Figure 3.

Regulation of epigenetic signaling by cofactor depletion. SAM functions as a universal methyl donor for methylation of macromolecules and metabolites. Overactivity of metabolic methyltransferases such as NNMT can result in depletion of SAM and decreased SAM/SAH ratios, thereby reducing KMT/DNMT activity and genomic methylation. Replenishment of SAM requires the activity of the folate and SAM cycles, which utilize methyl groups derived from folate or choline (not shown) to replenish intracellular methionine for SAM biosynthesis. Disruption of the SAM cycle by inhibitors has been shown to decrease the activity of KMT enzymes in cancer. Cofactors and byproducts of most enzymatic reactions have been omitted for simplicity. NNMT, nicotinamide N-methyltransferase; SAHase, S-adenosylhomocysteine hydrolase; MTR, 5-methyltetrahydrofolate-homocysteine methyltransferase; MTHFR, methylenetetrahydrofolate reductase; SHMT, serine hydroxymethyltransferase; MAT, methionine adenosyltransferase; DZNep, 3-deazaneplanocin A.