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

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 (NET) 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.

Peptidyl arginine deiminase-4 activation exacerbates kidney ischemia-reperfusion injury

“…Citrullination or deamination is the posttranslational modification of peptidyl arginine to peptidyl citrulline residue catalyzed by the PAD family of enzymes (4,15,42). Of the five PAD subtypes in humans and rodents, PAD4 activity has received significant scientific and clinical interest due to its active role in innate immunity and autoimmune diseases, including rheumatoid arthritis, multiple sclerosis, ulcerative colitis, and lupus (2,4).…”

Downregulation of the Deiminase PADI2 Is an Early Event in Colorectal Carcinogenesis and Indicates Poor Prognosis

“…1). Five genes located in a well-organized cluster on human chromosome 1 encode the five enzymes PADI1, PADI2, PADI3, PADI4, and PADI6.…”

“…PADI enzymes are further involved in a range of auto-inflammatory diseases, including rheumatoid arthritis and multiple sclerosis due to their activation during NETosis, apoptosis, and autophagy (12). A common denominator in these diseases is an increase in enzymatic PADI activity and increased levels of antibodies against citrullinated antigens (1). These autoantogenic antibodies are used as biomarkers for diagnosis and prognosis for rheumatoid arthritis (13).…”

A molecular signature of preclinical rheumatoid arthritis triggered by dysregulated PTPN22

“…Citrullinated proteins are generated by deimination catalyzed by peptidyl arginine deiminases (PADs), including PAD1-4 and PAD6 (3). Although the etiology of RA is still not fully understood, alterations in protein citrullination probably contribute to certain risk factors in RA.…”