The most abundant marine sulfur-containing compounds are probably ovothiols, histidine-derived thiols, isolated from marine invertebrates, microalgae, and proteobacteria. In sea urchin eggs ovothiols play a key role in the protection of cells towards the oxidative burst associated with fertilization by controlling the cel- lular redox balance and recycling oxidized glutathione. Gamma- glutamyl transpeptidase (GGT) is a cell surface enzyme involved in glutathione metabolism. High expression of GGT on mem- brane surface of tumor cells is associated with increase of cell proliferation and resistance to chemotherapy. Moreover, GGT is considered a diagnostic marker in several liver and renal diseases, in asthma, and reperfusion injury. GGT is generally inhibited by glutamine analogues that compete with the substrate for the gamma-glutamyl binding site. However, the glutamine analogues that have been evaluated so far in clinical trials are too toxic for use in humans. Here we report that ovothiol A, 5(N)-methyl thiohistidine, isolated from sea urchin eggs, acts as a novel potent and less toxic inhibitor of GGT activity. In detail, 5-thiohistidine compounds are uncompetitive inhibitors, binding the c-glutamyl enzyme complex, with an intrinsic Ki of 26 lM. Ovothiols are 15-fold more potent than the GGT known inhibitor 6-diazo-5- oxo-L norleucine and are not toxic towards human kidney embryonal HEK293 cells. As GGT-overexpressing positive cell lines, we identified human liver cancer cells HepG2 and chronic B leukemic cells HG3. Ovothiol A treatment induced membrane- bound GGT inhibition and a cell death phenotype mediated by autophagy in HepG2 and HG3 cells. This study provides the basis for further development of 5-thiohistidines as therapeutics for GGT-positive tumors and GGT dependent pathologies, such as liver fibrosis.
|Titolo:||Therapeutic potential of marine sulfur- containing compounds|
|Data di pubblicazione:||2019|
|Appare nelle tipologie:||4.2 Abstract in Atti di convegno|