A structural and computational study of citrulline in biochemical reactions

Citrulline, a non-essential amino acid, is used therapeutically in mitochondrial diseases, especially since it is a well-tolerated medicinal compound. Athletes use citrulline to enhance performance during sustained exercise activity. In the body, citrullination is an important biochemical reaction in proteins which involves post-translational hydrolysis of arginine residues to form citrulline residues and ammonia. Proteins modified through extensive citrullination play a key role in the pathogenesis of a variety of diseases such as multiple sclerosis, autoimmune disorders, and potentially cancer. In our studies, we describe the experimental results of a structure determination using highly accurate X-ray data that were collected at low temperature (125 K). Through intensive crystallization studies, we obtained the delta polymorph of citrulline. There are seven strong N-H…O hydrogen bonds, an unusually high number for a small molecule. We utilized computational methods to understand the complex biochemistry of citrulline/arginine. Our DFT investigation offers clues for describing and understanding the complex biochemistry of citrulline/arginine. In addition, it is evident that the hydrolysis of arginine to citrulline is energetically favored and can be considered a driving force for important citrullination reactions.