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    Protein arginine deiminase 4: evidence for a reverse protonation mechanism

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    Authors
    Knuckley, Bryan
    Bhatia, Monica
    Thompson, Paul R
    UMass Chan Affiliations
    Department of Biochemistry and Molecular Pharmacology
    Document Type
    Journal Article
    Publication Date
    2007-06-05
    Keywords
    Amino Acid Sequence
    Arginine
    Binding Sites
    Citrulline
    Cysteine
    Histidine
    Humans
    Hydrogen-Ion Concentration
    Hydrolases
    Kinetics
    Molecular Sequence Data
    Mutagenesis, Site-Directed
    *Protein Processing, Post-Translational
    *Protons
    Recombinant Proteins
    Substrate Specificity
    Biochemistry
    Enzymes and Coenzymes
    Medicinal-Pharmaceutical Chemistry
    Therapeutics
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    Link to Full Text
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2212595/
    Abstract
    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.
    Source
    Biochemistry. 2007 Jun 5;46(22):6578-87. Epub 2007 May 12. Link to article on publisher's site
    DOI
    10.1021/bi700095s
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/50068
    Notes

    At the time of publication, Paul Thompson was not yet affiliated with UMass Medical School.

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    Link to Article in PubMed
    ae974a485f413a2113503eed53cd6c53
    10.1021/bi700095s
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