Munzarin F. Qayyum
Stanford University
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Chemical Reviews | 2014
Edward I. Solomon; David E. Heppner; Esther M. Johnston; Jake W. Ginsbach; Jordi Cirera; Munzarin F. Qayyum; Matthew T. Kieber-Emmons; Christian H. Kjaergaard; Ryan G. Hadt; Li Tian
Based on its generally accessible I/II redox couple and bioavailability, copper plays a wide variety of roles in nature that mostly involve electron transfer (ET), O2 binding, activation and reduction, NO2− and N2O reduction and substrate activation. Copper sites that perform ET are the mononuclear blue Cu site that has a highly covalent CuII-S(Cys) bond and the binuclear CuA site that has a Cu2S(Cys)2 core with a Cu-Cu bond that keeps the site delocalized (Cu(1.5)2) in its oxidized state. In contrast to inorganic Cu complexes, these metalloprotein sites transfer electrons rapidly often over long distances, as has been previously reviewed.1–4 Blue Cu and CuA sites will only be considered here in their relation to intramolecular ET in multi-center enzymes. The focus of this review is on the Cu enzymes (Figure 1). Many are involved in O2 activation and reduction, which has mostly been thought to involve at least two electrons to overcome spin forbiddenness and the low potential of the one electron reduction to superoxide (Figure 2).5,6 Since the Cu(III) redox state has not been observed in biology, this requires either more than one Cu center or one copper and an additional redox active organic cofactor. The latter is formed in a biogenesis reaction of a residue (Tyr) that is also Cu catalyzed in the first turnover of the protein. Recently, however, there have been a number of enzymes suggested to utilize one Cu to activate O2 by 1e− reduction to form a Cu(II)-O2•− intermediate (an innersphere redox process) and it is important to understand the active site requirements to drive this reaction. The oxidases that catalyze the 4e−reduction of O2 to H2O are unique in that they effectively perform this reaction in one step indicating that the free energy barrier for the second two-electron reduction of the peroxide product of the first two-electron step is very low. In nature this requires either a trinuclear Cu cluster (in the multicopper oxidases) or a Cu/Tyr/Heme Fe cluster (in the cytochrome oxidases). The former accomplishes this with almost no overpotential maximizing its ability to oxidize substrates and its utility in biofuel cells, while the latter class of enzymes uses the excess energy to pump protons for ATP synthesis. In bacterial denitrification, a mononuclear Cu center catalyzes the 1e- reduction of nitrite to NO while a unique µ4S2−Cu4 cluster catalyzes the reduction of N2O to N2 and H2O, a 2e− process yet requiring 4Cu’s. Finally there are now several classes of enzymes that utilize an oxidized Cu(II) center to activate a covalently bound substrate to react with O2. Figure 1 Copper active sites in biology. Figure 2 Latimer Diagram for Oxygen Reduction at pH = 7.0 Adapted from References 5 and 6. This review presents in depth discussions of all these classes of Cu enzymes and the correlations within and among these classes. For each class we review our present understanding of the enzymology, kinetics, geometric structures, electronic structures and the reaction mechanisms these have elucidated. While the emphasis here is on the enzymology, model studies have significantly contributed to our understanding of O2 activation by a number of Cu enzymes and are included in appropriate subsections of this review. In general we will consider how the covalency of a Cu(II)–substrate bond can activate the substrate for its spin forbidden reaction with O2, how in binuclear Cu enzymes the exchange coupling between Cu’s overcomes the spin forbiddenness of O2 binding and controls electron transfer to O2 to direct catalysis either to perform two e− electrophilic aromatic substitution or 1e− H-atom abstraction, the type of oxygen intermediate that is required for H-atom abstraction from the strong C-H bond of methane (104 kcal/mol) and how the trinuclear Cu cluster and the Cu/Tyr/Heme Fe cluster achieve their very low barriers for the reductive cleavage of the O-O bond. Much of the insight available into these mechanisms in Cu biochemistry has come from the application of a wide range of spectroscopies and the correlation of spectroscopic results to electronic structure calculations. Thus we start with a tutorial on the different spectroscopic methods utilized to study mononuclear and multinuclear Cu enzymes and their correlations to different levels of electronic structure calculations.
