دورية أكاديمية
أعرض في EDS

Cell-Impermeable Inhibitors Confirm That Intracellular Human Transglutaminase 2 Is Responsible for the Transglutaminase-Associated Cancer Phenotype.

التفاصيل البيبلوغرافية
العنوان: Cell-Impermeable Inhibitors Confirm That Intracellular Human Transglutaminase 2 Is Responsible for the Transglutaminase-Associated Cancer Phenotype.
المؤلفون: Gates EWJ; Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, ON K1N 6N5, Canada., Calvert ND; Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, ON K1N 6N5, Canada., Cundy NJ; Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, ON K1N 6N5, Canada., Brugnoli F; Department of Translational Medicine, University of Ferrara, 44021 Ferrara, Italy., Navals P; Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, ON K1N 6N5, Canada., Kirby A; Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, ON K1N 6N5, Canada., Bianchi N; Department of Translational Medicine, University of Ferrara, 44021 Ferrara, Italy., Adhikary G; Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD 21201, USA., Shuhendler AJ; Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, ON K1N 6N5, Canada., Eckert RL; Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD 21201, USA., Keillor JW; Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, ON K1N 6N5, Canada.
المصدر: International journal of molecular sciences [Int J Mol Sci] 2023 Aug 08; Vol. 24 (16). Date of Electronic Publication: 2023 Aug 08.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Basel, Switzerland : MDPI, [2000-
مواضيع طبية MeSH: Protein Glutamine gamma Glutamyltransferase 2* , Neoplasms*, Humans ; Transglutaminases ; Fluorescent Dyes ; Phenotype
مستخلص: Transglutaminase 2 (TG2) is a multifunctional enzyme primarily responsible for crosslinking proteins. Ubiquitously expressed in humans, TG2 can act either as a transamidase by crosslinking two substrates through formation of an N ε (ɣ-glutaminyl)lysine bond or as an intracellular G-protein. These discrete roles are tightly regulated by both allosteric and environmental stimuli and are associated with dramatic changes in the conformation of the enzyme. The pleiotropic nature of TG2 and multi-faceted activities have resulted in TG2 being implicated in numerous disease pathologies including celiac disease, fibrosis, and cancer. Targeted TG2 therapies have not been selective for subcellular localization, such that currently no tools exist to selectively target extracellular over intracellular TG2. Herein, we have designed novel TG2-selective inhibitors that are not only highly potent and irreversible, but also cell impermeable, targeting only extracellular TG2. We have also further derivatized the scaffold to develop probes that are intrinsically fluorescent or bear an alkyne handle, which target both intra- and extracellular TG2, in order to facilitate cellular labelling and pull-down assays. The fluorescent probes were internalized and imaged in cellulo, and provide the first implicit experimental evidence that by comparison with their cell-impermeable analogues, it is specifically intracellular TG2, and presumably its G-protein activity, that contributes to transglutaminase-associated cancer progression.
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معلومات مُعتمدة: RGPIN-2019-05893 Natural Sciences and Engineering Research Council; 950-230735 Canada Research Chairs
فهرسة مساهمة: Keywords: cancer; cell impermeable; chemical label; fluorescence microscopy; fluorescent probe; inhibition; transglutaminase 2
المشرفين على المادة: EC 2.3.2.13 (Protein Glutamine gamma Glutamyltransferase 2)
EC 2.3.2.13 (Transglutaminases)
0 (Fluorescent Dyes)
تواريخ الأحداث: Date Created: 20230826 Date Completed: 20230828 Latest Revision: 20230829
رمز التحديث: 20230830
مُعرف محوري في PubMed: PMC10454375
DOI: 10.3390/ijms241612546
PMID: 37628729
قاعدة البيانات: MEDLINE
الوصف
تدمد:1422-0067
DOI:10.3390/ijms241612546