To obtain mechanistic insights into the inherent reactivity patterns for copper(I)–O2 adducts, a new cupric–superoxo complex [(DMM-tmpa)CuII(O2•–)]+ (2) [DMM-tmpa = tris((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amine] has been synthesized and studied in phenol oxidation–oxygenation reactions. Compound 2 is characterized by UV–vis, resonance Raman, and EPR spectroscopies. Its reactions with a series of para-substituted 2,6-di-tert-butylphenols (p-X-DTBPs) afford 2,6-di-tert-butyl-1,4-benzoquinone (DTBQ) in up to 50% yields. Significant deuterium kinetic isotope effects and a positive correlation of second-order rate constants (k2) compared to rate constants for p-X-DTBPs plus cumylperoxyl radical reactions indicate a mechanism that involves rate-limiting hydrogen atom transfer (HAT). A weak correlation of (kBT/e) ln k2 versus Eox of p-X-DTBP indicates that the HAT reactions proceed via a partial transfer of charge rather than a complete transfer of charge in the electron transfer/proton transfer pathway. Product analyses, 18O-labeling experiments, and separate reactivity employing the 2,4,6-tri-tert-butylphenoxyl radical provide further mechanistic insights. After initial HAT, a second molar equiv of 2 couples to the phenoxyl radical initially formed, giving a CuII–OO–(ArO′) intermediate, which proceeds in the case of p-OR-DTBP substrates via a two-electron oxidation reaction involving hydrolysis steps which liberate H2O2 and the corresponding alcohol. By contrast, four-electron oxygenation (O–O cleavage) mainly occurs for p-R-DTBP which gives 18O-labeled DTBQ and elimination of the R group.
A new cupric-superoxo complex [LCu II (O 2 •− )] + , which possesses particularly strong O-O and Cu-O bonding, is capable of intermolecular C-H activation of the NADH analogue 1-benzyl-1,4-dihydronicotinamide (BNAH). Kinetic studies indicate a first-order dependence on both the Cucomplex and BNAH with a deuterium kinetic isotope effect (KIE) of 12.1, similar to that observed for certain copper monooxygenases.Copper(I) reactions with molecular oxygen play fundamental roles in many chemical and biological processes.1 , 2 Copper-dependent proteins perform a diverse array of oxidative and oxygenative reactions. This has inspired considerable efforts in the design of novel ligands and copper coordinated complexes as well as the study of ligand-copper(I) dioxygen adducts to elucidate their structures, electronic characteristics and substrate reactivity.2 -4 Compared to binuclear copper-dioxygen derived species, mononuclear analogues have been synthetically challenging and hence are less understood.3 , 5 However, they are fundamentally important and are directly relevant to copper proteins including dopamine-β-monooxygenase (DβM) and peptidlyglycine-α-hydroxylating monooxygenase (PHM).6 These enzymes possess a so-called non-coupled binuclear active site,7 which comprises two Cu centers separated by ~11Å. Dioxygen binding and substrate hydroxylation occur at one of the copper sites (designated Cu M ). In an important PHM X-ray structure, a dioxygen derived species presumed to be an end-on bound cupric superoxide species (i.e., Cu II -O-O •− ) resides adjacent to an inhibitory substrate analog.6c Along with biochemical,6a,b , 8 chemical and computational studies,5 , 9 the cupric-superoxo species is thought by many to be the reactive intermediate responsible for initiating oxidation via hydrogen-atom abstraction. However, other species have been considered as important intermediates in enzymatic turnover, either prior to or following substrate attack, including cuprichydroperoxo (Cu II -− OOH)10 and high-valent cupryl (Cu II -O• <-> Cu III =O) (1) is unreactive toward a number of commonly employed C-H substrates, such as dihydroanthracene, xanthene and 10-methyl-9,10-dihydroacridine -substrates possessing C-H bonds significantly weaker than those found for DBM and PHM substrates (dopamine, 85 kcal/mol; hippuric acid, 87 kcal/mol).6b However, the addition of an excess of 1-benzyl-1,4-dihydronicotinamide (BNAH) -an NADH analogue, which is both a strong H-atom (H (Figure 3b). This gives a kinetic isotope effect (KIE) of 12.1. This KIE value is comparable to that (KIE = 10) reported for C-H bond cleavage of BNAH by a trans-dioxomanganese(V) porphyrin.20 Product analysis of the [LCu II (O 2 •− )] + /BNAH reaction (following quenching with HCl at −130 °C)15 confirms that BNAH has undergone oxidation by 1. The substrate's 4' C-H bond has been oxidatively cleaved to form 1-benzylnicotinamidium ion (BNA + ) in 42% yield ( 1 H-NMR), based on the initial copper concentration (Scheme 1). Additionally, upon acidification, ...