Journal of the American Chemical Society | 2011
Zhiwei Liu; Munzarin F. Qayyum; Chao Wu; Matthew T. Whited; Peter I. Djurovich; Keith O. Hodgson; Britt Hedman; Edward I. Solomon; Mark E. Thompson
We demonstrate a new approach for utilizing CuI coordination complexes as emissive layers in organic light-emitting diodes that involves in situ codeposition of CuI and 3,5-bis(carbazol-9-yl)pyridine (mCPy). With a simple three-layer device structure, pure green electroluminescence at 530 nm from a Cu(I) complex was observed. A maximum luminance and external quantum efficiency (EQE) of 9700 cd/m(2) and 4.4%, respectively, were achieved. The luminescent species was identified as [CuI(mCPy)(2)](2) on the basis of photophysical studies of model complexes and X-ray absorption spectroscopy.
Proceedings of the National Academy of Sciences of the United States of America | 2014
Christian H. Kjaergaard; Munzarin F. Qayyum; Shaun D. Wong; Feng Xu; Glyn R. Hemsworth; Daniel J. Walton; Nigel A. Young; Gideon J. Davies; Paul H. Walton; Katja Salomon Johansen; Keith O. Hodgson; Britt Hedman; Edward I. Solomon
Significance Activation of the O-O bond in dioxygen is difficult but fundamental in biology. Nature has evolved several strategies to achieve this, often including copper as an enzyme cofactor. Copper-dependent enzymes usually use more than one metal to activate O2 by multielectron reduction, but recently it was discovered that cellulose and chitin degrading polysaccharide monooxygenase enzymes use only a single Cu center for catalysis, in a reaction that is of great interest to the biofuel industries. To understand this reactivity, we have determined the solution structures of both the reduced and oxidized Cu site, and determined experimentally and computationally how this site is capable of facile O2 activation by a thermodynamically difficult one-electron reduction, via an inner-sphere Cu-superoxide intermediate. Strategies for O2 activation by copper enzymes were recently expanded to include mononuclear Cu sites, with the discovery of the copper-dependent polysaccharide monooxygenases, also classified as auxiliary-activity enzymes 9–11 (AA9-11). These enzymes are finding considerable use in industrial biofuel production. Crystal structures of polysaccharide monooxygenases have emerged, but experimental studies are yet to determine the solution structure of the Cu site and how this relates to reactivity. From X-ray absorption near edge structure and extended X-ray absorption fine structure spectroscopies, we observed a change from four-coordinate Cu(II) to three-coordinate Cu(I) of the active site in solution, where three protein-derived nitrogen ligands coordinate the Cu in both redox states, and a labile hydroxide ligand is lost upon reduction. The spectroscopic data allowed for density functional theory calculations of an enzyme active site model, where the optimized Cu(I) and (II) structures were consistent with the experimental data. The O2 reactivity of the Cu(I) site was probed by EPR and stopped-flow absorption spectroscopies, and a rapid one-electron reduction of O2 and regeneration of the resting Cu(II) enzyme were observed. This reactivity was evaluated computationally, and by calibration to Cu-superoxide model complexes, formation of an end-on Cu-AA9-superoxide species was found to be thermodynamically favored. We discuss how this thermodynamically difficult one-electron reduction of O2 is enabled by the unique protein structure where two nitrogen ligands from His1 dictate formation of a T-shaped Cu(I) site, which provides an open coordination position for strong O2 binding with very little reorganization energy.
