Probing the Interactions of Sulfur-Containing Histidine Compounds with Human Gamma-Glutamyl Transpeptidase.
Aquatic Organisms
/ chemistry
Azo Compounds
/ pharmacology
Cell Proliferation
/ drug effects
Drug Development
Drug Resistance, Neoplasm
/ drug effects
Enzyme Assays
Glutathione
/ metabolism
HEK293 Cells
Histidine
/ chemistry
Humans
Molecular Docking Simulation
Neoplasms
/ drug therapy
Norleucine
/ analogs & derivatives
Substrate Specificity
Sulfur Compounds
/ chemistry
Toxicity Tests
gamma-Glutamyltransferase
/ antagonists & inhibitors
GGT
docking simulation
enzymatic inhibition
ergothioneine
marine antioxidant
marine drugs
molecular interactions
ovothiol
sulfur-containing histidine
γ-glutamyl transpeptidase
Journal
Marine drugs
ISSN: 1660-3397
Titre abrégé: Mar Drugs
Pays: Switzerland
ID NLM: 101213729
Informations de publication
Date de publication:
20 Nov 2019
20 Nov 2019
Historique:
received:
29
10
2019
revised:
11
11
2019
accepted:
18
11
2019
entrez:
24
11
2019
pubmed:
24
11
2019
medline:
21
4
2020
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 31757046
pii: md17120650
doi: 10.3390/md17120650
pmc: PMC6949936
pii:
doi:
Substances chimiques
Azo Compounds
0
Sulfur Compounds
0
Histidine
4QD397987E
Norleucine
832C8OV84S
gamma-Glutamyltransferase
EC 2.3.2.2
Glutathione
GAN16C9B8O
6-diazo-5-oxonorleucine
LOS90IK8XH
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Horizon 2020
ID : No 654008
Déclaration de conflit d'intérêts
The authors declare no conflict of interest.
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