Protein citrullination: inhibition, identification and insertion

Area of Science:

• Biochemistry and Molecular Biology
• Immunology
• Pathology

Background:

• Protein citrullination is a post-translational modification (PTM) catalyzed by protein arginine deiminase (PAD) enzymes, converting arginine to citrulline.
• This PTM plays roles in gene expression, neutrophil extracellular trap formation, and apoptosis, and is implicated in autoimmune diseases, neurodegeneration, and cancer.

Purpose of the Study:

• To review progress in developing protein arginine deiminase (PAD) inhibitors, both pan-PAD and isozyme-selective.
• To discuss advancements in identifying citrullinated proteins and site-specific citrulline incorporation.
• To highlight the diagnostic and biomarker potential of citrullinated proteins, particularly in rheumatoid arthritis.

Main Methods:

• Review of current literature on PAD inhibitors and citrullination detection techniques.
• Discussion of the challenges in identifying citrullinated residues due to minimal mass change.
• Exploration of the therapeutic efficacy of PAD inhibitors in preclinical and clinical studies.

Main Results:

• PAD inhibitors demonstrate significant efficacy in preclinical models of rheumatoid arthritis, lupus, atherosclerosis, and ulcerative colitis.
• Anti-citrullinated protein antibodies are valuable early diagnostic markers for rheumatoid arthritis.
• Progress has been made in developing targeted PAD inhibitors and methods for identifying citrullinated proteins.

Conclusions:

• Protein citrullination is a critical PTM with significant implications in health and disease.
• Targeting PAD enzymes offers a promising therapeutic strategy for various autoimmune and inflammatory conditions.
• Improved methods for citrullinated protein identification are crucial for advancing diagnostics and understanding disease mechanisms.