Bisamidate and Mixed Amine/Amidate NiN₂S₂ Complexes as Models for Nickel-Containing Acetyl Coenzyme A Synthase and Superoxide Dismutase: An Experimental and Computational Study

Abstract

The distal nickel site of acetyl-CoA synthase (Ni d -ACS) and reduced nickel superoxide dismutase (Ni-SOD) display similar square-planar Ni II N 2 S 2 coordination environments. One difference between these two sites, however, is that the nickel ion in Ni-SOD contains a mixed amine/amidate coordination motif while the Ni d site in Ni-ACS contains a bisamidate coordination motif. To provide insight into the consequences of the different coordination environments on the properties of the Ni ions, we systematically examined two square-planar Ni II N 2 S 2 complexes, one with bisthiolate-glycinamide] and another with bisthiolate-amine/amidate ligation K(Ni(HL2)) (3) [H 4 L2 = N-(2"-mercaptoethyl)-2-((2'-mercaptoethyl)amino)acetamide]. Although these two complexes differ only by a single amine vs. amidate ligand, the chemical properties of them are quite different. The stronger in-plane ligand field in the bisamidate complex (Ni II (L1)) 2− (2) results in an increase in the energies of the d → d transitions and a considerably more negative oxidation potential. Furthermore, while the bisamidate complex (Ni II (L1)) 2− (2) readily forms a trinuclear species (Et 4 N) 2 ({Ni(L1)} 2 Ni) ·H 2 O (1) and reacts rapidly with O 2 , presumably via sulfoxidation, the mixed amine/amidate complex (Ni II (HL2)) − (3) remains monomeric and is stable for days in air. Interestingly, the Ni III species of the bisamidate complex formed by chemical oxidation with I 2 can be detected by electron paramagnetic resonance (EPR) spectroscopy while the mixed amine/amidate complex immediately decomposes upon oxidation. In order to explain these experimentally observed properties, we performed S K-edge X-ray absorption spectroscopy and low-temperature (77 K) electronic absorption measurements as well as both hybrid density functional theory (hybrid-DFT) and spectroscopy oriented configuration interaction (SORCI) calculations. These studies demonstrate that the highest occupied molecular orbital (HOMO) of the bisamidate complex (Ni II (L1)) 2− (2) has more Ni character and is significantly destabilized relative to the mixed amine/amidate complex (Ni II (HL2)) − (3) by ~6.2 kcal mol −1 . The consequence of this destabilization is manifested in the

Cysteinate Protonation and Water Hydrogen Bonding at the Active-Site of a Nickel Superoxide Dismutase Metallopeptide-Based Mimic: Implications for the Mechanism of Superoxide Reduction

“…The integrated intensity for the thiolate S(1s) → Ψ 1 * transition is 0.43(1) units, which correlates to a %S(3p) character of 16(4)% to Ψ 1 *. 43 The pH 9.5 S K-edge X-ray absorption spectrum for {Ni II (SOD m1 )} also displays a sharp pre-edge feature, which is slightly blue-shifted relative to the {Ni II (SOD m1 C(6)C Me )} pre-edge peak (2472.1(1) eV). This reflects an overall destabilization of Ψ 1 * in the high pH form of {Ni II (SOD m1 )} relative to {Ni II (SOD m1 C(6)C Me )}.…”

Dipeptide-Based Models of Nickel Superoxide Dismutase: Solvent Effects Highlight a Critical Role to Ni–S Bonding and Active Site Stabilization

“…22 In DMF, the most intense visible band is broad and ranges from 463 nm (ε: 350 M −1 cm −1 ) for 5 to 484 nm (ε: 450 M −1 cm −1 ) for 3 (Figure 2, Table 1); similar visible transitions are observed in Ni-SOD red at 450 nm (ε: 480 M −1 cm −1 ) 22 and other square-planar Ni(II)N 2 S 2 complexes. 34–35,62–68 These absorptions are proposed to be ligand-field ( d -to- d ) transitions containing a minor charge-transfer (CT) contribution. 22 A second less intense ligand-field transition appears as a shoulder between 545 nm (ε: 160 M −1 cm −1 ) for 5 and 570 nm (230 M −1 cm −1 ) for 3 and mirrors a similar feature in Ni-SOD red at 543 nm (ε: 150 M −1 cm −1 ).…”

“…Irreversible CVs have been a hallmark of Ni(II)-N 2 S 2 SOD models 34–35,37–38 and indicate an overall change in the coordination environment after oxidation, most likely a result of a thiolate-disulfide conversion, which is prevented in the enzyme. Comparison of the potentials demonstrated patterns which can be roughly correlated to the donor strength of the monodentate RS − ligand.…”

“…17–18 In its oxidized Ni(III) state, the coordination geometry is square pyramidal with the imidazole-N of His1 occupying the apical position (Chart 1). 17–18 Although a growing body of protein, 15–16,19–25 polypeptide maquette 26–33 and small molecule 34–40 literature has shed some light upon the role of this unusual donor set, many outstanding questions remain as to the interplay between the Ni ion, ligands, secondary coordination sphere, substrate and products during SOD catalysis. 19–29,34–38,41–43 …”

Die Umsetzung von nickelgebundenem CO zum Thioester: Organometallchemie mit Bezug zum aktiven Zentrum der Acetyl‐Coenzym‐A‐Synthase

“…Die CODH/ACS hat in der Vergangenheit Anreiz für die Synthese einer Vielzahl an strukturellen [2,9,15,16] und funktionellen [2,5,16,17] niedermolekularen Analoga geboten. Auf dem Weg zu funktionellen Modellen wurden zunächst einkernige wie auch zweikernige NiKomplexe synthetisiert, die die elementaren Schritte der ACS-Untereinheit nachempfinden.…”