Leslie D. Pettit

Complexes of Cu(II) with Asn-Ser-Phe-Arg-Tyr-NH2; an example of metal ion-promoted conformational organization which results in exceptionally high complex stability

The pentapeptide fragment of ANF, Asn-Ser-Phe-Arg-Tyr-NH2, coordinates to Cu(II) using the same four nitrogen donor centers as simple pentapeptides such as pentaalanine yet the complexes are of much higher stability as a result of a highly organized side-chain structure which is present in the complex but absent from the free ligand.

Stability and structure of copper(II) complexes with 2-amino-2-deoxy-D-mannose and some derivatives thereof

Abstract Potentiometric and spectroscopic studies indicate that 2-amino-2-deoxy- d -mannose (ManN), its methyl α-glycopyranoside, and methyl 2-amino-2-deoxy-α,β- d -galactopyranoside are good chelating agents for cupric ions. The stability constants for the complexes with the manno compounds are higher than those of 2-amino-2-deoxy- d -galactose (GalN) and 2-amino-2-deoxy- d -glucose (GlcN). The primary binding site is the amino group and the most effective secondary site in the manno compounds is HO-3. Comparison of the co-ordination abilities of GalN, GlcN, ManN, and their methyl glycopyranosides indicates that various hydroxyl groups can be involved in the binding of metal ions. The stability constants of the Ni(II) and Co(II) complexes with ManN are also presented.

Specific interactions of the β-carboxylate group of the aspartic acid residue in oligopeptides containing one, two or three such residues with copper(II) ions. A potentiometric and spectroscopic study

Results are reported of a study of the influence of Asp and Glu residues in a peptide chain on the ability of the peptide to co-ordinate to copper(II) ions. The tetrapeptides Asp-Ala-Ala-Ala, Ala-Asp-Ala-Ala, Ala-Ala-Ala-Asp, Asp-Ala-Ala-Asp, Ala-Asp-Asp-Ala, Ala-Asp-Ala-Asp, Ala-Ala-Asp-Asp, Glu-Ala-Ala-Ala, Ala-Glu-Ala-Ala and Ala-Ala-Glu-Ala and the tripeptide Asp-Asp-Asp have been synthesised and their complexes with H+ and Cu2+ ions studied using potentiometry and spectroscopy (visible, CD and ESR). Results show that while the Glu residue has little influence on co-ordination equilibria, an N-terminal Asp residue stabilizes significantly the copper(II) complex with only one nitrogen atom co-ordinated (1N) as a result of chelation through the β-carboxylate group rather than the peptide CO oxygen. This stabilization is much greater than with aspartic acid itself. Aspartic acid residues in the second or third positions of the peptide sequence stabilize 2N and 3N complexed species respectively, delaying significantly and, in some cases preventing completely, formation of 4N complexes. An Asp residue in the fourth position has a much smaller effect.

Complex formation and stereoselectivity in the ternary systems copper(II)–D/L-histidine–L-amino-acids

Formation constants of the parent and ternary complexes of general formula [CuII(D/L-HisO)(L-A)](HisO = histidinate; HA = phenylalanine, tryptophan, valine, proline, methionine, leucine, serine, threonine, 2,4-diaminobutyric acid, ornithine, lysine, arginine, glutamic acid, aspartic acid, glycylvaline, glycylphenylalanine, or valyl-L-valine) have been measured potentiometrically at 25.0 °C and I= 0.10 mol dm–3(K[NO3]). The ternary systems of CuII and the substituted histidines N3-benzyl-L-histidine and NαN3-dibenzyl-L-histidine with D- and L-tryptophan, phenylalanine, valine, and glutamic acid have also been studied. The ternary complexes containing tryptophan and phenylalanine are unusually stable, complexes containing ligands of opposite chirality being significantly more stable than those with ligands of the same chirality. With ornithine, lysine, and arginine, stereoselectivity is significant in monoprotonated ternary complexes, those with ligands of the same chirality being more stable. This stereoselectivity is at a maximum at ca. pH 6 and vanishes when the proton is ionized. With aspartic acid, stereoselectivity is significant in the non-protonated ternary complex, that with ligands of opposite chirality being more stable. The stereoselectivity found may be explained by simple electrostatic interactions.

