Pentose phosphate pathway — oxidative branch (NADPH generation); G6PD deficiency / favism

The oxidative branch of the pentose phosphate pathway is the cytosolic route that diverts glucose-6-phosphate away from glycolysis to generate NADPH and pentose sugars. In three irreversible steps it converts glucose-6-phosphate to ribulose-5-phosphate, producing two molecules of NADPH and one CO2: glucose-6-phosphate dehydrogenase (G6PD) oxidises glucose-6-phosphate to 6-phosphogluconolactone (reducing NADP+ to NADPH) as the committed, rate-limiting step; 6-phosphogluconolactonase (PGLS) hydrolyses the labile lactone to 6-phosphogluconate; and 6-phosphogluconate dehydrogenase (PGD) oxidatively decarboxylates 6-phosphogluconate to ribulose-5-phosphate + CO2 (reducing a second NADP+). The NADPH produced is the cell's principal reducing power for reductive biosynthesis (fatty acids, cholesterol, nucleotides) and, critically in erythrocytes, for regenerating reduced glutathione to defend against oxidative stress; the ribulose-5-phosphate feeds the non-oxidative branch (and thence ribose-5-phosphate for nucleotide synthesis). Inherited G6PD deficiency is the most common human enzyme defect (~400 million people), X-linked, causing acute oxidant-triggered hemolytic anemia (favism, drug/infection-induced), neonatal jaundice, and — in severe class-I variants — chronic nonspherocytic hemolytic anemia.