Inorganic Chemistry | 2010
Zakaria Halime; Matthew T. Kieber-Emmons; Munzarin F. Qayyum; Biplab Mondal; Thirumanavelan Gandhi; Simona C. Puiu; Eduardo E. Chufán; Amy A. Narducci Sarjeant; Keith O. Hodgson; Britt Hedman; Edward I. Solomon; Kenneth D. Karlin
The nature of the ligand is an important aspect of controlling the structure and reactivity in coordination chemistry. In connection with our study of heme-copper-oxygen reactivity relevant to cytochrome c oxidase dioxygen-reduction chemistry, we compare the molecular and electronic structures of two high-spin heme-peroxo-copper [Fe(III)O(2)(2-)Cu(II)](+) complexes containing N(4) tetradentate (1) or N(3) tridentate (2) copper ligands. Combining previously reported and new resonance Raman and EXAFS data coupled to density functional theory calculations, we report a geometric structure and more complete electronic description of the high-spin heme-peroxo-copper complexes 1 and 2, which establish mu-(O(2)(2-)) side-on to the Fe(III) and end-on to Cu(II) (mu-eta(2):eta(1)) binding for the complex 1 but side-on/side-on (mu-eta(2):eta(2)) mu-peroxo coordination for the complex 2. We also compare and summarize the differences and similarities of these two complexes in their reactivity toward CO, PPh(3), acid, and phenols. The comparison of a new X-ray structure of mu-oxo complex 2a with the previously reported 1a X-ray structure, two thermal decomposition products respectively of 2 and 1, reveals a considerable difference in the Fe-O-Cu angle between the two mu-oxo complexes ( angleFe-O-Cu = 178.2 degrees in 1a and angleFe-O-Cu = 149.5 degrees in 2a). The reaction of 2 with 1 equiv of an exogenous nitrogen-donor axial base leads to the formation of a distinctive low-temperature-stable, low-spin heme-dioxygen-copper complex (2b), but under the same conditions, the addition of an axial base to 1 leads to the dissociation of the heme-peroxo-copper assembly and the release of O(2). 2b reacts with phenols performing H-atom (e(-) + H(+)) abstraction resulting in O-O bond cleavage and the formation of high-valent ferryl [Fe(IV)=O] complex (2c). The nature of 2c was confirmed by a comparison of its spectroscopic features and reactivity with those of an independently prepared ferryl complex. The phenoxyl radical generated by the H-atom abstraction was either (1) directly detected by electron paramagnetic resonance spectroscopy using phenols that produce stable radicals or (2) indirectly detected by the coupling product of two phenoxyl radicals.
Journal of the American Chemical Society | 2010
Anthony J. Augustine; Christian H. Kjaergaard; Munzarin F. Qayyum; Lynn Ziegler; Daniel J. Kosman; Keith O. Hodgson; Britt Hedman; Edward I. Solomon
The multicopper oxidase Fet3p catalyzes the four-electron reduction of dioxygen to water, coupled to the one-electron oxidation of four equivalents of substrate. To carry out this process, the enzyme utilizes four Cu atoms: a type 1, a type 2, and a coupled binuclear, type 3 site. Substrates are oxidized at the T1 Cu, which rapidly transfers electrons, 13 A away, to a trinuclear copper cluster composed of the T2 and T3 sites, where dioxygen is reduced to water in two sequential 2e(-) steps. This study focuses on two variants of Fet3p, H126Q and H483Q, that perturb the two T3 Cus, T3alpha and T3beta, respectively. The variants have been isolated in both holo and type 1 depleted (T1D) forms, T1DT3alphaQ and T1DT3betaQ, and their trinuclear copper clusters have been characterized in their oxidized and reduced states. While the variants are only mildly perturbed relative to T1D in the resting oxidized state, in contrast to T1D they are both found to have lost a ligand in their reduced states. Importantly, T1DT3alphaQ reacts with O(2), but T1DT3betaQ does not. Thus loss of a ligand at T3beta, but not at T3alpha, turns off O(2) reactivity, indicating that T3beta and T2 are required for the 2e(-) reduction of O(2) to form the peroxide intermediate (PI), whereas T3alpha remains reduced. This is supported by the spectroscopic features of PI in T1DT3alphaQ, which are identical to T1D PI. This selective redox activity of one edge of the trinuclear cluster demonstrates its asymmetry in O(2) reactivity. The structural origin of this asymmetry between the T3alpha and T3beta is discussed, as is its contribution to reactivity.
