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NDT Advance Access originally published online on June 13, 2008
Nephrology Dialysis Transplantation 2008 23(9):3033; doi:10.1093/ndt/gfn342
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© The Author [2008]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org


‘O’, erythropoietin carbamoylation versus carbamylation

E-mail: jelkmann{at}physio.uni-luebeck.de

Sir,

Kitamura and co-workers [1] have convincingly shown that recombinant human erythropoietin (rhEPO) and a nonerythropoietic derivative thereof are protective against tubulointerstitial injury in rats with unilateral ureteral obstruction. Indeed, the past 15 years have yielded a plethora of novel EPO targets, including kidneys, liver, blood vessels, heart and brain. rhEPO derivatives that are devoid of erythropoiesis-stimulating activity but still confer tissue protection are of primary therapeutic interest because an unwanted rise in haematocrit can increase peripheral flow resistance and cause disturbances in the microcirculation. In their studies, Kitamura et al. [1] used CEPO as rhEPO derivative in which EPO's lysines were in vitro transformed to homocitrulline with KOCN as described in detail elsewhere [2]. Unfortunately, like in the present article, it has become common to call CEPO ‘carbamylated’ EPO, which is not correct. The irreversible interaction of cyanate with non-protonated {varepsilon}-amino groups of lysine should be correctly referred to as ‘carbamoylation’ (Figure 1).


Figure 1
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  		Fig. 1 Carbamoylation versus carbamylation of the amino groups of proteins. Carbamoylation is the irreversible formation of homocitrulline ({varepsilon}-amino-carbamoyl-lysine) by interaction of cyanate with the non-protonated {varepsilon}-amino group of lysine. Carbamylation describes the reversible interaction of CO2 with {alpha}- and {varepsilon}-amino groups of proteins.

 
In contrast, carbamylated proteins (‘carbamates’) derive from the reversible interaction of proteins with CO2. For example, CO2 binds to {alpha}- and {varepsilon}-amino groups of haemoglobin (‘carbaminohaemoglobin’). The contribution of carbamate to overall CO2 exchange in the lung and the peripheral tissues amounts to ~5% of the total [3].

Cyanate formed from urea carbamoylates proteins in chronic kidney disease (CKD) [4]. Homocitrulline has been demonstrated in glomeruli and tubules in CKD patients with elevated blood urea nitrogen levels (BUN) in association with CKD, while it is absent in proteinuric patients with a normal BUN [5]. EPO loses its in vivo erythropoietic activity on change of the positive charges of its lysines to neutral or negative charges through carbamoylation. This reaction may contribute to EPO resistance in CKD patients with high urea levels.

Conflict of interest statement. None declared.

Wolfgang Jelkmann

Institute of Physiology, University of Luebeck, Luebeck, Germany

References

  1. Kitamura H, Isaka Y, Takabatake Y, et al. Nonerythropoietic derivative of erythropoietin protects against tubulointerstitial injury in a unilateral ureteral obstruction model. Nephrol Dial Transplant (2008) 23:152–1528.
  2. Leist M, Ghezzi P, Grasso G, et al. Derivatives of erythropoietin that are tissue protective but not erythropoietic. Science (2004) 305:239–242.[Abstract/Free Full Text]
  3. Geers C, Gros G. Carbon dioxide transport and carbonic anhydrase in blood and muscle. Physiol Rev (2000) 80:681–715.[Abstract/Free Full Text]
  4. Galle J, Wanner Ch. Modification of lipoproteins in uremia: oxidation, glycation and carbamoylation. Miner Electrolyte Metab (1999) 25:263–268.[CrossRef][Web of Science][Medline]
  5. Kraus LM, Kraus AP Jr. Carbamoylation of amino acids and proteins in uremia. Kidney Int Suppl (2001) 78:S102–S107.[CrossRef][Medline]

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This Article
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