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A Functional Nitric Oxide Reductase Model

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A Functional Nitric Oxide Reductase Model A functional nitric oxide reductase model James P. Collman*, Ying Yang, Abhishek Dey, Richard A. Decre´ au, Somdatta Ghosh, Takehiro Ohta, and Edward I. Solomon Department of Chemistry, Stanford University, Stanford, CA 94305 Contributed by James P. Collman, September 2, 2008 (sent for review August 7, 2008) A functional heme/nonheme nitric oxide reductase (NOR) model is presented. The fully reduced diiron compound reacts with two equivalents of NO leading to the formation of one equivalent of N2O and the bis-ferric product. NO binds to both heme Fe and nonheme Fe complexes forming individual ferrous nitrosyl species. The mixed-valence species with an oxidized heme and a reduced nonheme FeB does not show NO reduction activity. These results are consistent with a so-called ‘‘trans’’ mechanism for the reduc- tion of NO by bacterial NOR. functional model ͉ NO reduction ͉ N2O ͉ “trans” mechanism Fig. 1. Schematic representation of the bimetallic active sites of NOR and itric oxide reductase (NOR) is a membrane-bound enzyme CcO. Nthat catalyzes the 2eϪ reduction of nitric oxide (NO) to nitrous oxide (N2O), an obligatory step involved in the sequen- Ϫ tial reduction of nitrate to dinitrogen known as bacterial deni- FTIR reveals a heme ferric nitrosyl band at 1,924 cm 1 that shifts trification. The active site of NOR consists of a monohistidine to 1,887 cmϪ1 when 15NO is used, whereas the EPR spectrum ligated five-coordinate heme and a trisimidazole ligated non- manifests a low-spin ferric signal that is assigned to the nonheme heme FeB. This structure strongly resembles the active site of FeB because a ferric heme nitrosyl would be EPR silent. The NO oxygen reduction enzyme-cytochrome c oxidase (CcO), which adducts of both heme Fe and FeB were obtained separately from II II II possesses a heme-a3/CuB center (Fig. 1) (1, 2). Essentially, the the reaction of NO with LFe and LZn /Fe . These NO adducts distal metal CuB in CcO is replaced by a nonheme Fe metal in were characterized with a series of spectroscopic methods in- NOR; NOR and CcO are thought to be distant relatives. cluding UV-vis, EPR, resonance Raman, FTIR, and mass spec- The dinuclear iron active site in NOR was confirmed a decade troscopy. The reaction of NO with the mixed-valence compound ago by spectroscopic studies (3). Presumably, two NO molecules LFeIII/FeII was also investigated. Our data show the formation of II III III II are turned over to give one molecule of N2O and one molecule a mixture of LFe -NO/Fe and LFe -NO/Fe -NO species, but of H2O at the diiron center with the consumption of two no N2O was detected. These results are consistent with a electrons and two protons. Although many enzyme studies of so-called ‘‘trans’’ mechanism for the reduction of NO to N2Oby NOR have been focused on the intermediate trapping and NOR. elucidation of the reaction mechanism (4–15), the details of the catalytic cycle are still unresolved because of the lack of Results structural information and uncertainty regarding short-lived Syntheses and Characterization of Dinuclear Complexes. The re- intermediates. duced diiron complex LFeII/FeII is readily synthesized by reaction In contrast to enzyme studies, synthetic biomimetic model II of LFe complex (25) with 1 equivalent of Fe(OTf)2(MeCN)2 in complexes provide a straightforward and controlled method to THF at room temperature under a N2 atmosphere. The UV-vis understand how this chemical transformation proceeds at the spectrum shows a fast and clean formation of a dinuclear product enzyme active site. However, only a few synthetic models have with shifts for both the Soret (426–424 nm) and Q bands been developed that mimic the active site of NOR; moreover, (535–530 nm) and a slightly diminished intensity in both bands these compounds either lack a proximal imidazole ligand (16, 17) (Fig. 3, solid to dotted line). The dinuclear compound LZnII/FeII or use pyridine as a replacement for the histidine ligands was synthesized by using a similar method from reaction of LZnII (18–20). No functional NOR models have been reported to date. with Fe(OTf)2(MeCN)2 [UV-vis spectra are in supporting in- Our CcO model complexes have proved to be functionally active formation (SI) Fig. S1]. The mixed-valence compound LFeIII/ for oxygen reduction reaction with minimal reactive oxygen FeII was obtained by oxidation of LFeII/FeII with one equivalent species (ROS) formation (21–24). These