The human fungal pathogens Candida albicans and Histoplasma capsulatum have been reported to protect against the oxidative burst of host innate immune cells using a family of extracellular proteins with similarity to Cu/Zn superoxide dismutase 1 (SOD1). We report here that these molecules are widespread throughout fungi and deviate from canonical SOD1 at the primary, tertiary, and quaternary levels. The structure of C. albicans SOD5 reveals that although the β-barrel of Cu/Zn SODs is largely preserved, SOD5 is a monomeric copper protein that lacks a zinc-binding site and is missing the electrostatic loop element proposed to promote catalysis through superoxide guidance. Without an electrostatic loop, the copper site of SOD5 is not recessed and is readily accessible to bulk solvent. Despite these structural deviations, SOD5 has the capacity to disproportionate superoxide with kinetics that approach diffusion limits, similar to those of canonical SOD1. In cultures of C. albicans, SOD5 is secreted in a disulfide-oxidized form and apo-pools of secreted SOD5 can readily capture extracellular copper for rapid induction of enzyme activity. We suggest that the unusual attributes of SOD5-like fungal proteins, including the absence of zinc and an open active site that readily captures extracellular copper, make these SODs well suited to meet challenges in zinc and copper availability at the host-pathogen interface. E ukaryotes are known to express two highly related classes of copper-containing superoxide dismutase (SOD) enzymes that play widespread roles in oxidative stress resistance and signaling. These two classes include an intracellular, largely cytosolic SOD1 (1) and an extracellular SOD (EC-SOD) (2), both of which are bimetallic enzymes with copper and zinc cofactors. The redox active copper catalyzes the disproportionation of superoxide anion to oxygen and hydrogen peroxide, whereas the zinc helps stabilize the protein (3-5) and promotes pH independence of the reaction (6-8). Additionally, all eukaryotic copper and zinc SODs contain an active site channel that consists of a cluster of charges in loop VII that culminate with an invariant arginine adjacent to the copper site. This element, commonly known as the electrostatic loop, is proposed to provide long-and short-range guidance for the superoxide substrate, thereby facilitating the remarkable kinetics of the SOD reaction (2, 9, 10). SOD1 is among the fastest enzymes known, with rates (10 9 M −1 s −1 ) that approach diffusion limits (9, 11, 12). Very recently, certain pathogenic fungi have been reported to express a class of extracellular proteins that are homologous to SOD1 and are covalently attached to the cell wall through GPI anchors. These SODs were first described for the opportunistic fungal pathogen Candida albicans. C. albicans is a common commensal microbe of the human gut, but under conditions of a weakened immune system, the organism can become invasive and pathogenic, with infections ranging from mild mucosal candidiasis to life-threatening system...
A mononuclear Cu II complex acts as an efficient catalyst for four-electron reduction of O 2 to H 2 O by a ferrocene derivative via formation of the dinuclear Cu II peroxo complex that is further reduced in the presence of protons by a ferrocene derivative to regenerate the Cu II complex.Cytochrome c oxidases (CcOs), with a bimetallic active-site consisting of a heme a and Cu (Fe a3 /Cu B ), are the terminal enzymes of respiratory chains, catalyzing the reduction of molecular oxygen to water by the soluble electron carrier, cytochrome c. 1,2 Synthetic Fe a3 / Cu B analogs have attracted significant attention, because the four-electron reduction of O 2 is not only of great biological interest,3 , 4 but also of technological significance such as in fuel cells.5 ,6 Multicopper oxidases such as laccase also activate oxygen at a site containing a threeplus-one arrangement of 4 Cu atoms, exhibiting remarkable electroactivity for the four-electron reduction of oxygen at potentials approaching 1.2 V (vs RHE). 7 Such electrocatalytic reduction of O 2 has frequently been used to probe the catalytic reactivity of synthetic CcO model complexes3 -5 and some copper (only) complexes have also been investigated. 8-10 However, there has been no report on the copper complex catalyzed four-electron reduction of O 2 employing one-electron reductants in homogeneous solution; such situations are amenable to systematic studies which provide considerable mechanistic insights. 11 fukuzumi@chem.eng.osaka-u.ac.jp, karlin@jhu.edu. Supporting Information Available. Experimental section, kinetic analysis, and figures ( Figure S1-S7). This material is available free of charge via the Internet at http://pubs.acs.org. Figure S1). It has also been confirmed that no H 2 O 2 is detected via iodometric titration experiments ( Figure S2 Figure S3). 14 Thus, the stoichiometry of the catalytic reduction of O 2 by Fc * is given by eq 1. 15 NIH Public AccessThe time profile of the four-electron reduction of O 2 with Fc * catalyzed by 1 in the presence of HClO 4 in acetone at 298 K was examined by stopped-flow measurements. Figure 2a shows the observed absorption spectral change during the catalytic reaction. Under the conditions employed with relative concentrations of reagents as given in the Figure 2 caption, it is only after Fc *+ (λ max = 780 nm) is completely formed that the peroxo species, [(tmpa)Cu II (O 2 ) Cu II (tmpa)] 2+ (2: λ max = 520 nm) 16 starts to be produced. 17 This is more clearly seen in Figure 2b, the time profiles for the absorbance at 780 nm due to Fc *+ , by comparison to the absorbance at 520 nm due to 2. The rate of formation of Fc *+ in Figure 2b appears to be constant with respect to the concentration of Fc *+ , when the concentration of Fc * is in large excess compared to that of HClO 4 . The constant rate (M s −1 ) increases linearly with increasing concentration of 1 and Fc * ( Figure S5). The second-order rate constant (k obs ) is determined to be (1.1 ± 0.1) × 10 5 M −1 s −1 from the slope of Figure S5, which ...
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