Fig. 4.

Key metabolic pathways fuelling NADPH generation. 1.) The pentose phosphate pathway, shunts from glucose-6-phosphate (G6P) to regenerate two nicotinamide adenine dinucleotide phosphates (NADPH) in two dehydrogenase steps i. G6P to 6-phosphogluconate (6PG) via glucose 6-phosphate dehydrogenase (G6PD) and ii. 6PG to ribose 5-phosphate (Ru5P) via 6 phosphogluconate dehydrogenase (6PGD). 2.) Malic enzymes 1, 2 and 3. Malic enzymes located within cytoplasm (ME1) and mitochondria (ME2 and ME3) catalyse the oxidative decarboxylation of malate to pyruvate while concurrently generating NADPH from NADP. 3.) Isocitrate dehydrogenases (IDHs) catalyse oxidative decarboxylation to produce NADPH. IDH1 localizes to varying extents to the cytoplasm, and IDH2/3 localise to the mitochondria. 4.) One-carbon (1 C) and folate metabolism which involves a series of 1 C transformations that generate and consume redox equivalents including the oxidisation of 10-Formyltetrahydrofolate (10-formyl-THF) to carbon dioxide (CO₂) by cytosolic (1)/mitochondrial (2) 10-formyltetrahydrofolate dehydrogenase (ALDH1L1/2). NADPH can also be produced by reversible conversions of 5,10-methylene-tetrahydrofolate (5,10-meTHF) to 10-formylTHF by cytosolic (1) and mitochondrial (2) Methylenetetrahydrofolate Dehydrogenase (MTHFD1/2 L). Figure created using Biorender.com