Dataset Information

Substrates, inhibitors, and probes of mammalian transglutaminase 2.

ABSTRACT: Transglutaminase 2 (TG2) is a ubiquitous but enigmatic mammalian protein to which a number of biological functions have been ascribed but not definitively proven. As a member of the transglutaminase family, TG2 can catalyze deamidation or alternatively transamidation of selected Gln residues in proteins and peptides. It is also known to harbor other enzymatic properties, including protein disulfide isomerase, GTP-dependent signal transduction, and ATP dependent protein kinase activity. Given its multifunctional chemistry, it is unsurprising that a long list of proteins from the mammalian proteome have been identified as substrates and/or binding partners; however, the biological relevance of none of these protein-protein interactions has been clarified as yet. Remarkably, the most definitive insights into the biology of TG2 stem from its pathophysiological role in gluten peptide deamidation in celiac disease. Meanwhile our understanding of TG2 chemistry has been leveraged to engineer a spectrum of inhibitors and other molecular probes of TG2 biology in vivo. This review summarizes our current knowledge of the enzymology and regulation of human TG2 with a focus on its physiological substrates as well as tool molecules whose engineering was inspired by their identities.

SUBMITTER: Zhuang R

PROVIDER: S-EPMC6948143 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Substrates, inhibitors, and probes of mammalian transglutaminase 2.

Zhuang Ruize R Khosla Chaitan C

Analytical biochemistry 20191224

Transglutaminase 2 (TG2) is a ubiquitous but enigmatic mammalian protein to which a number of biological functions have been ascribed but not definitively proven. As a member of the transglutaminase family, TG2 can catalyze deamidation or alternatively transamidation of selected Gln residues in proteins and peptides. It is also known to harbor other enzymatic properties, including protein disulfide isomerase, GTP-dependent signal transduction, and ATP dependent protein kinase activity. Given its ...[more]

PMID: 31874171

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Project description:BackgroundCurrent vector-based malaria control strategies are threatened by the rise of biochemical and behavioural resistance in mosquitoes. Researching mosquito traits of immunity and fertility is required to find potential targets for new vector control strategies. The seminal transglutaminase AgTG3 coagulates male Anopheles gambiae seminal fluids, forming a 'mating plug' that is required for male reproductive success. Inhibitors of AgTG3 can be useful both as chemical probes of A. gambiae reproductive biology and may further the development of new chemosterilants for mosquito population control.MethodsA targeted library of 3-bromo-4,5-dihydroxoisoxazole inhibitors were synthesized and screened for inhibition of AgTG3 in a fluorescent, plate-based assay. Positive hits were tested for in vitro activity using cross-linking and mass spectrometry, and in vivo efficacy in laboratory mating assays.ResultsA targeted chemical library was screened for inhibition of AgTG3 in a fluorescent plate-based assay using its native substrate, plugin. Several inhibitors were identified with IC50 < 10 μM. Preliminary structure-activity relationships within the library support the stereo-specificity and preference for aromatic substituents in the chemical scaffold. Both inhibition of plugin cross-linking and covalent modification of the active site cysteine of AgTG3 were verified. Administration of an AgTG3 inhibitor to A. gambiae males by intrathoracic injection led to a 15% reduction in mating plug transfer in laboratory mating assays.ConclusionsA targeted screen has identified chemical inhibitors of A. gambiae transglutaminase 3 (AgTG3). The most potent inhibitors are known inhibitors of human transglutaminase 2, suggesting a common binding pose may exist within the active site of both enzymes. Future efforts to develop additional inhibitors will provide chemical tools to address important biological questions regarding the role of the A. gambiae mating plug. A second use for transglutaminase inhibitors exists for the study of haemolymph coagulation and immune responses to wound healing in insects.

Dataset Information

Substrates, inhibitors, and probes of mammalian transglutaminase 2.

Publications

Substrates, inhibitors, and probes of mammalian transglutaminase 2.

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