S-Adenosylhomocysteine (Synonyms: AdoHcy, SAH)

S-adenosylhomocysteine (SAH), an amino acid derivative, is a key intermediate metabolite in methionine metabolism^[1]. It is an intermediate in the synthesis of cysteine and adenosine^[2]. S-adenosylhomocysteine inhibited METTL3-14 activity with an IC50 value of 0.9 ¡À 0.1 ?M^[3].

S-adenosylhomocysteine(25 ?M) inhibited the growth of CBS deficient yeast, but had no effect on wild-type yeast. Growth inhibition by S-adenosylhomocysteine in CBS deficient yeast can be totally reversed by addition of SAM to the media^[4]. High S-adenosylhomocysteine levels inhibited NF¦ʂ-mediated gene expression and sensitized primary hepatocytes and HepG2 cells to the cytotoxic effects of TNF^[5]. Increased adipose S-adenosylhomocysteine levels generate methylation defects that promote lipolysis. Alcohol-induced increases in hepatocellular S-adenosylhomocysteine and the resultant lowering of SAM/SAH ratio lead to the pathogenesis and progression of ALD^[6].

S-adenosylhomocysteine enhances the interaction between AHCYL1 and PIK3C3. When cells are in the presence of S-adenosylhomocysteine, the enhanced interaction suppresses the production of PtdIns3P, which blocks the autophagy initiation. When in the absence of S-adenosylhomocysteine, the decreased interaction releases PIK3C3 to produce PtdIns3P, eventually promotes autophagy^[1]. CKD was associated with a low SAM level and SAM/SAH ratio in urine. The use of the SAM level or the SAM/SAH ratio in urine could be considered as a promising, noninvasive indicator of renal dysfunction^[7].

References:
[1] Huang W, Li N, et al. AHCYL1 senses SAH to inhibit autophagy through interaction with PIK3C3 in an MTORC1-independent manner. Autophagy. 2022;18(2):309-319.
[2] DE LA HABA G, et al. The enzymatic synthesis of S-adenosyl-L-homocysteine from adenosine and homocysteine. J Biol Chem. 1959;234(3):603-608.
[3] Li F, Kennedy S, et al. A Radioactivity-Based Assay for Screening Human m6A-RNA Methyltransferase, METTL3-METTL14 Complex, and Demethylase ALKBH5. J Biomol Screen. 2016;21(3):290-297.
[4] Christopher SA, Melnyk S, et al. S-adenosylhomocysteine, but not homocysteine, is toxic to yeast lacking cystathionine beta-synthase. Mol Genet Metab. 2002;75(4):335-343.
[5] Watson WH, Burke TJ, et al. S-adenosylhomocysteine inhibits NF-¦ʂ-mediated gene expression in hepatocytes and confers sensitivity to TNF cytotoxicity. Alcohol Clin Exp Res. 2014;38(4):889-896.
[6] Arumugam MK, Chava S, et al. Elevated S-adenosylhomocysteine induces adipocyte dysfunction to promote alcohol-associated liver steatosis. Sci Rep. 2021;11(1):14693. Published 2021 Jul 19.
[7] Kruglova MP, Grachev SV, et al. Low S-adenosylmethionine/ S-adenosylhomocysteine Ratio in Urine is Associated with Chronic Kidney Disease. Lab Med. 2020;51(1):80-85.