The pentose phosphate pathway includes an irreversible oxidative phase followed by a series of reversible sugar–phosphate interconversions (Fig. 13.14). No ATP is directly consumed or produced in the pathway. The reduced nicotinamide adenine dinucleotide phosphate (NADPH)-producing oxidative portion of the pathway is important in providing reducing equivalents for reductive biosynthesis and detoxification reactions. In this part of the pathway, glucose 6-phosphate is irreversibly converted to ribulose 5-phosphate, and two NADPH are produced. The regulated step is catalyzed by glucose 6-phosphate dehydrogenase (G6PD), which is strongly inhibited by a rise in the NADPH/NADP+ ratio. Reversible nonoxidative reactions interconvert sugars. This part of the pathway converts ribulose 5-phosphate to ribose 5-phosphate, required for nucleotide and nucleic acid synthesis, or to fructose 6-phosphate and glyceraldehyde 3-phosphate (glycolytic intermediates). NADPH is a source of reducing equivalents in reductive biosynthesis, such as the production of fatty acids in liver, adipose tissue, and the mammary gland; cholesterol in the liver; and steroid hormones in the placenta, ovaries, testes, and adrenal cortex. It is also required by red blood cells (RBC) for hydrogen peroxide reduction. Reduced glutathione (G-SH) is used by glutathione peroxidase to reduce the peroxide to water. The oxidized glutathione (G-S-S-G) produced is reduced by glutathione reductase, using NADPH as the source of electrons. NADPH provides reducing equivalents for the mitochondrial cytochrome P450 monooxygenase system, which is used in steroid hormone synthesis in steroidogenic tissue, bile acid synthesis in the liver, and vitamin D activation in the liver and kidneys. The microsomal system uses NADPH to detoxify foreign compounds (xenobiotics), such as drugs and a variety of pollutants. NADPH provides the reducing equivalents for phagocytes in the process of eliminating invading microorganisms. NADPH oxidase uses molecular oxygen (O2) and electrons from NADPH to produce superoxide radicals, which, in turn, can be converted to peroxide by superoxide dismutase. Myeloperoxidase catalyzes the formation of bactericidal hypochlorous acid from peroxide and chloride ions. Rare genetic defects in NADPH oxidase cause chronic granulomatous disease characterized by severe, persistent, infections and granuloma formation. NADPH is required for the synthesis of nitric oxide (NO), an important free radical gas that causes vasodilation by relaxing vascular smooth muscle, acts as a neurotransmitter, prevents platelet aggregation, and helps mediate macrophage bactericidal activity. NO is made from arginine and O2 by three different NADPH-dependent NO synthases (NOS). The endothelial (eNOS) and neuronal (nNOS) isozymes constantly produce very low levels of NO for vasodilation and neurotransmission, respectively. The inducible isozyme (iNOS) produces large amounts of NO for defense against pathogens. G6PD deficiency impairs the ability of the cell to form the NADPH that is essential for the maintenance of the G-SH pool. The cells most affected are RBC because they do not have additional sources of NADPH. G6PD deficiency is an X-linked disease characterized by hemolytic anemia caused by the production of free radicals and peroxides following administration of oxidant drugs, ingestion of fava beans, or severe infections. The extent of the anemia depends on the amount of residual enzyme. Class I variants, the most severe (and least common), are associated with chronic nonspherocytic hemolytic anemia. Babies with G6PD deficiency may experience neonatal jaundice.