Using differential display analysis, we have identified a novel rat gene whose expression is increased during tumor progression in rat mammary carcinoma cell lines. This gene is an ortholog of the human chromosome 7 open reading frame 24 gene (C7orf24) and encodes a protein of 188 amino acids with no recognized protein domains. C7orf24 has been identified as γ-glutamyl cyclotransferase (GGCT), an important enzyme functioning in glutathione homeostasis. Our Northern and Western blot analyses revealed that the GGCT gene is expressed in various normal human and tumor tissues, as well as in cancer cell lines. Among the tumor tissues tested, lung tumor tissue expressed GGCT mRNA more strongly than normal lung tissue. The GGCT protein was found to be localized in the cytoplasmic region of cultured cells, where it forms a homodimer. Analysis of various deletion mutants of the GGCT protein revealed that the region containing amino acid residues 61-120 of the protein is required for its cytoplasmic localization. The comparison of the soft agar colony formation of HBL-100 cells stably expressing GGCT with that of control HBL-100 cells revealed that GGCT does not promote colony formation, suggesting that the role it plays in lung cancer cells is not related to tumorigenesis.
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http://dx.doi.org/10.3892/mmr_00000110 | DOI Listing |
Cancer Sci
March 2025
Institute of Biology and Medicine, College of Life and Health Sciences, Wuhan University of Science and Technology, Wuhan, Hubei, People's Republic of China.
γ-Glutamine cyclotransferase (GGCT) is an enzyme involved in the metabolic cycle of glutathione (GSH). Abnormal GSH metabolism is mostly related to ferroptosis. However, the mechanisms supporting aberrant GGCT expression in PTC remain to be investigated.
View Article and Find Full Text PDFBioorg Med Chem
April 2025
Beijing Institute of Pharmacology and Toxicology, 27 Taiping Road, Beijing 100850 China. Electronic address:
Human glutaminyl cyclase (hQC) has emerged as a critical target in Alzheimer's disease (AD) due to its role in generating pyroglutamate-modified amyloid β (pE-Aβ). In this study, 13 compounds were designed as target compounds by fragment-based drug design (FBDD) and molecular docking, and subsequently assessed for drug-like properties and predicted inhibitory activities through ADMET analysis and Uni-QSAR modeling. Target compounds were synthesized via systematic multi-step approaches, with acceptable yields.
View Article and Find Full Text PDFAntioxidants (Basel)
November 2024
Department of Medical Surgical and Health Sciences, ASUGI, University of Trieste, 34127 Trieste, Italy.
Hypokinesia triggers oxidative stress and accelerates the turnover of the glutathione system via the γ-glutamyl cycle. Our study aimed to identify the regulatory checkpoints controlling intracellular glutathione levels. We measured the intermediate substrates of the γ-glutamyl cycle in erythrocytes from 19 healthy young male volunteers before and during a 10-day experimental bed rest.
View Article and Find Full Text PDFJ Med Chem
January 2025
Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Glutaminyl cyclases, including glutaminyl-peptide cyclotransferase (QPCT) and glutaminyl-peptide cyclotransferase-like protein (QPCTL), primarily catalyze the cyclization of N-terminal glutamine or glutamate to pyroglutamate (pGlu). QPCTL, in particular, modifies the N-terminus of CD47, thereby regulating its interaction with signal-regulatory protein alpha (SIRPα) and modulating phagocytosis of tumor cells by immune cells. Additionally, QPCTL cyclizes the N-termini of CCL2, CCL7, and CX3CL1, influencing the tumor microenvironment and inflammatory responses in cancer and other disorders.
View Article and Find Full Text PDFInt J Biol Macromol
March 2025
Laboratory for Structural Bioinformatics, Center for Biosystems Dynamics Research, RIKEN, 1-7-22 Suehiro, Tsurumi, Yokohama, Kanagawa 230-0045, Japan. Electronic address:
The formation of the pyroglutamate variant of amyloid beta (pGlu-Aβ), which is extremely hydrophobic, rapidly aggregating, and highly neurotoxic, is mediated by the action of secretory glutaminyl cyclase (sQC). The pGlu-Aβ often acts as a seed for the aggregation of the full length Aβ and contributes to the overall load of Aβ plaques in Alzheimer's disease (AD). Therefore, inhibiting sQC is a potential approach to limit the formation of pGlu-Aβ and to modify the progression of AD.
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