GGsTop is an irreversible inhibitor of γ-glutamyl transpeptidase (GGT) (Ki = 170μM) [1]. GGsTop covalently binds to the active site of GGT, inhibiting its catalytic activity, thereby regulating the intracellular reduction state, impacting amino acid metabolism, and modulating cellular redox balance [2-3]. GGsTop is primarily used to alleviate liver damage [4].
In human periodontal ligament cells (hPLCs), the proliferation of hPLCs was enhanced after treatment with GGsTOP (0-50μM; 7d) [5]. In HCC-1806 cells, Glutathione activity was inhibited after GGsTOP (0.01-10000nM; 4h) treatment [6].
In cyclophosphamide-induced neutropenic tumor mice model, GGsTop (5mg/kg; ip; 6d) abolishes the tumor growth-promoting effect of granulocyte colony stimulating factor [7]. In Otsuka Long-Evans Tokushima Fatty (OLETF) rats, GGsTop (1mg/kg; iv; single injection) resulted in significant reduction of serum ALT, AST and γ-GT levels [8].
References:
[1]. Han L, Hiratake J, Kamiyama A, et al. Design, synthesis, and evaluation of γ-phosphono diester analogues of glutamate as highly potent inhibitors and active site probes of γ-glutamyl transpeptidase[J]. Biochemistry, 2007, 46(5): 1432-1447.
[2]. Kamiyama A, Nakajima M, Han L, et al. Phosphonate-based irreversible inhibitors of human γ-glutamyl transpeptidase (GGT). GGsTop is a non-toxic and highly selective inhibitor with critical electrostatic interaction with an active-site residue Lys562 for enhanced inhibitory activity[J]. Bioorganic & Medicinal Chemistry, 2016, 24(21): 5340-5352.
[3]. Terzyan S S, Nguyen L T, Burgett A W G, et al. Crystal structures of glutathione-and inhibitor-bound human GGT1: Critical interactions within the cysteinylglycine binding site[J]. Journal of Biological Chemistry, 2021, 296.
[4]. Tamura K, Hayashi N, George J, et al. GGsTop, a novel and specific γ-glutamyl transpeptidase inhibitor, protects hepatic ischemia-reperfusion injury in rats[J]. American Journal of Physiology-Gastrointestinal and Liver Physiology, 2016, 311(2): G305-G312.
[5]. Jiang Y, Wang X, Li Y, et al. GGsTOP increases migration of human periodontal ligament cells in vitro via reactive oxygen species pathway[J]. Molecular Medicine Reports, 2016, 13(5): 3813-3820.
[6]. Hecht F, Zocchi M, Tuttle E T, et al. Catabolism of extracellular glutathione supplies amino acids to support tumor growth[J]. bioRxiv, 2024.
[7]. Xie Z, Kawasaki T, Zhou H, et al. Targeting GGT1 eliminates the tumor-promoting effect and enhanced immunosuppressive function of myeloid-derived suppressor cells caused by G-CSF[J]. Frontiers in Pharmacology, 2022, 13: 873792.
[8]. Kubota R, Hayashi N, Kinoshita K, et al. Inhibition of γ‐glutamyltransferase ameliorates ischaemia‐reoxygenation tissue damage in rats with hepatic steatosis[J]. British Journal of Pharmacology, 2020, 177(22): 5195-5207.
GGsTop是γ-谷氨酰转肽酶（GGT）的不可逆抑制剂（Ki = 170μM） [1]。GGsTop与GGT的活性位点共价结合，抑制其催化活性，从而调节细胞内还原状态，影响氨基酸代谢，并调节细胞氧化还原平衡 [2-3]。GGsTop 主要用于缓解肝损伤 [4]。
在人牙周膜细胞（hPLC）中，GGsTOP（0-50μM；7d）处理后，hPLC的增殖得到增强 [5]。在HCC-1806细胞中，GGsTOP（0.01-10000nM；4h）处理后，谷胱甘肽活性受到抑制 [6]。
在环磷酰胺诱发的中性粒细胞减少性肿瘤小鼠模型中，GGsTop（5mg/kg；ip；6d）可消除粒细胞集落刺激因子的促肿瘤生长作用 [7]。在大冢Long-Evans Tokushima Fatty（OLETF）大鼠中，GGsTop（1mg/kg；iv；单次注射）可显著降低血清ALT、AST和γ-GT水平 [8]。