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dc.contributor.authorOsborne, Tanesha C.
dc.contributor.authorObianyo, Obiamaka
dc.contributor.authorZhang, Xing
dc.contributor.authorCheng, Xiaodong
dc.contributor.authorThompson, Paul R
dc.date2022-08-11T08:11:00.000
dc.date.accessioned2022-08-23T17:28:22Z
dc.date.available2022-08-23T17:28:22Z
dc.date.issued2007-11-20
dc.date.submitted2015-06-03
dc.identifier.citationBiochemistry. 2007 Nov 20;46(46):13370-81. <a href="http://dx.doi.org/10.1021/bi701558t">Link to article on publisher's site</a>. Epub 2007 Oct 26.
dc.identifier.issn0006-2960 (Linking)
dc.identifier.doi10.1021/bi701558t
dc.identifier.urihttp://hdl.handle.net/20.500.14038/50067
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) are a group of eukaryotic enzymes that catalyze the methylation of Arg residues in a variety of proteins (e.g., histones H3 and H4), and their activities influence a wide range of cellular processes, including cell growth, RNA splicing, differentiation, and transcriptional regulation. Dysregulation of these enzymes has been linked to heart disease and cancer, suggesting this enzyme family as a novel therapeutic target. To aid the development of PRMT inhibitors, we characterized the substrate specificity of both the rat and human PRMT1 orthologues using histone based peptide substrates. N- and C-terminal truncations to identify a minimal peptide substrate indicate that long-range interactions between enzyme and substrate are important for high rates of substrate capture. The importance of these long-range interactions to substrate capture were confirmed by "mutagenesis" experiments on a minimal peptide substrate. Inhibition studies on S-adenosyl-homocysteine, thioadenosine, methylthioadenosine, homocysteine, and sinefungin suggest that potent and selective bisubstrate analogue inhibitor(s) for PRMT1 can be developed by linking a histone based peptide substrate to homocysteine or sinefungin. Additionally, we present evidence that PRMT1 utilizes a partially processive mechanism to dimethylate its substrates.
dc.language.isoen_US
dc.relation<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=17960915&dopt=Abstract">Link to Article in PubMed</a>
dc.relation.urlhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC2723811/
dc.subjectAmino Acid Sequence
dc.subjectAnimals
dc.subjectBinding Sites
dc.subjectCatalysis
dc.subjectEnzyme Inhibitors
dc.subjectHistones
dc.subjectHumans
dc.subjectKinetics
dc.subjectMass Spectrometry
dc.subjectMethylation
dc.subjectModels, Molecular
dc.subjectMolecular Sequence Data
dc.subjectPeptides
dc.subjectProtein-Arginine N-Methyltransferases
dc.subjectinhibitors
dc.subjectRats
dc.subjectRecombinant Proteins
dc.subjectRepressor Proteins
dc.subjectSubstrate Specificity
dc.subjectBiochemistry
dc.subjectEnzymes and Coenzymes
dc.subjectMedicinal-Pharmaceutical Chemistry
dc.subjectTherapeutics
dc.titleProtein arginine methyltransferase 1: positively charged residues in substrate peptides distal to the site of methylation are important for substrate binding and catalysis
dc.typeJournal Article
dc.source.journaltitleBiochemistry
dc.source.volume46
dc.source.issue46
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/thompson/73
dc.identifier.contextkey7172294
html.description.abstract<p>Protein arginine methyltransferases (PRMTs) are a group of eukaryotic enzymes that catalyze the methylation of Arg residues in a variety of proteins (e.g., histones H3 and H4), and their activities influence a wide range of cellular processes, including cell growth, RNA splicing, differentiation, and transcriptional regulation. Dysregulation of these enzymes has been linked to heart disease and cancer, suggesting this enzyme family as a novel therapeutic target. To aid the development of PRMT inhibitors, we characterized the substrate specificity of both the rat and human PRMT1 orthologues using histone based peptide substrates. N- and C-terminal truncations to identify a minimal peptide substrate indicate that long-range interactions between enzyme and substrate are important for high rates of substrate capture. The importance of these long-range interactions to substrate capture were confirmed by "mutagenesis" experiments on a minimal peptide substrate. Inhibition studies on S-adenosyl-homocysteine, thioadenosine, methylthioadenosine, homocysteine, and sinefungin suggest that potent and selective bisubstrate analogue inhibitor(s) for PRMT1 can be developed by linking a histone based peptide substrate to homocysteine or sinefungin. Additionally, we present evidence that PRMT1 utilizes a partially processive mechanism to dimethylate its substrates.</p>
dc.identifier.submissionpaththompson/73
dc.contributor.departmentDepartment of Biochemistry and Molecular Pharmacology
dc.source.pages13370-81


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