Homocitrulline is a modified amino acid that exists in mammalian metabolism as a free-form metabolite of ornithine and as residues within proteins. While not one of the 20 standard amino acids that build proteins, its presence is discussed in medical contexts due to its association with various physiological processes and health conditions. Understanding homocitrulline involves recognizing its unique formation and its subsequent interactions within the body.
The Science of Homocitrulline Formation
Homocitrulline is primarily formed through a non-enzymatic chemical reaction, carbamylation. This process involves the binding of isocyanic acid, which spontaneously derives from high concentrations of urea, with amino groups. It reacts with lysine residues in proteins, forming homocitrulline residues.
Carbamylation can also lead to the formation of N-terminally carbamylated proteins. While carbamylation can occur spontaneously, a significant amount takes place during inflammation when the enzyme myeloperoxidase is released from neutrophils. Myeloperoxidase converts thiocyanate into cyanate, which then carbamylates lysine residues.
The molecule is structurally similar to citrulline, differing by one additional carbon atom. In conditions like renal failure, elevated urea concentrations can increase carbamylation, leading to higher levels of detectable homocitrulline.
Homocitrulline’s Connection to Health Conditions
Homocitrulline, particularly in its protein-bound form, has been implicated in several health conditions, acting as a marker or contributing to disease progression. Its presence reflects protein modification that can alter protein structure and function, leading to metabolic dysfunctions.
In kidney disease, impaired kidney function leads to urea accumulation in the blood. This elevated urea concentration drives increased carbamylation of proteins, forming homocitrulline residues on various proteins, including low-density lipoprotein (LDL). Carbamylated LDL (cLDL) is considered atherogenic, contributing to cardiovascular complications in patients with chronic kidney disease and end-stage renal disease.
Homocitrulline also serves as a marker in certain metabolic disorders, specifically urea cycle disorders. A depletion of ornithine supply can lead to carbamyl-phosphate accumulation, which enhances homocitrulline synthesis. Elevated levels of homocitrulline, along with homoarginine, can be detected in the urine of individuals with these disorders, such as hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome.
Homocitrulline plays a role in autoimmune diseases like rheumatoid arthritis (RA). Carbamylated proteins, including those containing homocitrulline, can become targets for the immune system, leading to inflammatory responses. Antibodies that bind to homocitrulline-containing antigens have been found in the blood of RA patients, and homocitrulline-containing proteins are present in the joints of individuals with RA, contributing to disease pathogenesis.
Detection and Interpretation of Homocitrulline Levels
Measuring homocitrulline levels, or the presence of carbamylated proteins, provides insights into the extent of protein modification in the body. These measurements are typically performed using specialized assays on biological fluids such as blood (plasma or serum) or urine. Techniques like liquid chromatography-tandem mass spectrometry (LC-MS/MS) are employed for precise quantification.
Elevated homocitrulline levels can indicate increased carbamylation, which is often a consequence of high urea concentrations, as seen in kidney dysfunction. For instance, in individuals with urea cycle disorders, higher amounts of homocitrulline are detectable in urine. An optimal homocitrulline result in blood is typically in the range of 0 to 1.7 µmol/L.
Interpreting these levels requires considering the patient’s overall clinical picture and other relevant biomarkers. While elevated levels generally point towards increased carbamylation activity, the specific implications depend on the suspected underlying condition. For example, in urea cycle disorders, a significant increase in homocitrulline in urine can aid in diagnosis, with levels in affected individuals ranging from 13.3 to 108.2 mmol/mol creatinine, compared to control values of 0-9 mmol/mol creatinine.