Study of the coordination of ortho-tyrosine and trans-4-hydroxyproline with aluminum(III) and iron(III) Donatella Aiello a,1 , Emilia Furia a,1 , Carlo Siciliano b, ⁎, David Bongiorno c , Anna Napoli a a Dipartimento di Chimica e Tecnologie Chimiche (CTC), Via P. Bucci, Cubo 12/D, Università della Calabria, I-87030 Arcavacata di Rende (CS), Italy b Dipartimento di Farmacia e Scienze della Salute e della Nutrizione, Università della Calabria, I-87030 Arcavacata di Rende (CS), Italy c Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche (STEBICEF), Università degli Studi di Palermo, Via Archirafi 32, I-90123 Palermo, Italy abstract article info Article history: Received 24 May 2018 Received in revised form 1 August 2018 Accepted 11 August 2018 Available online 13 August 2018 The coordination of amino acids ortho-tyrosine (o-Tyr, 1) and trans-4-hydroxyproline (HPro, 2) with the biolog- ically important trivalent metal ions Al(III) and Fe(III) in aqueous solution was investigated by 1 H and 13 C high resolution NMR, Laser Desorption Mass Spectrometry (LD-MS), and MS/MS experiments. Potentiometric mea- surements were also carried out in 0.16 M NaCl, 37 °C, by varying the pH between 2.0 and 3.5. NMR spectra re- corded on aqueous solutions of amino acids 1 or 2 in the presence of the appropriate trivalent metal chloride suggested that binding of Al(III) and Fe(III) involved the COOH and NH 2 functional groups of ligands, while their phenolic and alcoholic groups which did not participate in the metal coordination. Potentiometry indicated the prevalent formation of complexes having the general stoichiometry ML and ML 2 . Laser desorption mass spec- trometry (LD-MS) and MS/MS investigation proved the isotopic compositions of ML and ML 2 complexes, demon- strating their structures. © 2018 Published by Elsevier B.V. 1. Introduction Aluminum and iron are relevant metals in almost all living organ- isms. High doses of Al(III) are generally toxic or detrimental and the ab- sorption of this metal in humans can determine metabolic diseases [1–3]. Fe(III) metabolism plays a key role in diseases, lipid peroxidation, amino acid and protein modification, and DNA damage [4]. Moreover, very low or high levels of Fe(III) may strongly affect iron homeostasis [5]. Natural or modified amino acids, and their hydroxy and N- alkylated derivatives [6–9] might coordinate trivalent metals, affecting their speciation and binding to bioactive peptides and metalloenzymes in living organisms, thus regulating the bioavailability of metal species [10,11]. Many studies have been focused on the interactions of Al(III) with amino acids [12,13]. The literature indicates that aluminum com- plexes with amino acids are generally weak (the pK a value of carboxyl group is 2–3), and that this metal also coordinates to other N, S, O donat- ing ligands preferably at pH lower than neutrality [14–20]. Fe(III) com- plexes of natural amino acids have drawn much attention due to their biological, clinical, and nutritional significance [21–24]. Moreover, inter- est in the complexation of this metal species has grown due to the re- cent identification of the large family of non-heme metalloproteins which feature a Fe(III)-tyrosine coordination center. Consequently, the preparation of chelating amino acids, peptides, and their metal com- plexes as suitable biological sources of Fe(III) has been exploited [25–27]. In this context, hydroxylated amino acids, such as tyrosine, serine, threonine, might play a dominant role [28] in metal coordination, and they are also prevalent as the constituents of natural Fe(III) soluble car- riers, namely siderophores, which are produced by microorganisms [29,30]. In designing new synthetic amphiphilic siderophores, tyrosine may be substituted by its ortho-isomer. Ortho-Tyrosine (o-Tyr, 1; Chart 1) is produced in the human body from tyrosine by disruptions of metabolic pathways involving oxidative radical hydroxylation of the phenyl ring in aromatic amino acids [6,31]. trans-4-Hydroxyproline (HPro, 2; Chart 1) is another hydroxylated amino acid which is abundant in collagen and milk proteins [32,33]. It can be produced from proline by enzymatic hydroxylation [34], and it is implicated in human nutrition [35,36], and has recently been found in siderophores isolated from marine animal sources. A reviewing of the available literature data [37] shows that no unambiguous descriptions of Al(III) complexation with 1 and 2 exists. Thus, it is important to explore how these non-coded amino acids could coordinate Al(III) and Fe(III), and whether their hydroxyl groups are involved in metal binding. Potentiometry have largely been employed in observing the com- plex formation between metals and amino acids [38–41] or other natu- ral low molecular weight compounds [42–47]. Potentiometric titrations generally require high amino acid to metal ratios. The strong buffering effects of amino acids could limit reliability and accuracy of data, thus Journal of Molecular Liquids 269 (2018) 387–397 ⁎ Corresponding author. E-mail address: carlo.siciliano@unical.it (C. Siciliano). 1 These authors contributed equally. https://doi.org/10.1016/j.molliq.2018.08.074 0167-7322/© 2018 Published by Elsevier B.V. Contents lists available at ScienceDirect Journal of Molecular Liquids journal homepage: www.elsevier.com/locate/molliq