Erythroid heme metabolism and its dependence on glycine and pyridoxine. Glycine is imported into erythroid precursors by the surface transporter SLC6A9 and then into mitochondria by SLC25A38. Serine can readily be converted to glycine in the cytosol and mitochondrion by serine hydroxymethylase 1 (SHMT1) and SHMT2, respectively, which are pyridoxal phosphate-dependent enzymes that provide 1 carbon fragment to convert tetrahydrofolate (THF) to form methylene-THF (CH₂-THF), promoting multiple pathways important to erythrocytes, including DNA and glutathione synthesis that require other PLP enzymes. Serine can be transported into mitochondria by members of the sideroflexin (SFXN) family, which may support the synthesis of the heme precursor ALA by ALAS2 by indirectly providing a source of glycine in the absence of SLC25A38. CoA, coenzyme A; GCS, glycine cleavage system; PLP, pyridoxal 5 phosphate or vitamin B6; SAH, S-adenosylhomocysteine hydrolase; SAM, S-adenosyl methionine.