FIGURE 2: The indirect SAM transport schematic. The polar nature of SAM and the likely absence of SAM transporters in the plasma membrane presents challenges for the direct transport of SAM across the plasma membrane and limits its bioavailability. Under physiological conditions, however, SAM readily degrades into MTA. Unlike SAM, MTA can cross cell membrane through both nonspecific nucleoside transport system and passive diffusion. Once inside the cell, MTA can participate in the methionine salvage pathway to regenerate methionine, which can be utilized by the SAM synthase, methionine adenosyltransferase (MAT), to replenish intracellular SAM. When viewed as a whole, MTA effectively brings in the sulfur and activated methyl group of the extracellular SAM into the cell, overcomes the challenges of direct SAM transport across plasma membrane, and enables the utilization of those functional groups for reactions such as methylation and transsulfuration.