Choi Hee Shim, Shim Joong Sup, Kim Ju-A, Kang Sang Won, Kwon Ho Jeong
Chemical Genomics Laboratory, Department of Biotechnology, College of Engineering, Yonsei University, 134 Shinchon-dong, Seodaemun-gu, Seoul 120-749, Republic of Korea.
Biochem Biophys Res Commun. 2007 Aug 3;359(3):523-8. doi: 10.1016/j.bbrc.2007.05.139. Epub 2007 May 29.
Thioredoxin redox system has been implicated as an intracellular anti-oxidant defense system leading to reduction of cellular oxidative stresses utilizing electrons from NADPH. From high content screening of small molecules targeting the system, gliotoxin, a fungal metabolite, was identified as an active compound. Gliotoxin potently accelerates NADPH oxidation and reduces H(2)O(2). The compound reduces H(2)O(2) to H(2)O by replacing the function of peroxiredoxin in vitro and decreases intracellular level of H(2)O(2) in HeLa cells. The anti-oxidant activity of gliotoxin was further validated H(2)O(2)-mediated cellular phenotype of angiogenesis. The proliferation of endothelial cells was inhibited by the compound at nanomolar range. In addition, H(2)O(2)-induced tube formation and invasion of the cells were blocked by gliotoxin. Together, these results demonstrate that gliotoxin is a new small molecule targeting thioredoxin redox system.
硫氧还蛋白氧化还原系统被认为是一种细胞内抗氧化防御系统，可利用来自NADPH的电子减少细胞氧化应激。通过对靶向该系统的小分子进行高内涵筛选，发现了一种真菌代谢产物——gliotoxin（麦角硫因）作为活性化合物。Gliotoxin能有效加速NADPH氧化并减少H₂O₂。该化合物在体外通过取代过氧化物还原酶的功能将H₂O₂还原为H₂O，并降低HeLa细胞内H₂O₂的水平。Gliotoxin的抗氧化活性通过H₂O₂介导的血管生成细胞表型得到进一步验证。该化合物在纳摩尔范围内抑制内皮细胞的增殖。此外，gliotoxin可阻断H₂O₂诱导的细胞管形成和侵袭。总之，这些结果表明gliotoxin是一种靶向硫氧还蛋白氧化还原系统的新型小分子。
