Human Deiminases: Isoforms, Substrate Specificities, Kinetics, and Detection

Abstract

Peptidylarginine deiminase (PAD) enzymes are of enormous interest in biomedicine. They catalyze the conversion of a positively-charged guanidinium at an arginine side chain into a neutral ureido group. As a result of this conversion, proteins acquire the non-ribosomally encoded amino acid "citrulline". This imposes critical influences on the structure and function of the target molecules. In multiple sclerosis, myelin hyper-citrullination promotes demyelination by reducing its compaction and triggers auto-antibody production. Immune responses to citrulline-containing proteins play a central role in the pathogenesis of autoimmune diseases. Moreover, auto-antibodies, specific to citrullinated proteins, such as collagen type I and II and filaggrin, are early detectable in rheumatoid arthritis, serving as diagnostic markers of the disease. Despite their significance, little is understood about the role in demyelinating disorders, diversified cancers, and auto-immune diseases. To impart their biological and pathological effects, it is crucial to better understand the reaction mechanism, kinetic properties, substrate selection, and specificities of peptidylarginine deiminase isoforms.Many aspects of PAD biochemistry and physiology have been ignored in past, but, herein is presented a comprehensive survey to improve our current understandings of the underlying mechanism and regulation of PAD enzymes.