Once taken up by the enterocyte, the enzyme dihydrofolate reductase mediates the conversion of folic acid to methyltetrahydrofolate through a two-step reaction. The folate then exits the enterocyte via the basolateral membrane and is either taken into the systemic circulation or the enterohepatic cycle (liver, bile acids, intestine). In the systemic circulation, 66% binds to albumin, 33% remains free, and a small amount (1%) binds to FBP. This is how it is transported to the cells where it will be used. It enters the cells either by binding to RTF-1 or RTF-2 or to folate receptor 1 (alpha) or 2 (beta). Intracellular folate transport is mediated by clathrin-mediated endocytosis. Once inside the cell (methyltetrahydrofolate), it must be demethylated to become tetrahydrofolate (functional folate that can accept glutamic acid chains; these in turn prevent it from exiting the cell, in other words, they “anchor” it inside the cell).13 and 15