S-adenosylmethionine: Simple agent of methylation and secret to aging and metabolism?

Abstract

S-adenosylmethionine (SAM) is a sulfur-containing molecule at the heart of metabolism of all organisms. It is well known as the methyl donor for the majority of methyltransferases that modify DNA, RNA, histones, and many other proteins such as Tp53, lipids, and a variety of other small molecules including toxic compounds, such as arsenic, whose actions affect replication, transcription, and translation, DNA repair and chromatin modeling, epigenetic modifications, and imprinting. Transmethylation by SAM generates S-adenosylhomocysteine, which is converted back to SAM via the methionine cycle or to the antioxidant glutathione via the transsulfuration pathway. So far 15 superfamilies of SAM-binding proteins have been identified with additional vital roles in polyamine synthesis and in the generation of radicals for difficult chemical reactions such as the synthesis of biotin. Surprisingly, SAM also serves as an essential cofactor in specific recognition and cutting of DNA by nucleases, such as EcoKI, and in FeS cluster-containing proteins such as the transcription elongator Elp3. Finally, on a completely different track, SAM can bind certain RNA structures called riboswitches that control transcription and/or translation. In this way, gene expression can be regulated in a SAM-dependent manner, a recent finding that opens up new avenues into gene control by alternative RNA secondary structure formation. Deregulation of SAM through folate or vitamin shortage and/or radical surplus via dietary insufficiency, alcohol abuse, arsenic poisoning, irradiation, and/or other environmental or hereditary factors leads to a wide variety of human diseases, e.g., autoimmune disease, cancer, depression, and other neurological illnesses, and is implicated in longevity and aging. This review gives an overview of the roles of this small metabolite and discusses the implications of deregulation of SAM to longevity and aging.