Functional Analogues of the Dioxygen Reduction Site in Cytochrome Oxidase:  Mechanistic Aspects and Possible Effects of Cu<sub>B</sub>

Boulatov, Roman; Collman, James P.; Shiryaeva, Irina M.; Sunderland, Christopher J.

doi:10.1021/ja026179q

Cited by 149 publications

(150 citation statements)

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“…Tyr I-288 is at the end of the K channel, hydrogen-bonded to the water on heme a 3 ( Figure 2). Oxygen reduction chemistry is likely to involve a coupled electron (92)(93)(94) and proton (75,95,96) transfer from this Tyr to O 2 . The Tyr could also serve as a proton acceptor when the BNC is reduced, if it is deprotonated in the fully oxidized state.…”

Section: Resultsmentioning

confidence: 99%

Calculated Proton Uptake on Anaerobic Reduction of CytochromecOxidase: Is the Reaction Electroneutral?

2006

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Cytochrome c oxidase is a transmembrane proton pump that builds an electrochemical gradient using chemical energy from the reduction of O 2 . Ionization states of all residues were calculated with Multi-Conformation Continuum Electrostatics (MCCE) in seven anaerobic oxidase redox states ranging from fully oxidized to fully reduced. One long-standing problem is how proton uptake is coupled to the reduction of the active site binuclear center (BNC). The BNC has two cofactors: heme a 3 and Cu B . If the protein needs to maintain electroneutrality, then 2 protons will be bound when the BNC is reduced by 2 electrons in the reductive half of the reaction cycle. The effective pK a s of ionizable residues around the BNC are evaluated in Rhodobacter sphaeroides cytochrome c oxidase. At pH 7, only a hydroxide coordinated to Cu B shifts its pK a from below 7 to above 7 and so picks up a proton when heme a 3 and Cu B are reduced. Glu I-286, Tyr I-288, His I-334, and a second hydroxide on heme a 3 all have pK a s above 7 in all redox states, although they have only 1.6-3.5 ∆pK units energy cost for deprotonation. Thus, at equilibrium, they are protonated and cannot serve as proton acceptors. The propionic acids near the BNC are deprotonated with pK a s well below 7. They are well stabilized in their anionic state and do not bind a proton upon BNC reduction. This suggests that electroneutrality in the BNC is not maintained during the anaerobic reduction. Proton uptake on reduction of Cu A , heme a, heme a 3 , and Cu B shows ≈2.5 protons bound per 4 electrons, in agreement with prior experiments. One proton is bound by a hydroxyl group in the BNC and the rest to groups far from the BNC. The electrochemical midpoint potential (E m ) of heme a is calculated in the fully oxidized protein and with 1 or 2 electrons in the BNC. The E m of heme a shifts down when the BNC is reduced, which agrees with prior experiments. If the BNC reduction is electroneutral, then the heme a E m is independent of the BNC redox state.Heme-copper oxidases are the terminal electron acceptors in anaerobic organisms. These transmembrane proteins reduce dioxygen and convert the released chemical energy into an electrochemical gradient, across the eukaryotic mitochondrial membrane or the bacterial cell membrane (1-4). Cytochrome c oxidases are the most prevalent hemecopper oxidases. In this protein 4 electrons, provided by 4 cytochromes c, are used to reduce dioxygen to water. The 4 protons needed to make water are taken from the negative cytoplasmic side of the membrane, adding to the electrochemical gradient. Four additional protons are pumped across the membrane (5). Thus, each dioxygen molecule reduced by cytochrome c oxidase is coupled to the transfer of 8 charges across the membrane.The first step of electron transfer is from cytochrome c to Cu A , a dicopper center in subunit II which extends beyond the membrane on the proton release side of the protein (Figure 1). After receiving the electron, Cu A reduces the 6-coordinate, low-spin, bis-Hi...

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Section: Resultsmentioning

confidence: 99%

Calculated Proton Uptake on Anaerobic Reduction of CytochromecOxidase: Is the Reaction Electroneutral?

2006

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“…Under slow electron flux, the 95% selectivity for 4e O 2 reduction (i.e., 5% production of H 2 O 2 ) is comparable with the FeCuPhOH catalyst previously reported and is much greater than an Fe-only catalyst, which shows as much as 20 Ϯ 2% PROS, i.e., 20% H 2 O 2 production. The primary mechanism by which PROS are produced during electrocatalytic O 2 reduction is proposed to be the hydrolysis of the initial Fe-O 2 adduct formed (step B, Scheme 1) (60). This leads to the generation of O 2 Ϫ , which would be detected either by itself or as H 2 O 2 resulting from its disproportionation.…”

