The Angiotensin Metabolite His-Leu Is a Strong Copper Chelator Forming Highly Redox Active Species

• Published in: Inorganic chemistry Vol. 63; no. 26; pp. 12268 - 12280
• Main Authors: Wezynfeld, Nina E., Sudzik, Dobromiła, Tobolska, Aleksandra, Makarova, Katerina, Stefaniak, Ewelina, Frączyk, Tomasz, Wawrzyniak, Urszula E., Bal, Wojciech
• Format: Journal Article
• Language: English
• Published: American Chemical Society 01.07.2024
• ISSN: 0020-1669; 1520-510X; 1520-510X
• DOI: 10.1021/acs.inorgchem.4c01640

His-Leu is a hydrolytic byproduct of angiotensin metabolism, whose concentration in the bloodstream could be at least micromolar. This encouraged us to investigate its Cu­(II) binding properties and the concomitant redox reactivity. The Cu­(II) binding constants were derived from isothermal titration calorimetry and potentiometry, while identities and structures of complexes were obtained from ultraviolet–visible, circular dichroism, and room-temperature electronic paramagnetic resonance spectroscopies. Four types of Cu­(II)/His-Leu complexes were detected. The histamine-like complexes prevail at low pH. At neutral and mildly alkaline pH and low Cu­(II):His-Leu ratios, they are superseded by diglycine-like complexes involving the deprotonated peptide nitrogen. At His-Leu:Cu­(II) ratios of ≥2, bis-complexes are formed instead. Above pH 10.5, a diglycine-like complex containing the equatorially coordinated hydroxyl group predominates at all ratios tested. Cu­(II)/His-Leu complexes are also strongly redox active, as demonstrated by voltammetric studies and the ascorbate oxidation assay. Finally, numeric competition simulations with human serum albumin, glycyl-histydyl-lysine, and histidine revealed that His-Leu might be a part of the low-molecular weight Cu­(II) pool in blood if its abundance is >10 μM. These results yield further questions, such as the biological relevance of ternary complexes containing His-Leu.