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  • Review Article
  • Published:

Mechanisms and consequences of carbamoylation

Nature Reviews Nephrology volume 13, pages 580–593 (2017)Cite this article

Subjects

Key Points

  • Carbamoylation is a non-enzymatic reaction during which a carbamoyl moiety is added to proteins, peptides or amino acids; this post-translational molecular modification contributes to the molecular ageing of proteins

  • Carbamoylation-derived products are formed by the reaction of proteins, peptides or amino acids with isocyanic acid, which originates from urea or by oxidation of thiocyanate by myeloperoxidase in inflammatory conditions and in atherosclerotic plaques

  • Carbamoylation has important effects on the immune system, atherosclerosis, lipid metabolism, and the progression of chronic kidney disease

  • Carbamoylation-derived products are emerging as important markers of survival in the general population as well as in patients on dialysis

Abstract

Protein carbamoylation is a non-enzymatic post-translational modification that binds isocyanic acid, which can be derived from the dissociation of urea or from the myeloperoxidase-mediated catabolism of thiocyanate, to the free amino groups of a multitude of proteins. Although the term 'carbamoylation' is usually replaced by the term “carbamylation” in the literature, carbamylation refers to a different chemical reaction (the reversible interaction of CO2 with α and ε-amino groups of proteins). Depending on the altered molecule (for example, collagen, erythropoietin, haemoglobin, low-density lipoprotein or high-density lipoprotein), carbamoylation can have different pathophysiological effects. Carbamoylated proteins have been linked to atherosclerosis, lipid metabolism, immune system dysfunction (such as inhibition of the classical complement pathway, inhibition of complement-dependent rituximab cytotoxicity, reduced oxidative neutrophil burst, and the formation of anti-carbamoylated protein antibodies) and renal fibrosis. In this Review, we discuss the carbamoylation process and evaluate the available biomarkers of carbamoylation (for example, homocitrulline, the percentage of carbamoylated albumin, carbamoylated haemoglobin, and carbamoylated low-density lipoprotein). We also discuss the relationship between carbamoylation and the occurrence of cardiovascular events and mortality in patients with chronic kidney disease and assess the effects of strategies to lower the carbamoylation load.

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Figure 1: Carbamoylation.
Figure 2: Effects of carbamoylation on endothelial function.

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Authors and Affiliations

  1. Department of Nephrology, Ghent University Hospital, De Pintelaan 185, Ghent, 9000, Belgium

    Sigurd Delanghe, Wim Van Biesen & Marijn M. Speeckaert

  2. Department of Clinical Chemistry, Ghent University Hospital, De Pintelaan 185, Ghent, 9000, Belgium

    Joris R. Delanghe & Reinhart Speeckaert

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Glossary

Tautomer

Constitutional isomer of organic compounds that readily interconvert into another tautomer, usually by the realocation of a proton.

pKa values

Negative logarithm of the ionization constant of an acid, which is a measure of the strength of an acid.

Halides

Binary compounds consisting of a halogen atom and an element or radical that is less electronegative (or more electropositive) than the halogen.

Stable-isotope-dilution

Method to determine the quantity of chemical substances in a sample, involving the addition of known amounts of an isotopically-enriched substance to the sample to be analysed.

High-performance liquid chromatography

(HPLC). Analytical method to separate, identify and quantify each component present in a mixture.

Tandem mass spectrometry

(MS/MS). Multiple step mass spectrometry, with some form of fragmentation occurring between the stages, to determine the mass of a sample.

Linearity

The linearity of an analytical procedure is its ability (within a given range) to obtain test results that are directly proportional to the concentration (amount) of analyte in the sample.

Coefficient of variation

(CV). Widely used term in analytical chemistry to express the precision and repeatability of an assay.

Kt/V

Baseline parameter of dialysis adequacy that represents the blood volume cleared of urea relative to the distribution volume of urea.

Uraemic toxins

Chemical solutes that accumulate in patients with chronic kidney disease and have negative effects on the body.

Intravasation

Invasion of cancer cells through the basal membrane into a blood or lymphatic vessel.

Immunodominant

Epitope that elicits the stronger immune response.

Bleeding diathesis

Increased tendency to bleed mostly due to hypocoagulability, which in turn is caused by a coagulopathy.

Elasmobranchs

Subclass of Chondrichthyes or cartilaginous fish.

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Delanghe, S., Delanghe, J., Speeckaert, R. et al. Mechanisms and consequences of carbamoylation. Nat Rev Nephrol 13, 580–593 (2017). https://doi.org/10.1038/nrneph.2017.103

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