Section: Discussionmentioning

confidence: 99%

O ₂ reduction by a functional heme/nonheme bis-iron NOR model complex

Collman

Dey

Yang

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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O2 reactivity of a functional NOR model is investigated by using electrochemistry and spectroscopy. The electrochemical measurements using interdigitated electrodes show very high selectivity for 4e O2 reduction with minimal production of partially reduced oxygen species (PROS) under both fast and slow electron flux. Intermediates trapped at cryogenic temperatures and characterized by using resonance Raman spectroscopy under single-turnover conditions indicate that an initial bridging peroxide intermediate undergoes homolytic OOO bond cleavage generating a trans heme/nonheme bis-ferryl intermediate. This bis ferryl species can oxygenate 2 equivalents of a reactive substrate.C ytochrome c oxidase (CcO) and nitric oxide reductase (NOR) belong to the heme copper oxidase superfamily of enzymes (1, 2). CcO is the terminal enzyme in the respiratory chain of higher organisms, located in their mitochondrial membrane, that reduces O 2 to H 2 O as source of energy. The O 2 reduction process in CcO generates a pH gradient across the bilayer membrane, which provides the driving force for ATP synthesis. The bimetallic active site of CcO has a heme ligated to the protein by a proximal histidine ligand and a distal Cu B site coordinated by 3 histidine ligands ( Fig. 1) (3). In addition to the bimetallic site, there is a conserved tyrosine ligand covalently attached to one of the histidines coordinated to Cu B (4, 5). The NORs are the older member of the family and are found in bacteria using NO 3 Ϫ as source of energy instead of O 2 (2, 6, 7). Although there are no high-resolution crystal structures of NOR, biochemical studies and computer modeling indicate that these enzymes have a histidine-ligated heme, quite like the CcOs, and a distal Fe B , unlike Cu B in CcO, coordinated by 3 histidines ( Fig. 1) (8-10). NORs do not have the conserved tyrosine residue of CcO but have a few conserved key glutamate residues (11,12). Although the NOR enzymes are proposed to have specific proton channels, they are probably not involved in generating proton gradients (13-16).These 2 enzymes exhibit complementary reactivity toward 2 very significant diatomic molecules in nature; O 2 and NO. In eukaryotes CcO (aa 3 type) reduces O 2 to H 2 O and is reversibly but strongly inhibited by [17][18][19][20]. Several other CcOs (ba 3 , caa 3 , cbb 3 ) are reported to exhibit limited (Ͻ1%) NOR activity, i.e., reduce NO to N 2 O (7, 21). On the other hand, NORs that reduce NO to N 2 O are reversibly but strongly inhibited by O 2 , and some of them show modest (Ϸ10%) O 2 reduction activity (12). The parallels in their reactivities toward O 2 and NO and similarities in their secondary structures have led to a hypotheses regarding NOR's and CcO's similar evolutionary origins (6,22).Electrochemistry is a very powerful technique that can provide fundamental insights into reaction mechanisms of redox catalysts (23-27). Conventionally, a catalyst is deposited on a conducting electrode material (e.g., graphite); however, this approach does not allow site isola...

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“…29 Additionally, enhanced reactivity of some porphyrin electrocatalysts is observed when the second coordination site is empty or replaced with an appropriate Lewis acidic metal ion. 17,[30][31][32] …”

Section: Oxygen Reduction By Cobalt Pacman Complexesmentioning

confidence: 99%

“…39 Finally, the mechanistic cycle clarifies some perplexing observations that porphyrin templates bearing a distal metal-binding cap exhibit comparable selectivities for the four-proton, fourelectron pathway with or without a second redox-active metal ion bound in the distal cap. 17,30,31 The mechanism shown in Figure 7 suggests that the second functional site, whether that be another porphyrin, a metal complex, or a metal-free coordination sphere, is to adjust the pK a of the protonated dioxygen adduct. Since a cooperative redox activity is not required from two cofacial porphyrins, the second site may be redox-inactive or completely absent.…”

Section: A Pcet Mechanism For O 2 Reduction By Pacman Constructsmentioning

confidence: 99%

Role of Proton‐Coupled Electron Transfer in O—O Bond Activation

Rosenthal

Nocera

2007

ChemInform

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The selective reduction of oxygen to water requires four electrons and four protons. The design of catalysts that promote oxygen reduction therefore requires the management of both electron and proton inventories. Pacman and Hangman porphyrins provide a cleft for oxygen binding, a redox shuttle for oxygen reduction, and functionality for tuning the acid-base properties of bound oxygen and its intermediates. With proper control of the proton-coupled electron transfer events, O-O bond breaking of oxygen, and more generally oxygenated substrates, may be achieved with high efficiencies. The rule set developed for oxygen reduction may be applied to a variety of other small molecule activation reactions of consequence to energy conversion.

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Functional Analogues of the Dioxygen Reduction Site in Cytochrome Oxidase: Mechanistic Aspects and Possible Effects of Cu_B

Cited by 149 publications

References 50 publications

Calculated Proton Uptake on Anaerobic Reduction of CytochromecOxidase: Is the Reaction Electroneutral?

Calculated Proton Uptake on Anaerobic Reduction of CytochromecOxidase: Is the Reaction Electroneutral?

O ₂ reduction by a functional heme/nonheme bis-iron NOR model complex

Role of Proton‐Coupled Electron Transfer in O—O Bond Activation

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Functional Analogues of the Dioxygen Reduction Site in Cytochrome Oxidase: Mechanistic Aspects and Possible Effects of CuB

Cited by 149 publications

References 50 publications

Calculated Proton Uptake on Anaerobic Reduction of CytochromecOxidase: Is the Reaction Electroneutral?

Calculated Proton Uptake on Anaerobic Reduction of CytochromecOxidase: Is the Reaction Electroneutral?

O 2 reduction by a functional heme/nonheme bis-iron NOR model complex

Role of Proton‐Coupled Electron Transfer in O—O Bond Activation

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Product

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Functional Analogues of the Dioxygen Reduction Site in Cytochrome Oxidase: Mechanistic Aspects and Possible Effects of Cu_B

O ₂ reduction by a functional heme/nonheme bis-iron NOR model complex