Abstract
Gamma-glutamyl transpeptidase (GGT) is a cell surface enzyme involved in glutathione metabolism and maintenance of redox homeostasis. High expression of GGT on tumor cells is associated with an increase of cell proliferation and resistance against chemotherapy. GGT inhibitors that have been evaluated in clinical trials are too toxic for human use. We have previously identified ovothiols, 5(Nπ)-methyl-thiohistidines of marine origin, as non-competitive-like inhibitors of GGT that are more potent than the known GGT inhibitor, 6-diazo-5-oxo-l-norleucine (DON), and are not toxic for human embryonic cells. We extended these studies to the desmethylated form of ovothiol, 5-thiohistidine, and confirmed that this ovothiol derivative also acts as a non-competitive-like GGT inhibitor, with a potency comparable to ovothiol. We also found that both 5-thiohistidine derivatives act as reversible GGT inhibitors compared to the irreversible DON. Finally, we probed the interactions of 5-thiohistidines with GGT by docking analysis and compared them with the 2-thiohistidine ergothioneine, the physiological substrate glutathione, and the DON inhibitor. Overall, our results provide new insight for further development of 5-thiohistidine derivatives as therapeutics for GGT-positive tumors.
Highlights
Sulfur-containing histidine compounds are a class of amino acid derivatives with unique chemical properties, which make them powerful scavengers of radicals and peroxides [1]
We have previously demonstrated that sulfur-containing histidine compounds act as non-competitive-like inhibitors of Gamma-glutamyl transpeptidase (GGT), which are more potent compared to other compounds of chemical synthesis that have been abandoned in clinical trials due to toxicity [19]
To confirm that the des-methylated form 5-thio acts as a GGT inhibitor, enzymatic assays were carried out using equine kidney GGT, maintaining fixed and saturating concentrations of γ-glutamyl-para-nitroanilide (GpNa) as a donor substrate and glycyl-glycine (GlyGly) as the acceptor, and varying the concentrations of 5-thio, used in its disulfide form
Summary
Sulfur-containing histidine compounds are a class of amino acid derivatives with unique chemical properties, which make them powerful scavengers of radicals and peroxides [1]. The organisms known to be able to synthesize l-ergothioneine are bacteria, mycobacteria and cyanobacteria [2,3], and fungi of the phyla Ascomycota, Zygomycota and Basidiomycota, including higher edible fungi [4]. 5-thiohistidine derivatives, characterized by a methyl group on the imidazole ring of histidine, are naturally present in marine invertebrates, bacteria and protists [8,9,10,11] and occur either as free amino acids, or as building blocks of complex thioalkaloids or iron chelating pigments [12].
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