Ggt1, or gamma-glutamyltransferase 1, is a critical enzyme involved in the hydrolysis and/or transfer of gamma-glutamyl groups of glutathione, helping maintain cysteine levels in plasma [3]. It is associated with multiple biological pathways, and its dysregulation is linked to various diseases, highlighting its biological importance. Genetic models, such as gene knockout mouse models, have been valuable in studying Ggt1's functions.

In mouse retinal ganglion cells (RGCs), Ggt1 knockdown led to cell damage, aberrant iron homeostasis, and oxidative stress, while its overexpression alleviated these effects. Ggt1 was found to interact with glutamate cysteine ligase catalytic subunit (GCLC) to inhibit autophagy and ferroptosis in RGC-5 cells, suggesting its role in suppressing ferroptosis and autophagy in RGCs [1]. In a mouse model of hereditary γ-glutamyltransferase deficiency (Ggt1(dwg/dwg) mice), GGT1 activity was reduced, leading to changes in glutathione (GSH) levels. Growth retardation and other abnormalities in these mice were reversed by N-acetyl-L-cysteine, indicating that Ggt1 affects GSH levels and related phenotypes [2]. Also, in an EL4 lymphoma-bearing neutropenic mouse model, G-CSF upregulated Ggt1 in myeloid-derived suppressor cells (MDSCs), enhancing their immunosuppressive activity. Targeting Ggt1 with GGsTop could prevent G-CSF-induced tumor growth [4].

In conclusion, Ggt1 is essential for maintaining glutathione-related processes and normal cellular functions. Gene knockout mouse models have revealed its role in diseases such as glaucoma, hereditary γ-glutamyltransferase deficiency-related phenotypes, and cancer-related immunosuppression, providing insights into potential therapeutic targets for these conditions.

References:

1. Xu, Guihua, Wang, Juanjuan, Zhang, Yiting, Chen, Zilin, Deng, Ruidong. 2023. GGT1 Suppresses the Development of Ferroptosis and Autophagy in Mouse Retinal Ganglion Cell Through Targeting GCLC. In Eye and brain, 15, 139-151. doi:10.2147/EB.S434280. https://pubmed.ncbi.nlm.nih.gov/38020723/

2. Yamada, Kaoru, Tsuji, Takehito, Kunieda, Tetsuo. . Phenotypic characterization of Ggt1(dwg/dwg) mice,a mouse model for hereditary γ-glutamyltransferase deficiency. In Experimental animals, 62, 151-7. doi:. https://pubmed.ncbi.nlm.nih.gov/23615310/

3. Bist, Ganesh, Luong, Nguyen T, Mahabubur Rahman, Kazi Md, Hanigan, Marie H, You, Youngjae. 2023. SAR of L-ABBA analogs for GGT1 inhibitory activity and L-ABBA's effect on plasma cysteine and GSH species. In Bioorganic & medicinal chemistry letters, 92, 129406. doi:10.1016/j.bmcl.2023.129406. https://pubmed.ncbi.nlm.nih.gov/37423504/

4. Xie, Zhiqi, Kawasaki, Takahiro, Zhou, Haoyang, Okada, Naoki, Tachibana, Masashi. 2022. Targeting GGT1 Eliminates the Tumor-Promoting Effect and Enhanced Immunosuppressive Function of Myeloid-Derived Suppressor Cells Caused by G-CSF. In Frontiers in pharmacology, 13, 873792. doi:10.3389/fphar.2022.873792. https://pubmed.ncbi.nlm.nih.gov/35548341/