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dc.contributor.authorWang, Min
dc.contributor.authorXu, Rui-Ming
dc.contributor.authorThompson, Paul R
dc.date2022-08-11T08:11:00.000
dc.date.accessioned2022-08-23T17:28:07Z
dc.date.available2022-08-23T17:28:07Z
dc.date.issued2013-08-13
dc.date.submitted2015-05-22
dc.identifier.citationBiochemistry. 2013 Aug 13;52(32):5430-40. doi: 10.1021/bi4005123. Epub 2013 Aug 1. <a href="http://dx.doi.org/10.1021/bi4005123">Link to article on publisher's site</a>
dc.identifier.issn0006-2960 (Linking)
dc.identifier.doi10.1021/bi4005123
dc.identifier.urihttp://hdl.handle.net/20.500.14038/50013
dc.description<p>At the time of publication, Paul Thompson was not yet affiliated with UMass Medical School.</p>
dc.description.abstractProtein arginine methyltransferases (PRMTs) have emerged as attractive therapeutic targets for heart disease and cancers. PRMT5 is a particularly interesting target because it is overexpressed in blood, breast, colon, and stomach cancers and promotes cell survival in the face of DNA damaging agents. As the only known member of the PRMT enzyme family to catalyze the formation of mono- and symmetrically dimethylated arginine residues, PRMT5 is also mechanistically unique. As a part of a program to characterize the mechanisms and regulation of the PRMTs and develop chemical probes targeting these enzymes, we characterized the substrate specificity, processivity, and kinetic mechanism of bacterially expressed Caenorhabditis elegans PRMT5 (cPRMT5). In this report, we demonstrate that distal positively charged residues contribute to substrate binding in a synergistic fashion. Additionally, we show that cPRMT5 catalyzes symmetric dimethylation in a distributive fashion. Finally, the results of initial velocity, product, and dead-end inhibition studies indicate that cPRMT5 uses a rapid equilibrium random mechanism with dead-end EAP and EBQ complexes. In total, these studies will guide PRMT5 inhibitor development and lay the foundation for studying how the activity of this medically relevant enzyme is regulated.
dc.language.isoen_US
dc.relation<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=23866019&dopt=Abstract">Link to Article in PubMed</a>
dc.relation.urlhttp://dx.doi.org/10.1021/bi4005123
dc.subjectAmino Acid Sequence
dc.subjectAnimals
dc.subjectArginine
dc.subjectCaenorhabditis elegans
dc.subjectCaenorhabditis elegans Proteins
dc.subjectCatalysis
dc.subjectKinetics
dc.subjectMethylation
dc.subjectMolecular Sequence Data
dc.subjectProtein-Arginine N-Methyltransferases
dc.subjectSubstrate Specificity
dc.subjectBiochemistry
dc.subjectEnzymes and Coenzymes
dc.subjectMedicinal-Pharmaceutical Chemistry
dc.subjectTherapeutics
dc.titleSubstrate specificity, processivity, and kinetic mechanism of protein arginine methyltransferase 5.
dc.typeJournal Article
dc.source.journaltitleBiochemistry
dc.source.volume52
dc.source.issue32
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/thompson/24
dc.identifier.contextkey7135678
html.description.abstract<p>Protein arginine methyltransferases (PRMTs) have emerged as attractive therapeutic targets for heart disease and cancers. PRMT5 is a particularly interesting target because it is overexpressed in blood, breast, colon, and stomach cancers and promotes cell survival in the face of DNA damaging agents. As the only known member of the PRMT enzyme family to catalyze the formation of mono- and symmetrically dimethylated arginine residues, PRMT5 is also mechanistically unique. As a part of a program to characterize the mechanisms and regulation of the PRMTs and develop chemical probes targeting these enzymes, we characterized the substrate specificity, processivity, and kinetic mechanism of bacterially expressed Caenorhabditis elegans PRMT5 (cPRMT5). In this report, we demonstrate that distal positively charged residues contribute to substrate binding in a synergistic fashion. Additionally, we show that cPRMT5 catalyzes symmetric dimethylation in a distributive fashion. Finally, the results of initial velocity, product, and dead-end inhibition studies indicate that cPRMT5 uses a rapid equilibrium random mechanism with dead-end EAP and EBQ complexes. In total, these studies will guide PRMT5 inhibitor development and lay the foundation for studying how the activity of this medically relevant enzyme is regulated.</p>
dc.identifier.submissionpaththompson/24
dc.contributor.departmentDepartment of Biochemistry and Molecular Pharmacology
dc.source.pages5430-40


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