Biomarkers

Target: Citrulline

Citrulline, also known as Cit or δ-ureidonorvaline, belongs to the class of organic compounds known as l-alpha-amino acids. These are alpha amino acids which have the L-configuration of the alpha-carbon atom. Citrulline has the formula H2NC(O)NH(CH2)3CH(NH2)CO2H. Citrulline exists in all living species, ranging from bacteria to humans. Within humans, citrulline participates in a number of enzymatic reactions. In particular, citrulline can be biosynthesized from carbamoyl phosphate and ornithine which is catalyzed by the enzyme ornithine carbamoyltransferase. In addition, citrulline and L-aspartic acid can be converted into argininosuccinic acid through the action of the enzyme argininosuccinate synthase. In humans, citrulline is involved in the metabolic disorder called argininemia. Citrulline has also been found to be associated with several diseases such as ulcerative colitis, rheumatoid arthritis, and citrullinemia type II. Citrulline has also been linked to several inborn metabolic disorders including argininosuccinic aciduria and fumarase deficiency. Outside of the human body, citrulline is found, on average, in the highest concentration in a few different foods such as wheats, oats, and cucumbers and in a lower concentration in swiss chards, yellow wax beans, and potato. Citrulline has also been detected, but not quantified in several different foods, such as epazotes, lotus, common buckwheats, strawberry guava, and italian sweet red peppers. Citrulline is a potentially toxic compound. Proteins that normally contain citrulline residues include myelin basic protein (MBP), filaggrin, and several histone proteins, whereas other proteins, such as fibrin and vimentin are susceptible to citrullination during cell death and tissue inflammation. Citrulline is also produced as a byproduct of the enzymatic production of nitric oxide from the amino acid arginine, catalyzed by nitric oxide synthase. It is also produced from arginine as a byproduct of the reaction catalyzed by NOS family (NOS; EC1.14.13.39). Citrulline is associated with several diseases such as ulcerative colitis, rheumatoid arthritis, and citrullinemia type II. Circulating citrulline concentration is a biomarker of intestinal functionality (PMID: 29511548 ). In adults (>18 years old) with citrullinemia type II, citrulline is elevated in the blood at a concentration of 86-1542 μM (PMID: 18620775) compared to normal adults at a concentration of <43 μM (PMID: 18620775). Citrulline is also associated with permanent intestinal failure. In adults (>18 years old) with permanent intestinal failure, citrulline in the blood is significantly reduced at a concentration of 13.0 (6.0-20.0) μM (PMID: 11113071) compared to normal adults at a concentration of 38.0 (30.0-46.0) μM (PMID: 11113071). Citrulline has also been shown to be associated with argininosuccinic aciduria (ASL), a rare genetic disorder characterized by deficiency or lack of the enzyme argininosuccinate lyase. In infants (0-1 year old) with ASL, citrulline is reduced in the blood at a concentration of 284 μM (PMID: 12408190) compared to normal infants at a concentration of 19-51 μM (PMID: 12408190). Finally, citrulline has also shown association with Alzheimer’s Disease (AD) where adults (>18 years old) with AD have a significantly elevated citrulline concentration in the cerebrospinal fluid at a concentration of 27.0 +/- 2.6 μM (PMID: 17031479) compared to normal adults at a concentration of 2.62 (1.35-3.89) μM (PMID: 12834252).