S-adenosylmethionine: A metabolite critical to the regulation of autophagy

Abstract

Autophagy is a mechanism that enables cells to maintain cellular homeostasis by removing damaged materials and mobilizing energy reserves in conditions of starvation. Although nutrient availability strongly impacts the process of autophagy, the specific metabolites that regulate autophagic responses have not yet been determined. Recent results indicate that S-adenosylmethionine (SAM) represents a critical inhibitor of methionine starvation-induced autophagy. SAM is primarily involved in four key metabolic pathways: transmethylation, transsulphuration, polyamine synthesis and 5'-deoxyadenosyl 5'-radical-mediated biochemical transformations. SAM is the sole methyl group donor involved in the methylation of DNA, RNA and histones, modulating the autophagic process by mediating epigenetic effects. Moreover, the metabolites of SAM, such as homocysteine, glutathione, decarboxylated SAM and spermidine, also exert important influences on the regulation of autophagy. From our perspective, nuclear-cytosolic SAM is a conserved metabolic inhibitor that connects cellular metabolic status and the regulation of autophagy. In the future, SAM might be a new target of autophagy regulators and be widely used in the treatment of various diseases.

Figure 1

S‐adenosylmethionine (SAM) biosynthesis and metabolism. Methionine (Met) is converted into SAM by MAT in an ATP‐dependent process. SAM is linked to four key metabolic pathways: transmethylation, transsulphuration, polyamine synthesis and 5′‐deoxyadenosyl 5′‐radical–mediated biochemical transformations. In transmethylation, SAM donates its methyl group to many substrates, including DNA, RNA and proteins, which are catalysed by specific methyltransferases (MTs). After transmethylation reactions, SAM is converted to S‐adenosylhomocysteine (SAH), which is hydrolysed by a reversible enzyme called SAH hydrolase (AHCY) to form homocysteine (Hcy) and adenosine. Hcy has two fates: to be remethylated to regenerate Met or to enter the transsulphuration pathway. In transsulphuration, Hcy is first converted to cystathionine and then to cysteine (Cys) and α‐ketobutyrate, catalysed by the enzyme cystathionine β‐synthase (CBS). Then, Cys is converted to various sulphur‐containing molecules, including glutathione (GSH), taurine, hydrogen sulphide (H₂S) and sulphate (SO₄), which is catalysed by the enzyme cystathionase (CSE). Both CBS and CSE require vitamin B6 as a cofactor. α‐Ketobutyrate is converted to succinyl‐CoA, which is metabolized in the mitochondria. Hcy is remethylated to regenerate Met via two routes: the MS pathway and the betaine homocysteine S‐methyltransferase (BHMT) pathway. In the MS pathway, 5‐methyltetrahydrofolate (MTHF) donates a methyl group to Hcy, which requires folate and vitamin B12. In the BHMT route, Hcy uses betaine as a methyl donor. In polyamine synthesis, SAM is first decarboxylated to form decarboxylated SAM (dcSAM). Then, putrescine uses dcSAM as a propylamine donor, which is transformed to spermidine (SPD) and spermine (SPM), yielding 5′‐methylthioadenosine (MTA) as a by‐product. MTA is used to regenerate methionine through the methionine salvation pathway. In 5′‐deoxyadenosyl 5′‐radical–mediated biochemical transformations, SAM initiates various radical chemical reactions, which are catalysed by a large family of SAM radical enzymes. These enzymes share a CX₃CX₂C motif forming a characteristic [4Fe‐4S] cluster. SAM is converted to [4Fe‐4S]‐methionine and a 5′‐deoxyadenosyl 5′‐radical through binding to the [4Fe‐4S] cluster

Figure 2

Working model for SAM‐mediated modulation of autophagy. SAM is an essential metabolite that acts as a high‐energy methyl donor for most methylation modifications of non‐histone, histone, DNA and RNA, which epigenetically affect autophagic flux. Moreover, SAM is the biosynthetic precursor for HCY and cysteine and other sulphur‐containing metabolites such as GSH. All of these roles significantly contribute to the modulation of autophagy. In addition, the SAM metabolite SPD has also been shown to be a physiological inducer of autophagy. Collectively, the metabolites of SAM and the key enzymes in SAM biosynthesis and metabolism influence the core autophagy machinery. S‐adenosylmethionine: SAM, homocysteine: HCY, glutathione: GSH, spermidine: SPD, AMP‐dependent protein kinase: AMPK, mechanistic target of rapamycin: mTOR, migration inhibitory factor: MIF, cystic fibrosis transmembrane conductance regulator: CFTR, mTOR complex 1: mTORC1, protein phosphatase 2A: PP2A, nitrogen permease regulating protein: NPR2P, ten‐eleven translocation methylcytosine dioxygenases: TET, N⁶‐methyladenosine: RNA methylation, m⁶A RNA methylation