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Geometric and Electronic Structure/Function Correlations in Non-Heme Iron Enzymes Edward I

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Geometric and Electronic Structure/Function Correlations in Non-Heme Iron Enzymes Edward I Chem. Rev. 2000, 100, 235−349 235 Geometric and Electronic Structure/Function Correlations in Non-Heme Iron Enzymes Edward I. Solomon,* Thomas C. Brunold, Mindy I. Davis, Jyllian N. Kemsley, Sang-Kyu Lee, Nicolai Lehnert, Frank Neese, Andrew J. Skulan, Yi-Shan Yang, and Jing Zhou Department of Chemistry, Stanford University, Stanford, California 94305-5080 Received September 29, 1999 Contents tures of the active sites of non-heme iron enzymes and the contributions of these sites to molecular I. Introduction 235 mechanisms. Tables 1 and 2 present fairly complete II. Mononuclear Non-Heme Iron 237 lists of the presently known key classes of mono- A. Spectroscopic Methodology 237 nuclear and binuclear non-heme iron enzymes. As 1. FeII 237 indicated in the tables, these enzymes participate in 2. FeIII 243 a range of reactions as extensive as those found in 3. Quantum Chemical Calculations of 251 heme chemistry but are generally much less well Molecular Properties understood. For most of the enzymes one of the B. Substrate Activation 251 reactants is dioxygen. The uncatalyzed reactions of 1. Lipoxygenases 251 O2 with organic substrates are thermodynamically 2. Intradiol Dioxygenases 257 favorable but kinetically slow since they are spin 3. Comparison of Strategies 263 forbidden and the one-electron reduction potential of O is low. In the mononuclear non-heme iron en- C. O2 Activation 264 2 1. Extradiol Dioxygenases 264 zymes, these reactions are catalyzed either by a high- 2. Pterin-Dependent Hydroxylases 269 spin ferrous site which is involved in dioxygen activation or by a high-spin ferric site which activates 3. R-Ketoglutarate-Dependent and Related 273 Enzymes substrates. For some of the ferrous enzymes, an additional organic cofactor, R-ketoglutarate or pterin, 4. Rieske-Type Dioxygenases 278 participates in a coupled reaction with dioxygen 5. Bleomycin 281 where both the substrate and cosubstrate are oxy- 6. General Strategy 285 genated. Thus far, the only well-characterized oxygen D. O2 Intermediates and Analogues 286 intermediate is that for bleomycin, activated bleo- 1. Model Systems 286 mycin, which is kinetically competent to cleave DNA 2. Intermediates 290 in a hydrogen-atom abstraction reaction. In the III. Binuclear Non-Heme Iron 294 binuclear non-heme iron enzymes, a diferrous site is A. Spectroscopic Methodology 294 involved in reversible O2 binding to hemerythrin and III 1. [Fe ]2 294 O2 activation in ribonucleotide reductase, methane II 9 2. [Fe ]2 300 monooxygenase, and ∆ desaturase. These show B. Reversible O2 Binding to Hemerythrin 306 interesting structural differences which could con- tribute to differences in reactivity (vide infra). Hem- C. O2 Activation 311 1. Methane Monooxygenase 311 erythrin has five histidine ligands, while methane monooxygenase, ribonucleotide reductase, and ∆9 2. Ribonucleotide Reductase 318 desaturase are rich in donor oxygen ligands. It had 3. 9 Desaturase 324 ∆ been thought that the strong donor ligation in the 4. General Strategy 328 latter enzymes activates the sites for dioxygen reac- D. O2 Intermediates 329 tivity; however, a series of membrane desaturases 1. Peroxo Intermediates 329 and monooxygenases has recently been determined 2. High-Valent Intermediates 331 to have binuclear iron sites which appear to be rich 3. Conversion of Peroxo Intermediates into 333 in histidine ligation. Dioxygen binding to hemeryth- High-Valent Fe−Oxo−Fe Species rin involves transfer of two electrons and a proton IV. Concluding Comments 336 to O2 binding at a single iron center, and oxygen V. Abbreviations 336 intermediates P, Q, and X (vide infra) have been VI. Acknowledgments 337 observed in ribonucleotide reductase, ∆9 desaturase, VII. References 337 and methane monooxygenase. An oxygen intermedi- ate has also been observed at the binuclear ferrooxi- dase site in ferritin, which appears to have structural I. Introduction and functional similarities to the binuclear iron site In recent years, significant progress has been made in rubrerythrin. Mononuclear non-heme iron sites are in understanding the geometric and electronic struc- also involved in superoxide dismutation (SOD, FeII 10.1021/cr9900275 CCC: $35.00 © 2000 American Chemical Society Published on Web 12/18/1999 236 Chemical Reviews, 2000, Vol. 100, No. 1 Solomon et al. Sang-Kyu Lee (B.S. in Chemistry from Lehigh University, Ph.D. from the University of Minnesota) was a graduate student with Professor John D. Lipscomb working on MMO. Sang-Kyu has since joined Professor Solomon as a postdoctoral fellow studying multicopper enzymes with MMO as a continuing hobby. Nicolai Lehnert (Diploma in Chemistry from