Human γ-Glutamyl Transpeptidase 1

Abstract

Background: ␥-Glutamyl transpeptidase 1 (GGT1) plays a role in asthma, reperfusion injury, and cancer. Results: We report four new crystal structures of human GGT1, including the free enzyme, inhibitor-bound transition states, and glutamate-bound enzyme. Conclusion: Novel enzyme-substrate interactions and movement of the catalytic nucleophile, oxyanion hole, and lid loop were revealed. Significance: This structural information is critical for developing GGT1 inhibitors.

Tumor and serum gamma-glutamyl transpeptidase, new prognostic and molecular interpretation of an old biomarker in gastric cancer

“…As an anti-oxidative enzyme, GGT plays an important role in the cancer cell under stress [8]. It has been reported that GGT elevation is accompanied by an increased invasive behavior in melanoma and breast cancer, which is in accordance with our results [16, 22].…”

Direct Monitoring of γ‐Glutamyl Transpeptidase Activity In Vivo Using a Hyperpolarized 13C‐Labeled Molecular Probe

“…Sensitivity for GGT activity may be improved with more reactive or better polarizing probes,o rw ith optimized formulations for polarization. Inset spectra:sum of individual scans containing HP signal (scans [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19]. Gly (20 mm)w ith kidney homogenate from rats treated or untreated with the GGT inhibitor acivicin (0 or 10 mg kg À1 ).…”

“…[2b] GGT has been implicated in the development and progression of malignant tumors,w here its elevated expression increases the availability of cysteine for intracellular GSH production, limiting damage from oxidative stress and facilitating GSH-dependent drug resistance mechanisms. [4] GGT requires substrates bearing a g-glutamyl moiety but accommodates ar ange of substituents at the g-position (Figure 1a), [5,6] providing astrategy for the design of molecular probes targeting GGT.A fluorogenic probe activated upon cleavage by GGT may be useful to identify GGT-expressing tumors during surgical resection. [3] GGT may therefore serve as at umor biomarker and its presence on the cell surface is particularly attractive for imaging applications.Recently,reagents capable of detecting the presence of GGT in vivo using fluorescence or radioactivity have been described.…”

Direct Monitoring of γ‐Glutamyl Transpeptidase Activity In Vivo Using a Hyperpolarized 13C‐Labeled Molecular Probe

“…[3] GGT may therefore serve as at umor biomarker and its presence on the cell surface is particularly attractive for imaging applications.Recently,reagents capable of detecting the presence of GGT in vivo using fluorescence or radioactivity have been described. [4] GGT requires substrates bearing a g-glutamyl moiety but accommodates ar ange of substituents at the g-position (Figure 1a), [5,6] providing astrategy for the design of molecular probes targeting GGT.A fluorogenic probe activated upon cleavage by GGT may be useful to identify GGT-expressing tumors during surgical resection. [4a] This particular application avoids the problem of tissue opacity often encountered with fluorescent probes.…”