucose-6-phosphate and NADP are well below saturating levels, (2) NADPH and ATP inhibit the enzyme, and (3) most of the NADP present is not free but bound to catalase. Oxidative stress leading to increased oxidation of NADPH simultaneously releases enzyme inhibition and increases the level of NADP, so that G6PD activity increases proportionately. Consequently, the normal red cell responds to oxidation by increasing its reducing capacity, and its large reserves allow it to deal with very significant levels of oxidative stress. This is why a major reduction in G6PD activity has little clinical effect under ordinary circumstances, but may become dramatically apparent in the presence of oxidative stress.

The activity of G6PD, like that of most other red cell enzymes, diminishes as the cell ages; in G6PD-normal red cells, lack of enzyme never endangers cell survival. However, in G6PD-deficient cases the older red cells are even more deficient than the younger ones, and G6PD eventually becomes a limiting factor. This is probably the main cause of the associated mild haemolysis and reduced red cell life-span. …

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