Synthetic Heme/Copper Assemblies: Toward an Understanding of Cytochrome c Oxidase Interactions with Dioxygen and Nitrogen Oxides

Abstract

Conspectus Our long-time niche in synthetic biological inorganic chemistry has been to design ligands and generate coordination complexes of copper and/or iron ions, those reacting with dioxygen (O2) and/or nitrogen oxides (e.g., nitric oxide (NO(g)) and nitrite (NO2−)). As inspiration for this work, we turn to mitochondrial cytochrome c oxidase which is responsible for dioxygen consumption and is also the predominant target for NO(g) and nitrite within mitochondria. In this Account, we highlight recent advances in studying synthetic heme/Cu complexes in two respects. First, there is the design, synthesis and characterization of new O2-adducts whose further study will add insights into O2-reductive cleavage chemistry. Second, we describe how related heme/Cu constructs reduce nitrite ion to NO(g) or the reverse, oxidize NO(g) to nitrite. The reactions of nitrogen oxides occur as part of CcO’s function, which is intimately tied to cellular O2-balance. We had first discovered that reduced heme/Cu compounds react with O2 giving μ-oxo heme-FeIII-O-CuII(L) products; their properties are discussed. The O-atom is derived from dioxygen and interrogations of these systems led to the construction and characterization of three distinctive classes of heme-peroxo-complexes, two high-spin and one low-spin species. Recent investigations include a new approach to the synthesis of low-spin heme-peroxo-Cu complexes, employing a “naked” synthon, where the copper ligand denticity and geometric types can be varied. The result is a collection of such complexes; spectroscopic and structural features (by DFT calculations) are described. Some of these compounds are reactive toward reductants/protons effecting subsequent O-O cleavage. This points to how subtle improvements in ligand environment lead to a desired local structure and resulting optimized reactivity, as known to occur at enzyme active-sites. The other sector of research is focused on heme/Cu assemblies mediating the redox interplay between nitrite and NO(g). In the nitrite reductase chemistry, the cupric center serves as a Lewis acid while the heme is the redox active center providing the electron. The orientation of nitrite in approaching the ferrous heme center and N-atom binding are important. Also, detailed spectroscopic and kinetic studies of the NO(g) oxidase chemistry, in excellent agreement with theoretical calculations, reveal the intermediates and key mechanistic steps. Thus, we suggest that both chemical and biochemical heme/Cu mediated nitrite reductase and NO(g) oxidase chemistry require N-atom binding to a ferrous heme along with cupric ion O-atom coordination, proceeding via a three-membered O-Fe-N chelate ring transition state. These important mechanistic features of heme/Cu systems interconverting NO(g) and nitrite are discussed for the first time.

Isocyanide or nitrosyl complexation to hemes with varying tethered axial base ligand donors: synthesis and characterization

“…One of our research group’s major foci has been and continues to be the study of dioxygen binding and reduction at heme-copper heterobinuclear metal ion centers [31]. We seek to determine how neighboring copper-ligand moieties influence the binding of O 2 to hemes, and in a complementary manner, see how hemes affect O 2 binding to copper ion in varying ligand environments.…”

“…Then, as such synthetic heme-O 2 -Cu assemblies can be compared and related to the active-site chemistry of heme-copper oxidases which bind and reduce O 2 to two water molecules (while also translocating protons through a mitochondrial membrane which downstream facilitates ATP biosynthesis), we are interested in elucidating detailed insights into the O–O reductive cleavage process, as a function of the exact nature (structure and electronics/bonding behavior) of the heme, the copper ligand and the source of electrons ( E ° value) and protons (pKa). Additional factors include heme or copper-ligand electron-donating ability (and thus the Fe III /Fe II and/or Cu II /Cu I E ° value), nature of porphyrinate peripheral groups, and/or copper-ligand denticity and their possible steric influences or affects upon the entire heme-O 2 -Cu(ligand) structure, for example the Fe…Cu distance in the heme-O 2 -Cu assembly [31–35]. …”

“…1, where also an added heme axial ‘base’, dicyclohexylimidazole (DCHIm), is present [35, 36]. As anticipated, the structural, spectroscopic properties and reactivity of this and other such assemblies significantly depend on the detailed nature of the heme, the copper ligand, the axial base, etc., as mentioned above [31, 36]. …”

Why copper is preferred over iron for oxygen activation and reduction in haem-copper oxidases

“…To overcome these limitations with studying complex metalloproteins like HCOs, synthetic models of HCOs using organic molecules have been prepared. 12–14 In particular, using small-molecule HCO models, Collman et. al.…”

A High‐Valent Non‐Heme μ‐Oxo Manganese(IV) Dimer Generated from a Thiolate‐Bound Manganese(II) Complex and Dioxygen

“…[1] In addition, O 2 is an environmentally benign oxidant in chemical catalysis [2] and the development of fuel cells requires electrocatalysts for its efficient and selective reductive activation. [3] Activating O 2 often requires transition metal ions to promote the process.…”