The protein arginine deiminases: Structure, function, inhibition, and disease

Authors

  • Kevin L. Bicker,

    1. Department of Chemistry, The Scripps Research Institute, Scripps Florida, 120 Scripps Way, Jupiter, FL 33458
    Search for more papers by this author
  • Paul R. Thompson

    Corresponding author
    1. Department of Chemistry, The Scripps Research Institute, Scripps Florida, 120 Scripps Way, Jupiter, FL 33458
    • Department of Chemistry, The Scripps Research Institute, Scripps Florida, 120 Scripps Way, Jupiter, FL 33458
    Search for more papers by this author

  • This article was originally published online as an accepted preprint. The “Published Online” date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com

Abstract

The post-translational modification of histones has significant effects on overall chromatin function. One such modification is citrullination, which is catalyzed by the protein arginine deiminases (PADs), a unique family of enzymes that catalyzes the hydrolysis of peptidyl-arginine to form peptidyl-citrulline on histones, fibrinogen, and other biologically relevant proteins. Overexpression and/or increased PAD activity is observed in several diseases, including rheumatoid arthritis, Alzheimer's disease, multiple sclerosis, lupus, Parkinson's disease, and cancer. This review discusses the important structural and mechanistic characteristics of the PADs, as well as recent investigations into the role of the PADs in increasing disease severity in RA and colitis and the importance of PAD activity in mediating neutrophil extracellular trap formation through chromatin decondensation. Lastly, efforts to develop PAD inhibitors with excellent potency, selectivity and in vivo efficacy are discussed, highlighting the most promising inhibitors. © 2012 Wiley Periodicals, Inc. Biopolymers 99: 155–163, 2013.

Ancillary