How non-bonding amino acid side-chains may enormously increase the stability of a Cu(II)—peptide complex

Abstract A combined pH-metric and spectroscopic (UV—Vis, circular dichroism and electron paramagnetic resonance) study of Cu(II) binding to analogues of Asn-Ser-Phe-Arg-Tyr-NH 2 systematically substituted with Ala residues revealed the presence of indirect, additive conformational effects resulting in a very high stability enhancement for 4N complexes. The major contribution to the stability is exerted by non-binding side-chains of 4th and 5th amino acids. This effect is explained on the basis of spectroscopic data by the formation of a secondary fence shielding the Cu(II) binding site from the bulk of the solution. Such a structure, not reported previously, is of possible importance for the understanding of interactions of metal ions with proteins.

Coordination abilities of tetrapeptides containing proline and tyrosine—A spectrophotometric and potentiometric study

Abstract The synthesis of three tetrapeptides, Gly-Pro-Gly-Tyr. Gly-Pro-Tyr-Gly. and Tyr-Pro-Gly-Gly, are described. All contain proline as the second amino acid subunit to act as a break point in metal complex formation. The proton and copper(II) complex formation constants have been measured at 22°C and l = 0.10 mol dm−3 (KNO3). The copper(II) complexes have also been studied spectrophotometrically over the pH range of 6–11 by absorption spectroscopy (800–200 nm), circular dichroism spectroscopy, and electron paramagnetic resonance spectroscopy. The experimental data have been combined to determine the complex species present as a function of pH and the coordination centers used.

Complexes of zinc, copper, and nickel with the nonprotein amino acid L-α-amino-β-methylaminopropionic acid: A naturally occurring neurotoxin

Abstract The non-protein amino acid L-α-amino-β-methylaminopropionic acid (L-MeDAP) causes motor neuron dysfunction in macaques. The amino acid is a potent chelator of divalent metal ions such as copper and zinc. Binding constants nickel(II) for copper(II) and zinc(II) with L-MeDAP have been measured. Some copper(II) complexes of L-MeDAP have been synthesized and characterized by their electronic, infrared, and epr spectra. These results are used to comment on the possibility that metal ion complexation in the central nervous system is involved in the expression of the meurotoxicity of L-MeDAP.

Metal complexes of luteinizing hormone-releasing hormone (LHRH). Potentiometric and spectroscopic studies

The results are reported of a potentiometric and spectroscopic study of the H+, Cu2+, and Ni2+ complexes of luteinizing hormone-releasing hormone (LHRH, HL) at 25 degrees C and an ionic strength 0.10 mol dm-3 (KNO3), since there is much evidence that the in vivo release of LHRH is influenced by the concentration of copper ions. With Cu2+ the hormone has been shown to behave similarly to the thyrotropin releasing factor, forming a very stable [CuH-1L] complex involving coordination of three nitrogen donors: the Nim atom of the imidazole side chain and the two amido-N atoms of the pyroglutamylhistidyl unit. With Ni2+, coordination proceeds differently to give four nitrogen coordination.

Competition between the terminal amino and imidazole nitrogen donors for coordination to Ni(II) ions in oligopeptides

Abstract Spectroscopic and potentiometric studies on Ni(II) complexes with oligopeptides containing a histidine (His) residue in the fourth position of the peptide sequence have shown that imidazole nitrogen can act as the major binding site for metal ions. As a result, coordination of Ni(II) to an imidazole nitrogen of a His residue leads to more stable species than those obtained for linear peptides containing non-coordinating side chains, such as tetraalanine.

Copper(II) complexes with some tetrapeptides containing the ‘break-point’ prolyl residue in the third position

The tetrapeptides Phe-Gly-Pro-Phe, Phe-Gly-Pro-Tyr, and Tyr-Gly-Pro-Phe have been synthesised and their complexes with H+ and Cu2+ studied by potentiometry and spectroscopy (u.v., visible, c.d., and e.s.r.) at 25 °C and l= 0.10 mol dm–3(KNO3). The results show that with both tetrapeptides containing the Tyr residue, TyrO––Cu bonding is present at pH > 8. With Tyr-Gly-Pro-Phe this is achieved through the formation of dimeric complexes while with Phe-Gly-Pro-Tyr a monomeric complex with a large chelate ring is formed.