Fig. 3.

Cytosolic and Mitochondrial Compartmentalization of One-Carbon Metabolism. Serine and glycine contribute to one-carbon metabolism in largely parallel cytoplasmic and mitochondrial pathways. Serine hydroxymethyltransferate (SHMT1/2) catalyzes the contribution of the serine beta carbon into the one carbon pool by production of 5,10-methyl tetrahydrofolate (MeTHF). Cytoplasmic 5,10-MeTHF can then contribute to dTMP synthesis or to most major methylation reactions of the cell via production of S-Adenosyl methionine. In the mitochondria, glycine can be further cleaved to form another molecule of 5,10-MeTHF whilst in the cytoplasm, glycine instead can contribute en masse to purine biosynthesis. One-carbon units are managed by the methylenetetrahydrofolate dehydrogenases (MTHFD1/2), which can produce appropriate THF derivatives for nucleotide biosynthesis in the cytoplasm or for the production of NADPH in either compartment. Serine and glycine are thought to move across the inner mitochondrial membrane (IMM) via unknown transporters, whilst THF derivatives and NADPH are not thought to translocate between these two compartments. Green text denotes the fate of serine derived nitrogen, gray boxes indicate major endpoint metabolites produced from serine. Key enzymes are shown in light blue.