期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 294, 期 40, 页码 14603-14614出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.RA119.009304
关键词
autophagy; enzyme inhibitor; enzyme kinetics; thiol; apoptosis; ergothioneine; GGT-positive cells; glutamyl transpeptidase; marine drugs; ovothiol
资金
- Stazione Zoologica Anton Dohrn
- Institute of Food Sciences
gamma-Glutamyl transpeptidase (GGT) is an enzyme located on the surface of cellular membranes and involved in GSH metabolism and maintenance of redox homeostasis. High GGT expression on tumor cells is associated with increased cell proliferation and resistance against chemotherapy. GGT inhibitors evaluated so far in clinical trials are too toxic for human use. In this study, using enzyme kinetics analyses, we demonstrate that ovothiols, 5(N pi)-methyl thiohistidines of marine origin, act as noncompetitive inhibitors of GGT, with an apparent K-i of 21 mu m, when we fixed the concentrations of the donor substrate. We found that these compounds are more potent than the known GGT inhibitor 6-diazo-5-oxo-L-norleucine and are not toxic toward human embryonic cells. In particular, cellular process-specific fluorescence-based assays revealed that ovothiols induce a mixed cell-death phenotype of apoptosis and autophagy in GGT-overexpressing cell lines, including human liver cancer and chronic B leukemic cells. The findings of our study provide the basis for further development of 5-thiohistidines as therapeutics for GGT-positive tumors and highlight that GGT inhibition is involved in autophagy.
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