Stability constant determination of sulfur and selenium amino acids with Cu(II) and Fe(II)

Sulfur- and selenium-containing amino acids are of great biological importance, but their metal-binding properties with biologically-relevant metal ions are not well investigated. Stability constants of the methionine, selenomethionine, methylcysteine, and methylselenocysteine with Cu(II) and Fe(II) were determined by potentiometric titration. Stability constants of Cu(II) with these thio- and selenoether amino acids are in the range of 8.0–8.2 ([CuL]+) and 14.5–14.7 (CuL2) (L = amino acid). Fe(II) interactions with the same thio- and selenoether amino acids are much weaker, with stability constants between 3.5 and 3.8 ([FeL]+) and −4.9 and −5.7 (FeL(OH)). Stability of Fe(II) with penicillamine, a thiol-containing amino acid, is much higher (FeL = 7.48(7) and [FeL]2− = 13.74(2)). For both copper and iron complexes, thio- and selenoether amino acid coordination occurs through the carboxylate and the amine groups as confirmed by infrared spectroscopy, with no stability afforded by thio- or selenoether coordination. The first single-crystal structure of Cu(II) with a selenium-containing amino acid, Cu(SeMet)2, also confirms binding through only the amine and carboxylate groups. The measured Cu(II)-amino-acid stability constants confirm that nearly 100% of the available Cu(II) can be coordinated by these amino acids at pH 7, but very little Fe(II) is bound under these conditions. The relative instability of Fe(II) complexes with thio- and selenoether amino acids is consistent with their inability to prevent metal-mediated oxidative DNA damage. In contrast, the stability constants of these amino acids with Cu(II) weakly correlate to their ability to inhibit DNA damage inhibition. The stability of sulfur and selenium amino acid complexes with Cu(II) is greater than with Fe(II). Selenoether amino acid coordination to Cu(II) occurs through the carboxylate and amine groups, with no stability afforded by the sulfur or selenium atom, as seen in the Cu(SeMet)2 structure. [Display omitted] •Sulfur and selenium amino acids form more stable complexes with Cu(II) than Fe(II).•Most amino acids bind Cu(II) or Fe(II) through only the carboxylate and amine groups.•Penicillamine coordinates Fe(II) through the thiolate group.•Penicillamine binding prevents in vitro Fe(II)-mediated oxidative DNA damage.•DNA damage prevention correlates with Cu(II) binding to sulfur and selenium amino acids.