Discovery of gliotoxin as a new small molecule targeting thioredoxin redox system.
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.
Choi
Hee Shim
HS
Chemical Genomics Laboratory, Department of Biotechnology, College of Engineering, Yonsei University, 134 Shinchon-dong, Seodaemun-gu, Seoul 120-749, Republic of Korea.
Shim
Joong Sup
JS
Kim
Ju-A
JA
Kang
Sang Won
SW
Kwon
Ho Jeong
HJ
D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005912:Gliotoxin / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D015394:Molecular Structure; D010084:Oxidation-Reduction / Q000187:drug effects; D009195:Peroxidase / Q000378:metabolism; D013879:Thioredoxins / Q000378:metabolism*; D014470:Umbilical Cord / Q000098:blood supply / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
D013879:Thioredoxins; D005912:Gliotoxin; D006861:Hydrogen Peroxide; D009195:Peroxidase