appear to be promising of ferrocenium tetrafluoroborate. The bis-ferric LFeIII/FeIII was NOR model candidates if the distal Cu metal is replaced by an generated by oxidation of LFeII/FeII with either two equivalents iron because the resulting diiron compound has almost all of the of ferrocenium tetrafluoroborate or with dioxygen. The struc- key components in NOR: a heme Fe with a proximal imidazole tures of these dinuclear compounds were confirmed by electro- ligand and a trisimidazole ligated nonheme Fe center. spray mass spectroscopy. In this report, we disclose the first synthetic functional NOR model LFeII/FeII (Fig. 2), which reacts with two equivalents of NO to give one equivalent of N2O and the bis-ferric product. We Author contributions: J.P.C. and Y.Y. designed research; Y.Y., A.D., R.A.D., S.G., and T.O. have shown that NO binds to both heme Fe and FeB to form a performed research; Y.Y. contributed new reagents/analytic tools; Y.Y., A.D., R.A.D., S.G., possible bis-nitrosyl intermediate; subsequently, the two bound T.O., and E.I.S. analyzed data; and Y.Y. and A.D. wrote the paper. NO molecules are reduced to N2O by electrons from both Fe The authors declare no conflict of interest. centers, leaving both heme Fe and FeB in an uncoupled ferric *To whom correspondence should be addressed. E-mail: [email protected]. state. N2O has been quantitatively identified by using an enzyme, This article contains supporting information online at www.pnas.org/cgi/content/full/ nitrous oxide reductase (N2OR) that reduces N2OtoN2. The 0808606105/DCSupplemental. bis-ferric product was characterized by both FTIR and EPR: © 2008 by The National Academy of Sciences of the USA 15660–15665 ͉ PNAS ͉ October 14, 2008 ͉ vol. 105 ͉ no. 41 www.pnas.org͞cgi͞doi͞10.1073͞pnas.0808606105 Downloaded by guest on September 29, 2021 .(Fig. 4. UV-vis spectra of LFeII (solid line) and LFeII؉NO (dotted line II Fig. 2. Representation of the model complexes of ligand L: LFe (no MB); II II 2ϩ II II 2ϩ 2ϩ III II 3ϩ LFe /Fe (M ϭ MB ϭ Fe ); LZn /Fe (M ϭ Zn ,MB ϭ Fe ); LFe /Fe (M ϭ Fe , ϭ 2ϩ III III ϭ 3ϩ ϭ 3ϩ MB Fe ); LFe /Fe (M Fe ,MB Fe ) (metals have triflate counterions). reveals a well characterized S ϭ 3/2 nonheme Fe-NO signal at g ϭ 4.0 (Fig. 8, dashed line). Note that the small perturbation of the Zn-porphyrin Soret implies that the NO probably binds in the Reaction of NO with LFeII, LZnII/FeII and LFeII/FeII. LFeII ؉ NO. Addition II pocket but does not bridge the two metals. Binding of NO to FeB of purified NO to a THF solution of LFe leads to formation of leads to LZnII/FeII-NO species. Both the LFeII-NO and LZnII/ its mono-nitrosyl derivative LFe-NO. This reaction is associated FeII-NO species are stable in the solid state for a prolonged with a decreased intensity of the Soret band at 427 nm and a Q period when exposed in air. These mononitrosyl complexes were band shift from 535 to 550 nm (Fig. 4). The EPR spectrum shows also characterized by high-resolution electrospray mass spec- ϭ aS 1/2 signal (Fig. 8, solid line) typical of a six-coordinate troscopy (Figs. S2–S5). ferrous NO complex akin to those reported for the active site in LFeII/FeII؉NO. Addition of NO to the THF solution of LFeII/FeII CcO (26–30). The FTIR spectrum shows a new band at 1,630 at room temperature leads to rapid changes in the UV-vis Ϫ1 Ϫ1 cm for the LFe-NO complex that shifts to 1,600 cm with spectrum. The Soret band shifts from 424 to 423 nm, and the Q 15NO (Fig. 5, dotted and dashed lines). The resonance Raman band shifts from 530 to 550 nm (Fig. 3, dotted to dashed line). spectrum obtained by excitation with a 425-nm laser shows an FTIR spectra obtained from solid samples of the end product Ϫ Ϫ Fe-N stretch at 581 cm 1 that shifts to 545 cm 1 with 15NO exhibit a new band at 1,924 cmϪ1 that is absent in LFeII/FeII (Fig. Ϫ CHEMISTRY substitution. An Fe-NImidazole stretch is also observed at 238 9, dotted and solid lines). This band is shifted to 1,887 cm 1 when Ϫ cm 1, providing further evidence for the presence of a six- 15NO is used for the sample preparation (Fig. 9, dashed line). coordinate iron nitrosyl (Fig. 6). The 37-cmϪ115N-isotope shift is consistent with literature data LZnII/FeII؉NO. Addition of NO to LZnII/FeII in THF results in for heme ferric nitrosyls (18, 31, 32). The resonance Raman data slight blue shifts (0.5 nm for the Soret band and 1 nm for the Q on this complex show a Fe-NO stretch at 610 cmϪ1 (Fig. 10, solid band) in the UV-vis spectra (Fig. S1). The FTIR of the 14NO line) that shifts to 598 cmϪ1 upon 15NO substitution (Fig.
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