Cyclic Phosphopeptides to Rationalize the Role of Phosphoamino Acids in Uranyl Binding to Biological Targets. Issue 22 (29th March 2017)

• Record Type: Journal Article
• Authors: Starck, Matthieu; Laporte, Fanny A.; Oros, Stephane; Sisommay, Nathalie; Gathu, Vicky; Solari, Pier Lorenzo; Creff, Gaëlle; Roques, Jérôme; Den Auwer, Christophe; Lebrun, Colette; Delangle, Pascale
• Is Part Of: Chemistry. Volume 23:Issue 22(2017)
• Page Start: 5281
• Page End: 5290
• Publication Date: 2017-03-29
• Subjects: affinity -- bioinorganic chemistry -- peptides -- phosphates -- uranium; Chemistry -- Periodicals; 540
• DOI: 10.1002/chem.201605481
• Languages: English
• ISSNs: 0947-6539

Abstract

Abstract: The specific molecular interactions responsible for uranium toxicity are not yet understood. The uranyl binding sites in high‐affinity target proteins have not been identified yet and the involvement of phosphoamino acids is still an important question. Short cyclic peptide sequences, with three glutamic acids and one phosphoamino acid, are used as simple models to mimic metal binding sites in phosphoproteins and to help understand the mechanisms involved in uranium toxicity. A combination of peptide design and synthesis, analytical chemistry, extended X‐ray absorption fine structure (EXAFS) spectroscopy, and DFT calculations demonstrates the involvement of the phosphate group in the uranyl coordination sphere together with the three carboxylates of the glutamate moieties. The affinity constants measured with a reliable analytical competitive approach at physiological pH are significantly enhanced owing to the presence of the phosphorous moiety. These findings corroborate the importance of phosphoamino acids in uranyl binding in proteins and the relevance of considering phosphoproteins as potential uranyl targets in vivo. Abstract : Phosphate coordination to uranyl in cyclic preorganized peptide scaffolds is demonstrated theoretically and experimentally at physiological pH and greatly enhances the uranyl complex stability. These peptide mimics of binding sites found in proteins corroborate the relevance of considering phosphoproteins as targets for this toxic metal ion in vivo (see figure).