Angewandte Chemie | 2012
Matthew T. Kieber-Emmons; Munzarin F. Qayyum; Yuqi Li; Zakaria Halime; Keith O. Hodgson; Britt Hedman; Kenneth D. Karlin; Edward I. Solomon
Cytochrome c oxidase (CcO) catalyzes the four electron reduction of dioxygen to form water in the terminal step of the electron transport chain.[1] Dioxygen binds to a unique heme-copper bimetallic active site, wherein the copper is ligated ~5 A above the heme by three His residues.[2–3] One of these ligating His residues is covalently crosslinked to a nearby Tyr residue. The crosslinked Tyr is thought to participate in catalysis by providing the fourth electron needed to cleave the O-O bond in a net H• abstraction.[4] This hypothesis stems from the observation of an intermediate state (PM) in CcO that occurs after O-O bond cleavage, which is suggested to contain a tyrosyl radical based on chemical and spectral evidence.[5–8] The only observable enzymatic dioxygen intermediate before O-O bond rupture has been assigned as a ferric-superoxo species (A),[9–10] leading some to suggest this species is directly responsible for the net H• abstraction from the Tyr.[11–12] We and others favor an alternative mechanistic scenario, in which an unobserved peroxo intermediate functions as the active oxidant.[13–15] A putative peroxo moiety would take advantage of the His-Tyr crosslink and the copper ion as a pathway to access the fourth electron necessary for cleavage of its O-O bond. However, heme-peroxo-copper adducts are generally unreactive towards phenols, motivating efforts towards understanding factors required for O-O bond rupture by heme-copper sites. Recently, we reported preliminary evidence that the reaction of a heme-peroxo-copper adduct {[F8Fe]-O2-[CuAN]}+ (1, F8 = 5,10,15,20-tetrakis-(2,6-difluorophenyl)-porphyrinate, AN = bis(3-(dimethylamino)-propyl)-amine) with a coordinating base DCHIm (DCHIm = 1,5-dicyclohexylimidazole) results in formation of a discrete complex (2) that has enhanced reactivity towards phenols.[16] Herein we report the molecular and electronic structure of 2, which is an example of a heme-peroxo-copper complex in which the electronic state of the heme fragment is low-spin (LS).[17] Concomitant with the change in spin of the heme fragment from high-spin (HS) to LS upon conversion from 1 to 2, the Fe-O2-Cu core undergoes a change from µ-η2:η2 (“side-on”) in 1 to µ-1,2 (“end-on”) in 2 (Scheme 1). This novel bridging mode has not been observed previously in heme-copper model complexes, but it has been proposed in recent crystallographic studies on resting CcO.[18–20] However, comparison of the spectral features of resting CcO to those described herein for 2 reveal inconsistencies suggesting a reevaluation of the bridging mode of the peroxo group in resting CcO and providing insight into the electronic structure requirements for O-O bond cleavage.
