The search for the uremic toxin: the case for carbamoylation of amino acids and proteins.
Urea and cyanate, spontaneously transformed from urea, are increased with decreased renal function becoming potential toxins. Isocyanic acid, the active form of cyanate, carbamoylates proteins, amino acids and other molecules, changing molecular structure and function in vivo. Carbamoylation can occur at multiple sites with a cumulative effect over the the life-span of the molecule. Carbamoylation converts free amino acids to carbamoyl-amino acids (C-AA). C-AA interfere with protein synthesis and transamination reactions and contribute, in part, to protein-malnutrition. Insulin-sensitive glucose uptake is decreased by carbamoyl-asparagine. Cyanate inhibits superoxide release from neutrophils to an extent that interferes with microbiocidal activity. Antihomocitrulline antibodies identified homocitrulline (epsilon-amino-carbamoyl lysine) in situ in proteins in neutrophils in end stage renal disease. Also in uremic patients, homocitrulline was located in proteins in renal tissue but was not found in normal transplanted kidneys. Carbamoylated human low density lipoprotein interferes with human receptor binding, has decreased clearance, and is auto-immunogenic in animals. Carbamoylated insulin has decreased biological activity and changed immunological reactivity. Carbamoylation at a site of molecular activity can affect molecular function of enzymes, co-enzymes, antibodies, hormones and receptors. Carbamoyl-molecules can block, enhance, or be excluded from metabolic pathways, and can affect binding and trafficking, thereby influencing the fate of non-carbamoylated molecules. Normal renal function removes C-AA. In uremia, C-AA are removed by residual renal function or dialysis. Toxicity of cyanate is not an "all or none" phenomenon, but the actions of cyanate are a contributing factor in uremia. Removal of urea, cyanate and carbamoyl-molecules partially alleviates the morbidity and mortality of renal disease.
Kraus
L M
LM
Department of Biochemistry, College of Medicine, University of Tennessee, Memphis, USA.
Kraus
A P
AP
D000596:Amino Acids / Q000097:blood*; D001798:Blood Proteins / Q000378:metabolism*; D003485:Cyanates / Q000097:blood*; D005919:Glomerular Filtration Rate; D006801:Humans; D014118:Toxins, Biological / Q000097:blood*; D014508:Urea / Q000097:blood*; D014511:Uremia / Q000503:physiopathology*
D000596:Amino Acids; D001798:Blood Proteins; D003485:Cyanates; D014118:Toxins, Biological; D014508:Urea