Rethinking the bioavailability and cellular transport properties of S-adenosylmethionine

Abstract

S-adenosylmethionine (SAM) is a versatile metabolite that participates in a wide range of reactions such as methylation and transsulfuration. These capabilities allow SAM to influence cellular processes such as gene expression and redox balancing. The importance of SAM is highlighted by its widespread usage as an over-the-counter nutrient supplement and as an experimental reagent in molecular biology. The bioavailability and cellular transport properties of SAM, however, are often overlooked under these contexts, putting limits on SAM's therapeutic potential and complicating the interpretation of experimental results. In this article, we examined the chemical stability and cellular permeability of SAM, proposed a schematic for indirect SAM transport across the mammalian plasma membrane, and lastly discussed the implications arising from such transport schematic.

Keywords: S-adenosyl-methionine; SAM; metabolism; methionine.

Figure 1. FIGURE 1: The chemical structures of S-adenosylmethionine (SAM) and 5'-methylthioadenosine (MTA).

With features of an amino acid (yellow) and a ribose nucleotide (blue), SAM is highly polar. Under physiological conditions, SAM can undergo a non-enzymatic cleavage reaction and degrade into homoserine and MTA.

Figure 2. 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.