Journal of the American Chemical Society | 2012
Ga Young Park; Munzarin F. Qayyum; Julia S. Woertink; Keith O. Hodgson; Britt Hedman; Amy A. Narducci Sarjeant; Edward I. Solomon; Kenneth D. Karlin
Certain side-on peroxo-dicopper(II) species with particularly low ν(O-O) (710-730 cm(-1)) have been found in equilibrium with their bis-μ-oxo-dicopper(III) isomer. An issue is whether such side-on peroxo bridges are further activated for O-O cleavage. In a previous study (Liang, H.-C., et al. J. Am. Chem. Soc.2002, 124, 4170), we showed that oxygenation of the three-coordinate complex [Cu(I)(MeAN)](+) (MeAN = N-methyl-N,N-bis[3-(dimethylamino)propyl]amine) leads to a low-temperature stable [{Cu(II)(MeAN)}(2)(μ-η(2):η(2)-O(2)(2-))](2+) peroxo species with low ν(O-O) (721 cm(-1)), as characterized by UV-vis absorption and resonance Raman (rR) spectroscopies. Here, this complex has been crystallized as its SbF(6)(-) salt, and an X-ray structure indicates the presence of an unusually long O-O bond (1.540(5) Å) consistent with the low ν(O-O). Extended X-ray absorption fine structure and rR spectroscopic and reactivity studies indicate the exclusive formation of [{Cu(II)(MeAN)}(2)(μ-η(2):η(2)-O(2)(2-))](2+) without any bis-μ-oxo-dicopper(III) isomer present. This is the first structure of a side-on peroxo-dicopper(II) species with a significantly long and weak O-O bond. DFT calculations show that the weak O-O bond results from strong σ donation from the MeAN ligand to Cu that is compensated by a decrease in the extent of peroxo to Cu charge transfer. Importantly, the weak O-O bond does not reflect an increase in backbonding into the σ* orbital of the peroxide. Thus, although the O-O bond is unusually weak, this structure is not further activated for reductive cleavage to form a reactive bis-μ-oxo dicopper(III) species. These results highlight the necessity of understanding electronic structure changes associated with spectral changes for correlations to reactivity.
Biochemistry | 2013
Christian H. Kjaergaard; Munzarin F. Qayyum; Anthony J. Augustine; Lynn Ziegler; Daniel J. Kosman; Keith O. Hodgson; Britt Hedman; Edward I. Solomon
Multicopper oxidases (MCOs) carry out the most energy efficient reduction of O2 to H2O known, i.e., with the lowest overpotential. This four-electron process requires an electron mediating type 1 (T1) Cu site and an oxygen reducing trinuclear Cu cluster (TNC), consisting of a binuclear type 3 (T3)- and a mononuclear type 2 (T2) Cu center. The rate-determining step in O2 reduction is the first two-electron transfer from one of the T3 Cus (T3β) and the T2 Cu, forming a bridged peroxide intermediate (PI). This reaction has been investigated in T3β Cu variants of the Fet3p, where a first shell His ligand is mutated to Glu or Gln. This converts the fast two-electron reaction of the wild-type (WT) enzyme to a slow one-electron oxidation of the TNC. Both variants initially react to form a common T3β Cu(II) intermediate that converts to the Glu or Gln bound resting state. From spectroscopic evaluation, the nonmutated His ligands coordinate linearly to the T3β Cu in the reduced TNCs in the two variants, in contrast to the trigonal arrangement observed in the WT enzyme. This structural perturbation is found to significantly alter the electronic structure of the reduced TNC, which is no longer capable of rapidly transferring two electrons to the two perpendicular half occupied π*-orbitals of O2, in contrast to the WT enzyme. This study provides new insight into the geometric and electronic structure requirements of a fully functional TNC for the rate determining two-electron reduction of O2 in the MCOs.
