The Cys-Xaa-His metal-binding motif: [N] versus [S] coordination and nickel-mediated formation of cysteinyl sulfinic acid.

Research paper by J David JD Van Horn, Grzegorz G Bulaj, David P DP Goldenberg, Cynthia J CJ Burrows

Indexed on: 27 Jun '03Published on: 27 Jun '03Published in: Journal of Biological Inorganic Chemistry


A series of peptide ligands containing the sequence -Cys-Xaa-His- (CXH; Xaa=Gly or Lys) has been prepared and the coordination chemistry of these peptides with nickel(II) investigated. Selective protection of either the N-terminal cysteine thiol or amine group gave complexes with amino or thiolato coordination, respectively, to nickel(II). Insertion of CGH into a pentapeptide, N-acetyl-Ala-Cys-Gly-His-Ala-CONH(2), allowed the formation of a square-planar thiolato Cys-Gly-His complex with nickel(II) in an internal position of the peptide. Inclusion of an N-terminal cysteine residue with a free amino terminus gave rise to pH- and dioxygen-dependent coordination behavior. Solutions of CGH-CONH(2) with nickel(II) at neutral pH yielded a red nickel-thiolate complex, but at higher pH (8.5 or above) or with exposure to dioxygen, yellow nickel complexes with N-terminal amino coordination were observed. The disulfide-bridged dimers formed from Ni(CGH-CONH(2)) in the presence of air were characterized and found to have the typical coordination found in the amino-terminal binding motif of the serum albumins. Nickel(II) coordination and thiol reactivity were also studied by determination of rates of thiol alkylation and by monitoring air oxidation in the presence of various metals. Zinc(II) effectively inhibits thiol alkylation and oxidation (disulfide formation) in all the peptides studied. Nickel(II) inhibits aerobic oxidation and alkylation of N-terminal protected peptides such as N-acetyl-Cys-Gly-His, but does not inhibit air oxidation of free amino terminal peptides such as Cys-Gly-His. Instead, nickel(II) mediates the formation an additional product under aerobic conditions, a cysteinesulfinic acid.