In TranslationProtein Carbamylation in Kidney Disease: Pathogenesis and Clinical Implications
Section snippets
Background
Proteins in the human body, in both health and disease, are exposed to chemical reactions capable of altering their structural and functional properties. Spontaneous posttranslational protein modifications are caused by the nonenzymatic attachment of reactive molecules to protein functional groups, as seen, for example, in glycation reactions. Because posttranslational modifications are capable of changing protein structure and function, they can create a mechanistic chemical link to the
Case Vignette
A 58-year-old Hispanic man with end-stage renal disease (ESRD) resulting from chronic hypertensive nephrosclerosis was evaluated for worsening dyspnea on exertion. He had been adherent to his thrice-weekly hemodialysis treatment regimen over the past 4 years and his latest Kt/V was 1.3. He had been dialyzed to his estimated dry weight of 72 kg at his last treatment and his recent predialysis blood pressures averaged 145/85 mm Hg. The patient did not have a prior cardiac history, and a nuclear
Biochemistry of Carbamylation and Its Link to Kidney Disease
In 1828, Friedrich Wöhler3 discovered that urea could be synthesized by reacting cyanate with ammonia, and in 1895 it was found that under physiologic conditions, urea slowly dissociates into cyanate and its tautomer isocyanate.4 Isocyanate is a highly reactive electrophile that quickly reacts with nucleophilic groups such as primary amines and free sulfhydryls, and by 1949, F. Schutz5 suggested that urea-derived cyanate could react with the amine and sulfhydryl groups on proteins and free
Recent Advances
Recent years have produced a number of important developments in the field of kidney disease and carbamylation. A first important technical advance was the application of mass spectrometry and proteomics to quantitatively measure global protein carbamylation and screen for individual carbamylation modifications on proteins in tissue and blood. Wang et al62 demonstrated the use of amino acid analysis to allow quantification of protein-bound homocitrulline after protein hydrolysis. In this
Summary
A rich literature reflecting decades of investigation demonstrates the mechanistic and pathophysiologic involvement of protein carbamylation in the adverse outcomes of kidney disease, which remain a major public health burden. There is evidence that select carbamylated proteins could serve as useful biomarkers of disease and therapeutic response in kidney failure. For example, by integrating information on urea clearance, amino acid balance, and inflammation, elevated carbamylation measurements
Acknowledgements
Support: Dr Kalim has received support from the National Kidney Foundation Young Investigator award; Dr Thadhani receives support from National Institutes of Health award K24 DK094872; Dr Karumanchi receives support from the Howard Hughes Medical Institute; and Dr Berg received support from the American Diabetes Association Junior Faculty Award (1-11-JF22).
Financial Disclosure: Provisional applications for US and International patents related to measurement of carbamylated albumin and treatment
References (128)
- et al.
Reaction of the cyanate present in aqueous urea with amino acids and proteins
J Biol Chem
(1960) On the reversible reaction of cyanate with sulfhydryl groups and the determination of NH2-terminal cysteine and cystine in proteins
J Biol Chem
(1964)Carbamylation of amino and tyrosine hydroxyl groups. Preparation of an inhibitor of oxytocin with no intrinsic activity on the isolated uterus
J Biol Chem
(1967)Modification of proteins with cyanate
Methods Enzymol
(1972)- et al.
Carbamoylation of amino acids and proteins in uremia
Kidney Int Suppl
(2001) - et al.
Essential carbamoyl-amino acids formed in vivo in patients with end-stage kidney disease managed by continuous ambulatory peritoneal dialysis: isolation, identification, and quantitation
J Lab Clin Med
(1998) - et al.
Gel isoelectric focusing for following the successive carbamylations of amino groups in chymotrypsinogen A
Anal Biochem
(1971) Enzyme regulation by substrate; rapid inactivation of glutamate dehydrogenase by carbamyl phosphate
Biochem Biophys Res Commun
(1968)- et al.
Carbamylation of pepsinogen and pepsin
J Biol Chem
(1968) - et al.
Impact of carbamylation on type I collagen conformational structure and its ability to activate human polymorphonuclear neutrophils
Chem Biol
(2006)