Inorganic Chemistry | 2016
Trinidad Arcos-López; Munzarin F. Qayyum; Lina Rivillas-Acevedo; Marco C. Miotto; Rafael Grande-Aztatzi; Claudio O. Fernández; Britt Hedman; Keith O. Hodgson; Alberto Vela; Edward I. Solomon; Liliana Quintanar
The ability of the cellular prion protein (PrPC) to bind copper in vivo points to a physiological role for PrPC in copper transport. Six copper binding sites have been identified in the nonstructured N-terminal region of human PrPC. Among these sites, the His111 site is unique in that it contains a MKHM motif that would confer interesting CuI and CuII binding properties. We have evaluated CuI coordination to the PrP(106–115) fragment of the human PrP protein, using NMR and X-ray absorption spectroscopies and electronic structure calculations. We find that Met109 and Met112 play an important role in anchoring this metal ion. CuI coordination to His111 is pH-dependent: at pH >8, 2N1O1S species are formed with one Met ligand; in the range of pH 5–8, both methionine (Met) residues bind to CuI, forming a 1N1O2S species, where N is from His111 and O is from a backbone carbonyl or a water molecule; at pH <5, only the two Met residues remain coordinated. Thus, even upon drastic changes in the chemical environment, such as those occurring during endocytosis of PrPC (decreased pH and a reducing potential), the two Met residues in the MKHM motif enable PrPC to maintain the bound CuI ions, consistent with a copper transport function for this protein. We also find that the physiologically relevant CuI-1N1O2S species activates dioxygen via an inner-sphere mechanism, likely involving the formation of a copper(II) superoxide complex. In this process, the Met residues are partially oxidized to sulfoxide; this ability to scavenge superoxide may play a role in the proposed antioxidant properties of PrPC. This study provides further insight into the CuI coordination properties of His111 in human PrPC and the molecular mechanism of oxygen activation by this site.
Journal of Chemical Physics | 2018
Patrick Frank; M. Benfatto; Munzarin F. Qayyum
High resolution (k = 18 Å-1 or k = 17 Å-1) copper K-edge EXAFS and MXAN (Minuit X-ray Absorption Near Edge) analyses have been used to investigate the structure of dissolved [Cu(aq)]2+ in 1,3-propanediol (1,3-P) or 1,5-pentanediol (1,5-P) aqueous frozen glasses. EXAFS analysis invariably found a single axially asymmetric 6-coordinate (CN6) site, with 4×Oeq = 1.97 Å, Oax1 = 2.22 Å, and Oax2 = 2.34 Å, plus a second-shell of 4×Owater = 3.6 Å. However, MXAN analysis revealed that [Cu(aq)]2+ occupies both square pyramidal (CN5) and axially asymmetric CN6 structures. The square pyramid included 4×H2O = 1.95 Å and 1×H2O = 2.23 Å. The CN6 sites included either a capped, near perfect, square pyramid with 5×H2O = 1.94 ± 0.04 Å and H2Oax = 2.22 Å (in 1,3-P) or a split axial configuration with 4×H2O = 1.94, H2Oax1 = 2.14 Å, and H2Oax2 = 2.28 Å (in 1,5-P). The CN6 sites also included an 8-H2O second-shell near 3.7 Å, which was undetectable about the strictly pyramidal sites. Equatorial angles averaging 94° ± 5° indicated significant departures from tetragonal planarity. MXAN assessment of the solution structure of [Cu(aq)]2+ in 1,5-P prior to freezing revealed the same structures as previously found in aqueous 1M HClO4, which have become axially compressed in the frozen glasses. [Cu(aq)]2+ in liquid and frozen solutions is dominated by a 5-coordinate square pyramid, but with split axial CN6 appearing in the frozen glasses. Among these phases, the Cu-O axial distances vary across 1 Å, and the equatorial angles depart significantly from the square plane. Although all these structures remove the dx2-y2 , dz2 degeneracy, no structure can be described as a Jahn-Teller (JT) axially elongated octahedron. The JT-octahedral description for dissolved [Cu(aq)]2+ should thus be abandoned in favor of square pyramidal [Cu(H2O)5]2+. The revised ligand environments have bearing on questions of the Cu(i)/Cu(ii) self-exchange rate and on the mechanism for ligand exchange with bulk water. The plasticity of dissolved Cu(ii) complex ions falsifies the foundational assumption of the rack-induced bonding theory of blue copper proteins and obviates any need for a thermodynamically implausible protein constraint.