Department of Physiology, University of Louisville, Louisville, Kentucky, 40202, USA.
School of Medicine, University of Louisville, Louisville, Kentucky, USA.
Mol Cell Biochem. 2024 Apr;479(4):825-829. doi: 10.1007/s11010-023-04761-9. Epub 2023 May 17.
One in 700 children is born with the down syndrome (DS). In DS, there is an extra copy of X chromosome 21 (trisomy). Interestingly, the chromosome 21 also contains an extra copy of the cystathionine beta synthase (CBS) gene. The CBS activity is known to contribute in mitochondrial sulfur metabolism via trans-sulfuration pathway. We hypothesize that due to an extra copy of the CBS gene there is hyper trans-sulfuration in DS. We believe that understanding the mechanism of hyper trans-sulfuration during DS will be important in improving the quality of DS patients and towards developing new treatment strategies. We know that folic acid "1-carbon" metabolism (FOCM) cycle transfers the "1-carbon" methyl group to DNA (H3K4) via conversion of s-adenosyl methionine (SAM) to s-adenosyl homocysteine (SAH) by DNMTs (the gene writers). The demethylation reaction is carried out by ten-eleven translocation methylcytosine dioxygenases (TETs; the gene erasers) through epigenetics thus turning the genes off/on and opening the chromatin by altering the acetylation/HDAC ratio. The S-adenosyl homocysteine hydrolase (SAHH) hydrolyzes SAH to homocysteine (Hcy) and adenosine. The Hcy is converted to cystathionine, cysteine and hydrogen sulfide (HS) via CBS/cystathioneγ lyase (CSE)/3-mercaptopyruvate sulfurtransferase (3MST) pathways. Adenosine by deaminase is converted to inosine and then to uric acid. All these molecules remain high in DS patients. HS is a potent inhibitor of mitochondrial complexes I-IV, and regulated by UCP1. Therefore, decreased UCP1 levels and ATP production can ensue in DS subjects. Interestingly, children born with DS show elevated levels of CBS/CSE/3MST/Superoxide dismutase (SOD)/cystathionine/cysteine/HS. We opine that increased levels of epigenetic gene writers (DNMTs) and decreased in gene erasers (TETs) activity cause folic acid exhaustion, leading to an increase in trans-sulphuration by CBS/CSE/3MST/SOD pathways. Thus, it is important to determine whether SIRT3 (inhibitor of HDAC3) can decrease the trans-sulfuration activity in DS patients. Since there is an increase in H3K4 and HDAC3 via epigenetics in DS, we propose that sirtuin-3 (Sirt3) may decrease H3K4 and HDAC3 and hence may be able to decrease the trans-sulfuration in DS. It would be worth to determine whether the lactobacillus, a folic acid producing probiotic, mitigates hyper-trans-sulphuration pathway in DS subjects. Further, as we know that in DS patients the folic acid is exhausted due to increase in CBS, Hcy and re-methylation. In this context, we suggest that folic acid producing probiotics such as lactobacillus might be able to improve re-methylation process and hence may help decrease the trans-sulfuration pathway in the DS patients.
唐氏综合征（DS）患儿的出生率为 1/700。在 DS 中，第 21 号染色体 X 有额外的一份拷贝（三体）。有趣的是，21 号染色体也含有额外的胱硫醚β合酶（CBS）基因拷贝。CBS 活性已知通过转硫途径有助于线粒体硫代谢。我们假设由于 CBS 基因的额外拷贝，DS 中存在高转硫作用。我们相信，了解 DS 中高转硫作用的机制对于提高 DS 患者的生活质量以及开发新的治疗策略非常重要。我们知道，叶酸“1 碳”代谢（FOCM）循环通过将“1 碳”甲基基团从 S-腺苷甲硫氨酸（SAM）转化为 S-腺苷同型半胱氨酸（SAH），从而将“1 碳”甲基基团转移到 DNA（H3K4）上，由 DNMTs（基因书写器）完成。去甲基化反应由 ten-eleven 易位甲基胞嘧啶双加氧酶（TET；基因橡皮擦）通过表观遗传学进行，通过改变乙酰化/HDAC 比值，从而关闭基因并打开染色质。S-腺苷同型半胱氨酸水解酶（SAHH）将 SAH 水解为同型半胱氨酸（Hcy）和腺苷。Hcy 通过 CBS/胱硫醚γ 合酶（CSE）/3-巯基丙酮酸硫转移酶（3MST）途径转化为胱硫醚、半胱氨酸和硫化氢（HS）。腺苷通过脱氨酶转化为肌苷，然后转化为尿酸。所有这些分子在 DS 患者中都保持较高水平。HS 是线粒体复合物 I-IV 的有效抑制剂，并受 UCP1 调节。因此，DS 患者可能会出现 UCP1 水平降低和 ATP 生成减少的情况。有趣的是，患有 DS 的儿童表现出 CBS/CSE/3MST/超氧化物歧化酶（SOD）/胱硫醚/半胱氨酸/HS 的水平升高。我们认为，表观遗传基因书写器（DNMTs）水平升高和基因橡皮擦（TETs）活性降低导致叶酸耗竭，导致 CBS/CSE/3MST/SOD 途径的转硫作用增加。因此，确定 SIRT3（HDAC3 抑制剂）是否可以降低 DS 患者的转硫作用非常重要。由于 DS 中通过表观遗传增加了 H3K4 和 HDAC3，我们提出 Sirt3 可能降低 H3K4 和 HDAC3，从而可能降低 DS 中的转硫作用。确定产叶酸益生菌乳杆菌是否可以减轻 DS 患者的高转硫途径，这将是值得的。此外，由于我们知道在 DS 患者中，由于 CBS、Hcy 和再甲基化的增加，叶酸被耗尽。在这种情况下，我们建议产叶酸益生菌，如乳杆菌，可能能够改善再甲基化过程，从而有助于降低 DS 患者的转硫途径。