Heinrich-Heine-Universita¨t Du¨sseldorf, Germany; Ph.D. from Johannes-Gutenberg-Universita¨t Mainz, Germany) did undergraduate research with Professor Hans-Herbert Schmidtke on the spectroscopy of osmium(IV) complexes and graduate research with Professors Felix Tuczek and Philipp Gu¨tlich performing spectroscopic and theoretical studies on nitrogenase model complexes. Since 1999, he has been a postdoctoral fellow in Professor Solomon’s group where he is working on non-heme iron enzymes and their oxygen intermediates. From left to right: Jing Zhou, Mindy I. E. Davis, Yi-Shan Yang, Edward I. Solomon, Jyllian N. Kemsley, Nicolai Lehnert, Andrew Skulan, and Sang- Frank Neese (Ph.D. in Biology from Konstanz University, Germany) did Kyu Lee. Side photographs: (top) Thomas C. Brunold and (bottom) Frank his graduate research with Professor Peter Kroneck on copper proteins. Neese. Background: “Gates of Hell”, Rodin Sculpture Garden, Stanford. He then joined the group of Professor Solomon as a postdoctoral fellow to experimentally and theoretically study non-heme iron centers and their oxygen intermediates. In 1999 he returned to Konstanz to work on his Edward I. Solomon grew up in North Miami Beach, FL, received his Ph.D. Habilitation which focuses on the electron structure, spectroscopy, and from Princeton University (with D. S. McClure), and was a postdoctoral mechanism of bacterial metalloproteins in the nitrogen cycle. Frank is fellow at the H. C. Ørsted Institute (with C. J. Ballhausen) and then at also developing a large-scale molecular orbital program and other Caltech (with H. B. Gray). He was a professor at MIT until 1982. He then approaches for the study of transition-metal spectroscopy. moved to Stanford University where he is now the Monroe E. Spaght Professor of Humanities and Sciences. His research is in the fields of physical-inorganic and bioinorganic chemistry with emphasis on the Andrew J. Skulan (B.A. in Chemistry and Physics from Kalamazoo College) application of a wide variety of spectroscopic methods to elucidate the studied magnetism in binuclear complexes with Professors Thomas J. electronic structures of transition-metal complexes and their contributions Smith and Thomas R. Askew as an undergraduate student. He is now a to physical properties and reactivity. Ph.D. student and NSF Predoctoral Fellow investigating oxygen activation and formation in binuclear iron and manganese enzymes and model systems. Thomas C. Brunold (Diploma in Chemistry, University of Bern, Switzerland; Ph.D. in Chemistry, University of Bern, Switzerland) did graduate research with Professor Hans U. Gu¨del. From 1997 to 1999, he was a postdoctoral Yi-Shan Yang (B.S. in Chemistry from National Sun, Yat-sen University, fellow in Professor Solomon’s lab studying oxygen intermediates and Kaohsiung, Taiwan, R.O.C.) did physical inorganic research for one year models of binuclear non-heme iron enzymes, and manganese catalase. at the Institute of Chemistry, Academia Sinica, in Taipei, Taiwan, R.O.C., Since August 1999, he has been an Assistant Professor at the University and is presently a Ph.D. student studying oxygen-activating binuclear non- of WisconsinsMadison where he employs a wide range of spectroscopic heme iron enzymes and purple acid phosphatases. methods to study structure and function of bioorganometallic species, metal complex interactions with nucleic acids, and second-sphere effects on Jing Zhou (B.S. in Chemistry from Fudan University, Shanghai, China; metalloprotein active sites. M.A. in Biochemistry from Temple University) did undergraduate research with Professor Anren Jiang on polytungstates. He is presently a Ph.D. R Mindy I. E. Davis (B.S. in Chemistry/Minor in Biology from MIT) did student studying non-heme iron enzymes including -ketoglutarate- undergraduate research with Professor Stephen J. Lippard on biomimetic dependent enzymes, ethylene-forming enzyme, and lipoxygenases. models for binuclear metalloproteins. She worked at Unilever and at Kodak as a Kodak Scholar. Her Ph.D. research at Stanford University combines in some cases (the intradiol dioxygenases and purple bioinorganic spectroscopy with theory to study the intra- and extradiol acid phosphatases), phenolate ligation and do not dioxygenases. exhibit the intense ligand π f π* absorption features of heme sites. The reduced (FeII) sites do not exhibit Jyllian N. Kemsley (B.A. in Chemistry from Amherst College) worked with charge transfer (CT) transitions and are generally not Professor David Dooley on amine oxidase and Professor Joan Broderick detectable by electron paramagnetic resonance (EPR), on lipoxygenase at Amherst and did process analytical research for two and while the oxidized sites (FeIII) do exhibit EPR years at Merck Research Laboratories. She is now a Ph.D. student at signals reflecting spin Hamiltonian parameters and Stanford University, working on pterin-dependent
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