Protein-arginine deiminase type-4 (PAD4)

Protein‐arginine deiminase type‐4 (**PAD4**) is a calcium-dependent enzyme encoded by the *PADI4* gene in humans. It catalyzes the post-translational conversion (“citrullination” or “deimination”) of specific arginine residues within proteins—most notably histones H3 and H4—into citrulline, releasing ammonia in the process. This enzymatic activity plays a crucial role in epigenetic regulation by antagonizing arginine methylation marks on histones, thus influencing chromatin structure, gene expression patterns, pluripotency maintenance in stem cells, and cellular differentiation. PAD4 is primarily localized to the cytoplasm and nucleus of granulocytes such as neutrophils but is also found at high levels within inflamed tissues like those seen in rheumatoid arthritis patients. Its action is essential for processes like neutrophil extracellular trap formation during innate immunity. Dysregulation or aberrant activation of PAD4 has been implicated in several disease states—including autoimmune disorders like rheumatoid arthritis where it contributes both directly through tissue damage mechanisms involving NETs/citrullinated antigens and indirectly via generation of autoantibodies—as well as certain cancers where it acts as an epigenetic modulator. Several small-molecule inhibitors targeting PAD enzymes have shown promise preclinically for modulating these disease processes by blocking pathological citrullination events.[1][2][3][5]

Other names

Peptidylarginine deiminase 4PADI4HL-60 PADPADI5 (less common, sometimes used)PDI5 (less common)Peptidylarginine deiminase IVProtein-arginine deiminase type IV[6][1]

Drugs targeting PAD4 typically act as enzyme inhibitors that block the citrullination activity, thereby affecting gene expression and immune responses. For example, Cl-amidine and F-amidine are irreversible inhibitors that covalently modify the active site cysteine residue in PAD4 to prevent its enzymatic function.[4]