Triuret as a potential hypokalemic agent: Structure characterization of triuret and triuret-alkali metal adducts by mass spectrometric techniques

Triuret (also known as carbonyldiurea, dicarbamylurea, or 2,4-diimidotricarbonic diamide) is a byproduct of purine degradation in living organisms. An abundant triuret precursor is uric acid, whose level is altered in multiple metabolic pathologies. Triuret can be generated via urate oxidation by peroxynitrite, the latter being produced by the reaction of nitric oxide radical with superoxide radical anion. From this standpoint, an excess production of superoxide radical anions could indirectly favor triuret formation; however very little is known about the potential in vivo roles of this metabolite. Triuret's structure is suggestive of its ability to adopt various conformations and act as a flexible ligand for metal ions. In the current study, HPLC-MS/MS, energy-resolved mass spectrometry, selected ion monitoring, collision-induced dissociation, IRMPD spectroscopy, Fourier transform-ion cyclotron resonance mass spectrometry and computational methods were employed to characterize the structure of triuret and its metal complexes, to determine the triuret-alkali metal binding motif, and to evaluate triuret affinity toward alkali metal ions, as well as its affinity for Na+ and K+ relative to other organic ligands. The most favored binding motif was determined to be a bidentate chelation of triuret with the alkali metal cation involving two carbonyl oxygens. Using the complexation selectivity method, it was observed that in solution triuret has an increased affinity for potassium ions, compared to sodium and other alkali metal ions. We propose that triuret may act as a potential hypokalemic agent under pathophysiological conditions conducive to its excessive formation and thus contribute to electrolyte disorders. The collision- or photo-induced fragmentation channels of deprotonated and protonated triuret, as well as its alkali metal adducts, are likely to mimic the triuret degradation pathways in vivo. (c) 2010 Elsevier Inc. All rights reserved.