J Bacteriol Virol.  2013 Sep;43(3):159-167. 10.4167/jbv.2013.43.3.159.

Peptidylarginine Deiminase and Citrullination: Potential Therapeutic Targets for Inflammatory Diseases

• Jang B
• Shin SJ

• KMID: 2286269
• DOI: http://doi.org/10.4167/jbv.2013.43.3.159

Abstract

The multiple post-translational modifications of proteins display specific gain- or loss-of-function under normal and abnormal conditions. These modifications are precisely regulated by post-translational modification enzymes. The altered molecular status perturbs the pattern of gene expression and decides on a direction to signal transduction cascades as well as intrinsic properties of the proteins. Ultimately, it strictly maintains intracellular environment or results in disease manifestations. Recently, it has become that enzyme-dependent modification of arginine residue to citrulline exerts an important role in the induction of autoimmunity including rheumatoid arthritis, multiple sclerosis, and cancer. The modification of arginine residue to citrulline on proteins is called 'citrullination' or 'deimination' and is regulated by the calcium-dependent enzyme peptidylarginine deiminase (PAD). Now many effective PAD inhibitors (for example, Cl-amidine) have developed that ameliorates disease phenotypes. In this review, we discuss crucial roles of PAD enzyme and citrullination, the effectiveness of PAD inhibitors, and the implication in pathology.

Keyword

Peptidylarginine deiminase; Cl-amidine; Autoimmunity; Citrullination

MeSH Terms

Arginine
Arthritis, Rheumatoid
Autoimmunity
Citrulline
Gene Expression
Hydrolases
Multiple Sclerosis
Ornithine
Phenotype
Protein Processing, Post-Translational
Proteins
Signal Transduction
Arginine
Citrulline
Hydrolases
Ornithine
Proteins

Figure

• 

  Figure 1. Peptidylarginine deiminase (PAD) and citrullination. (A) The conversion of peptidylarginine to peptidylcitrulline is a posttranslational process driven by peptidylarginine deiminase (PAD) in a calcium (Ca2+) dependent manner. Ca2+ is an essential cofactor for the activation of PAD, effective Ca2+ concentration is approximately 100-fold higher than physiological cytosolic Ca2+ concentration. (B) Citrullination loss of target positive charge, alters protein structure and susceptibility of protease, changes natural functions, and become autoantigen. (C) Histone citrullination is involved in chromatin decondensation and formation of neutrophil extracellular traps. Citrullinated histones regulate gene transcription including p53- and estrogen receptor α-targeted. (D) PAD and citrullinated proteins are implicated in human diseases including cancer, rheumatoid arthritis, skin physiology, and neurodegeneration.

• 

  Figure 2. Structures of Cl- and F-amidine, 2-Chloroacetamidine, and YW3-56. Each PAD inhibitors irreversibly inactivates PAD enzymes via the specific modification of Cys645, an active site residue that is critical for catalysis.

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