Nicotinamide adenine dinucleotide phosphate (NADPH) biosynthesis pathway (NADPH biosynthesis)

NADPH (reduced nicotinamide adenine dinucleotide phosphate) biosynthesis describes the metabolic network responsible for maintaining the cellular pool of NADPH, a fundamental cofactor for life. This process is primarily fueled by the oxidative branch of the pentose phosphate pathway and is supplemented by enzymes such as malic enzyme, isocitrate dehydrogenase, and those in the folate-mediated one-carbon metabolism. NADPH provides the essential reducing equivalents required for the synthesis of macromolecules, including fatty acids, steroids, and nucleotides, while also serving as the primary electron donor for antioxidant systems like glutathione and thioredoxin. In many pathological states, such as cancer and certain parasitic infections, this pathway is significantly upregulated to mitigate oxidative stress and fuel rapid growth, making it a critical focus for metabolic therapy. Targeting the enzymes of NADPH biosynthesis allows for the selective sensitization of diseased cells to oxidative damage and the inhibition of metabolic pathways necessary for survival and proliferation.

Other names

NADPH productionNADP+ reductionNADP biosynthesisPentose phosphate pathway (oxidative branch)Redox homeostasis pathway

Drugs targeting this pathway typically act as competitive or non-competitive inhibitors of key rate-limiting enzymes, such as glucose-6-phosphate dehydrogenase (G6PD) or NAD kinase (NADK). By inhibiting these enzymes, pharmacological agents deplete the cellular pool of reduced NADPH, which subsequently increases intracellular reactive oxygen species (ROS) levels and impairs the reductive biosynthesis of lipids and DNA, ultimately leading to oxidative stress-induced apoptosis or growth arrest in rapidly proliferating cells like cancer or pathogens.