Coordination abilities of neurokinin A and its derivative and products of metal-catalyzed oxidation

Abstract

The classical tachykinins, substance P, neurokinin A and neurokinin B are predominantly found in the nervous system where they act as neurotransmitters and neuromodulators. Significantly reduced levels of these peptides were observed in neurodegenerative diseases and it may be suggested that this reduction may also result from the copper(II)-catalyzed oxidation. The studies of the interaction of copper(II) with neurokinin A and the copper(II)-catalyzed oxidation were performed. Copper(II) complexes of the neurokinin A (His-Lys-Thr-Asp-Ser-Phe-Val-Gly-Leu-Met-NH 2) and acetyl-neurokinin A (Ac-His-Lys-Thr-Asp-Ser-Phe-Val-Gly-Leu-Met-NH 2) were studied by potentiometric, UV–Vis (UV–visible), CD (circular dichroism) and EPR spectroscopic methods to determine the stoichiometry, stability constants and coordination modes in the complexes formed. The histidine residue in first position of the peptide chain of neurokinin A coordinates strongly to Cu(II) ion with histamine-like {NH 2, N Im} coordination mode. With increasing of pH, the formation of a dimeric complex Cu 2H 2L 2 was found but this dimeric species does not prevent the deprotonation and coordination of the amide nitrogens. In the Ac-neurokinin A case copper(II) coordination starts from the imidazole nitrogen of the His; afterwards three deprotonated amide nitrogens are progressively involved in copper coordination. To elucidate the products of the copper(II)-catalyzed oxidation of the neurokinin A and Ac-neurokinin A, liquid chromatography-mass spectrometry (LC–MS) method and Cu(II)/hydrogen peroxide as a model oxidizing system were employed. Oxidation target for both studied peptides is the histidine residue coordinated to the metal ions. Both peptides contain Met and His residues and are very susceptible on the copper(II)-catalyzed oxidation.