Flavin reductase (NADPH) (BLVRB) (BLVRB)

Flavin reductase (NADPH), commonly referred to as NADPH-methemoglobin reductase in clinical contexts, is a cytosolic enzyme primarily responsible for the reduction of flavins and biliverdin IX-beta [18, 21]. While it plays a minor role (less than 5%) in the physiological reduction of methemoglobin under normal conditions, it becomes the critical pathway for the pharmacological treatment of methemoglobinemia [1, 3, 7]. When the drug methylene blue is administered, this enzyme reduces it to leukomethylene blue using NADPH as an electron donor [8, 10]. Leukomethylene blue then acts as a potent electron carrier to non-enzymatically reduce ferric iron (Fe3+) in methemoglobin back to the functional ferrous state (Fe2+) in hemoglobin [9, 15]. This enzyme's activity is strictly dependent on the availability of NADPH, which is primarily generated by the pentose phosphate pathway; consequently, its therapeutic efficacy is compromised in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency [10, 12]. Beyond its role in methemoglobinemia, the enzyme is involved in the reduction of biliverdin and various flavins, and it has been identified as a heme-binding protein in both erythrocytes and the liver [16, 21]. It also possesses protein nitrosyltransferase activity, contributing to the regulation of various signaling pathways [21]. The enzyme is distinct from the NADH-dependent cytochrome b5 reductase, which is the primary physiological system for methemoglobin maintenance [1, 19]. Therapeutic use of methylene blue targeting this enzyme requires careful monitoring due to risks of serotonin syndrome and interference with pulse oximetry readings [8, 25].

Other names

NADPH-methemoglobin reductaseBiliverdin reductase BNADPH-dependent methemoglobin reductaseNADPH-diaphoraseBiliverdin-IX beta-reductaseBVRB

Methylene blue acts as an artificial electron carrier; the enzyme reduces methylene blue to leukomethylene blue using NADPH, and leukomethylene blue then non-enzymatically reduces methemoglobin to hemoglobin.