Carbamoylation of amino acids and proteins in uremia

Abstract

Cyanate spontaneously transformed from urea increases as renal function decreased. Acting as a potential toxin, the active form of cyanate, isocyanic acid, carbamoylates amino acids, proteins, and other molecules, changing their structure, charge, and function. The resulting in vivo carbamoylation can modify the molecular activity of enzymes, cofactors, hormones, low-density lipoproteins, antibodies, receptors, and transport proteins. Antibodies specific for epsilon-amino-carbamoyl-lysine (homocitrulline) located carbamoylated proteins in situ in neutrophils, monocytes, and erythrocytes. Carbamoylated proteins were found in renal tissue from uremic patients but not in normal transplanted kidneys. The irreversible reaction with cyanate converts free amino acids (F-AAs) to carbamoyl-amino acids (C-AAs). The Carbamoylation Index (CI), C-AA/F-AA, quantifies the decrease of the F-AA pool for each essential amino acid. C-AAs contribute, in part, to malnutrition of uremia. C-AAs interfered with protein synthesis to lower 14C hemoglobin synthesis in human reticulocytes and osteocalcin synthesis in rat osteosarcoma-derived tissue culture. Insulin-sensitive glucose uptake was decreased 33% in cultured rat adipocytes by alpha-amino-carbamoyl-asparagine. alpha-Amino carbamoylation occurs primarily in F-AA, while epsilon-amino carbamoylation of lysine in protein occurs continuously during the protein life span. Protein catabolism releases epsilon-amino-carbamoyl-lysine. Quantitation of alpha versus epsilon carbamoylation may yield a more sensitive measurement of protein intake versus protein catabolism, and could be useful in decisions concerning the time to initiate dialysis or subsequent changes in dialysis prescription. Carbamoylated molecules can block, enhance, or be excluded from metabolic pathways, thereby influencing the fate of noncarbamoylated molecules. Although not an "all-or-none" phenomenon, urea-derived cyanate and its actions are contributing causes of toxicity in uremia.

High urea and NaCl carbonylate proteins in renal cells in culture andin vivo, and high urea causes 8-oxoguanine lesions in their DNA

“…It has been suggested that urea might be a uremic toxin because cyanate, which forms spontaneously from urea, is elevated in chronic renal failure, resulting in increased protein carbamylation (17). The present studies add to the evidence that urea is a uremic toxin, given our observation that protein carbonylation is increased over the range of urea concentration that occurs in chronic renal failure (Fig.…”

“…2A), indicating that high urea does cause oxidative damage to proteins. Cyanate, which forms spontaneously from urea, can modify proteins by carbamylating them (17). To assess the possibility that urea-induced carbonylation might be an indirect effect of cyanate-induced carbamylation, we used an ion-exchange resin to remove cyanate from the urea solutions that we used (see Materials and Methods).…”

Myeloperoxidase-mediated lipoprotein carbamylation as a mechanistic pathway for atherosclerotic vascular disease

“…The cyanate thus formed can become protonated and form isocyanic acid, which reacts with available α-and ε-NH 2 groups of proteins, resulting in the formation of a carbamylated polypeptide [51]. The strong correlation between protein carbamylation and renal disease is intuitive from this perspective and, in fact, several targets of carbamylation have been demonstrated in patients with renal failure, including free amino acids, plasma proteins, leucocyte proteins and haemoglobin [52][53][54][55][56][57][58][59][60][61][62]; however, the carbamylation of lipoproteins is most relevant to atherogenesis. In CKD patients, carbamylation of LDL has been identified as a novel risk factor for CVD and a biomarker for atherogenic progression [2].…”

Carbamylation of vimentin is inducible by smoking and represents an independent autoantigen in rheumatoid arthritis

“…Thus, uraemia secondary to renal diseases is a pathological state that leads to the formation of isocyanate. 7 The second key reactant for isocyanate formation is thiocyanate (SCN − ), a metabolite of cyanide that is present in cigarette smoke. Thiocyanate increases in urine, serum and saliva with the amount of cigarette smoke.…”