3.5.3.15 Peptidyl arginine deiminases (PADI): Introduction

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Protein arginine deimination (also known as citrullination) is a post-translational modification of protein arginine residues. The five human isozymes performing this modification (PDAI1, 2, 3, 4 and 6), show significant sequence homology but can be distinguished by their expression patterns [2]:

PADI2 is ubiquitously expressed an can citrullate
PADI1 is expressed in the skin
PADI3 is expressed in hair follicles
PADI4 is expressed in immune cells and is the only PADI containing a canonical nuclear localization signal. PADI4 is responsible for histone H2A, H3, and H4 citrullination. PADI4-mediated hypercitrullination of histones is critical for the innate immune system and the development of inflammatory diseases such as rheumatoid arthritis (RA) and lupus.
PADI6 is expressed in oocytes

This family of enzymes are known to regulate gene transcription, cellular differentiation, and the innate immune response. Histone citrullination is an epigenetic mark associated with both transcriptional repression and activation.

Protein arginine deiminase activity is upregulated in a number of human diseases, including rheumatoid arthritis, ulcerative colitis, and cancer, making these enzymes targets for pharmaceutical intervention. Selective PADI inhibitors such as o-F-amidine [1] are being developed to help elucidate the function of these enzymes in disease and to provide lead candidates for drug development.

References

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1. Causey CP, Jones JE, Slack JL, Kamei D, Jones LE, Subramanian V, Knuckley B, Ebrahimi P, Chumanevich AA, Luo Y et al.. (2011) The development of N-α-(2-carboxyl)benzoyl-N(5)-(2-fluoro-1-iminoethyl)-l-ornithine amide (o-F-amidine) and N-α-(2-carboxyl)benzoyl-N(5)-(2-chloro-1-iminoethyl)-l-ornithine amide (o-Cl-amidine) as second generation protein arginine deiminase (PAD) inhibitors. J. Med. Chem.54 (19): 6919-35. [PMID:21882827]

2. Vossenaar ER, Zendman AJ, van Venrooij WJ, Pruijn GJ. (2003) PAD, a growing family of citrullinating enzymes: genes, features and involvement in disease. Bioessays25 (11): 1106-18. [PMID:14579251]

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To cite this family introduction, please use the following:

3.5.3.15 Peptidyl arginine deiminases (PADI), introduction. Last modified on 20/03/2017. Accessed on 13/12/2017. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/FamilyIntroductionForward?familyId=918.