bioRxiv
Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York, 14853.
Published: July 2023
The glutaminase enzymes GAC and GLS2 catalyze the hydrolysis of glutamine to glutamate, satisfying the 'glutamine addiction' of cancer cells. They are the targets of anti-cancer drugs; however, their mechanisms of activation and catalytic activity have been unclear. Here we demonstrate that the ability of GAC and GLS2 to form filaments is directly coupled to their catalytic activity and present their cryo-EM structures which provide an unprecedented view of the conformational states essential for catalysis. Filament formation guides an 'activation loop' to assume a specific conformation that works together with a 'lid' to close over the active site and position glutamine for nucleophilic attack by an essential serine. Our findings highlight how ankyrin repeats on GLS2 regulate enzymatic activity, while allosteric activators stabilize, and clinically relevant inhibitors block, filament formation that enables glutaminases to catalyze glutaminolysis and support cancer progression.
Download full-text PDF |
Source |
---|---|
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9949068 | PMC |
http://dx.doi.org/10.1101/2023.02.16.528860 | DOI Listing |
Proc Natl Acad Sci U S A
January 2025
Maladies infectieuses et Vecteurs: Ecologie, Génétique, Evolution et Contrôle, University of Montpellier, CNRS, Institut de Recherche pour le Développement, Montpellier 34095, France.
Tubulin detyrosination has been implicated in various human disorders and is important for regulating microtubule dynamics. While in most organisms this modification is restricted to α-tubulin, in trypanosomatid parasites, it occurs on both α- and β-tubulin. Here, we show that in , a single vasohibin (LmVASH) enzyme is responsible for differential kinetics of α- and β-tubulin detyrosination.
View Article and Find Full Text PDFHum Cell
January 2025
Institute of Translational Medicine, Medical College, Yangzhou University, No. 136 Jiangyangzhonglu, Yangzhou, 225009, Jiangsu, China.
Cancer, a complicated disease characterized by aberrant cellular metabolism, has emerged as a formidable global health challenge. Since the discovery of abnormal aldolase A (ALDOA) expression in liver cancer for the first time, its overexpression has been identified in numerous cancers, including colorectal cancer (CRC), breast cancer (BC), cervical adenocarcinoma (CAC), non-small cell lung cancer (NSCLC), gastric cancer (GC), hepatocellular carcinoma (HCC), pancreatic cancer adenocarcinoma (PDAC), and clear cell renal cell carcinoma (ccRCC). Moreover, ALDOA overexpression promotes cancer cell proliferation, invasion, migration, and drug resistance, and is closely related to poor prognosis of patients with cancer.
View Article and Find Full Text PDFMethods Mol Biol
January 2025
Division of Hemostasis and Thrombosis, Department of Medicine, BIDMC, Harvard Medical School, Boston, MA, USA.
The actin cytoskeleton serves an important, but poorly characterized, role in controlling granule exocytosis. The dynamic nature of actin remodeling allows it to act both as a barrier to prevent indiscriminate granule release and as a facilitator of membrane fusion. In its capacity to promote exocytosis, filamentous actin binds to components of the exocytotic machinery through actin binding proteins, but also through direct interactions with SNAREs.
View Article and Find Full Text PDFJ Am Chem Soc
January 2025
State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, and MoE Frontiers Science Center for Precision Oncology, University of Macau, Taipa, Macau SAR 999078, China.
Despite the development of various controlled release systems for antitumor therapies, off-target side effects remain a persistent challenge. In situ therapeutic synthesis from biocompatible substances offers a safer and more precise alternative. This study presents a hypoxia-initiated supramolecular free radical system capable of inducing intracellular polymerization, thereby disrupting the cytoskeleton and organelles within 4T1 cells.
View Article and Find Full Text PDFCureus
December 2024
Department of Basic and Clinical Oral Sciences, Umm Al-Qura University, Makkah, SAU.
Objectives: Head and neck malignancies (HNMs) encompass a variety of cancers that affect the oral and para-oral tissues, the most common of which are squamous cell carcinomas. Radiotherapy is commonly used to treat these cancers, often involving radiation exposure to the salivary glands. This study aims to investigate the early impacts of radiotherapy on the internal microstructure of the salivary gland cells and identify which gland exhibits the highest level of radiosensitivity.
View Article and Find Full Text PDFEnter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!
© LitMetric 2025. All rights reserved.