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dc.contributor.authorKnuckley, Bryan
dc.contributor.authorBhatia, Monica
dc.contributor.authorThompson, Paul R
dc.date2022-08-11T08:11:00.000
dc.date.accessioned2022-08-23T17:28:23Z
dc.date.available2022-08-23T17:28:23Z
dc.date.issued2007-06-05
dc.date.submitted2015-06-03
dc.identifier.citationBiochemistry. 2007 Jun 5;46(22):6578-87. Epub 2007 May 12. <a href="http://dx.doi.org/10.1021/bi700095s">Link to article on publisher's site</a>
dc.identifier.issn0006-2960 (Linking)
dc.identifier.doi10.1021/bi700095s
dc.identifier.urihttp://hdl.handle.net/20.500.14038/50068
dc.description<p>At the time of publication, Paul Thompson was not yet affiliated with UMass Medical School.</p>
dc.description.abstractThe presumed role of an overactive protein arginine deiminase 4 (PAD4) in the pathophysiology of rheumatoid arthritis (RA) suggests that PAD4 inhibitors could be used to treat an underlying cause of RA, potentially offering a mechanism to stop further disease progression. Thus, the development of such inhibitors is of paramount importance. Toward the goal of developing such inhibitors, we initiated efforts to characterize the catalytic mechanism of PAD4 and thereby identify important mechanistic features that can be exploited for inhibitor development. Herein we report the results of mutagenesis studies as well as our efforts to characterize the initial steps of the PAD4 reaction, in particular, the protonation status of Cys645 and His471 prior to substrate binding. The results indicate that Cys645, the active site nucleophile, exists as the thiolate in the active form of the free enzyme. pH studies on PAD4 further suggest that this enzyme utilizes a reverse protonation mechanism.
dc.language.isoen_US
dc.relation<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=17497940&dopt=Abstract">Link to Article in PubMed</a>
dc.relation.urlhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC2212595/
dc.subjectAmino Acid Sequence
dc.subjectArginine
dc.subjectBinding Sites
dc.subjectCitrulline
dc.subjectCysteine
dc.subjectHistidine
dc.subjectHumans
dc.subjectHydrogen-Ion Concentration
dc.subjectHydrolases
dc.subjectKinetics
dc.subjectMolecular Sequence Data
dc.subjectMutagenesis, Site-Directed
dc.subject*Protein Processing, Post-Translational
dc.subject*Protons
dc.subjectRecombinant Proteins
dc.subjectSubstrate Specificity
dc.subjectBiochemistry
dc.subjectEnzymes and Coenzymes
dc.subjectMedicinal-Pharmaceutical Chemistry
dc.subjectTherapeutics
dc.titleProtein arginine deiminase 4: evidence for a reverse protonation mechanism
dc.typeJournal Article
dc.source.journaltitleBiochemistry
dc.source.volume46
dc.source.issue22
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/thompson/74
dc.identifier.contextkey7172295
html.description.abstract<p>The presumed role of an overactive protein arginine deiminase 4 (PAD4) in the pathophysiology of rheumatoid arthritis (RA) suggests that PAD4 inhibitors could be used to treat an underlying cause of RA, potentially offering a mechanism to stop further disease progression. Thus, the development of such inhibitors is of paramount importance. Toward the goal of developing such inhibitors, we initiated efforts to characterize the catalytic mechanism of PAD4 and thereby identify important mechanistic features that can be exploited for inhibitor development. Herein we report the results of mutagenesis studies as well as our efforts to characterize the initial steps of the PAD4 reaction, in particular, the protonation status of Cys645 and His471 prior to substrate binding. The results indicate that Cys645, the active site nucleophile, exists as the thiolate in the active form of the free enzyme. pH studies on PAD4 further suggest that this enzyme utilizes a reverse protonation mechanism.</p>
dc.identifier.submissionpaththompson/74
dc.contributor.departmentDepartment of Biochemistry and Molecular Pharmacology
dc.source.pages6578-87


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