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 ± 0.1 µM[3].
S-adenosylhomocysteine(25 µM) 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 NFκB-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-κB-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.
S-腺苷同型半胱氨酸 (SAH) （S-Adenosylhomocysteine）是一种氨基酸衍生物，是蛋氨酸代谢[1] 中的关键中间代谢产物。它是半胱氨酸和腺苷合成的中间体[2]。 S-腺苷同型半胱氨酸抑制 METTL3-14 活性，IC50 值为 0.9 ± 0.1 µM[3]。
S-腺苷同型半胱氨酸(25 µM)抑制CBS缺陷型酵母的生长，但对野生型酵母没有影响。在培养基中添加 SAM 可以完全逆转 S-腺苷高半胱氨酸对 CBS 缺陷酵母的生长抑制作用[4]。高 S-腺苷同型半胱氨酸水平抑制 NFκB 介导的基因表达，并使原代肝细胞和 HepG2 细胞对 TNF 的细胞毒性作用敏感[5]。增加的脂肪 S-腺苷同型半胱氨酸水平会产生促进脂肪分解的甲基化缺陷。酒精诱导的肝细胞 S-腺苷同型半胱氨酸增加以及由此导致的 SAM/SAH 比值降低导致 ALD 的发病机制和进展[6]。
S-腺苷同型半胱氨酸增强相互作用在 AHCYL1 和 PIK3C3 之间。当细胞存在 S-腺苷同型半胱氨酸时，增强的相互作用会抑制 PtdIns3P 的产生，从而阻止自噬启动。当 S-腺苷同型半胱氨酸不存在时，减少的相互作用释放 PIK3C3 产生 PtdIns3P，最终促进自噬[1]。 CKD 与尿液中的低 SAM 水平和 SAM/SAH 比值相关。尿液中 SAM 水平或 SAM/SAH 比值可被视为肾功能不全的有前途的非侵入性指标[7]。