An S=1 Iron(IV) Intermediate Revealed in a Non-Heme Iron Enzyme-Catalyzed Oxidative C—S Bond Formation

Paris, Jared C.; Hu, Sha; Wen, Aiwen; Weitz, Andrew C.; Cheng, Ronghai; Gee, Leland B.; Tang, Yijie; Kim, Hyomin; Vegas, Arturo; Chang, Wei‐chen; Elliott, Sean J.; Liu, Pinghua; Guo, Yisong

doi:10.1002/anie.202309362

Title: An S=1 Iron(IV) Intermediate Revealed in a Non-Heme Iron Enzyme-Catalyzed Oxidative C—S Bond Formation

Journal Article · 27 August 2023 · Angewandte Chemie (International Edition)

DOI: https://doi.org/10.1002/anie.202309362 · OSTI ID:2308799

^[1]; Hu, Sha ^[2]; Wen, Aiwen ^[2];

^[2]; Cheng, Ronghai ^[2];

^[3];

^[4]; Kim, Hyomin ^[2]; Vegas, Arturo ^[2];

^[5];

^[2];

^[4]

Carnegie Mellon Univ., Pittsburgh, PA (United States); slac
Boston Univ., MA (United States)
SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States)
Carnegie Mellon Univ., Pittsburgh, PA (United States)
North Carolina State University, Raleigh, NC (United States)

Ergothioneine (ESH) and ovothiol A (OSHA) are two natural thiol-histidine derivatives. ESH has been implicated as a longevity vitamin and OSHA inhibits the proliferation of hepatocarcinoma. The key biosynthetic step of ESH and OSHA in the aerobic pathways is the O₂-dependent C—S bond formation catalyzed by non-heme iron enzymes (e.g., OvoA in ovothiol biosynthesis), but due to the lack of identification of key reactive intermediate the mechanism of this novel reaction is unresolved. In this study, we report the identification and characterization of a kinetically competent S=1 iron(IV) intermediate supported by a four-histidine ligand environment (three from the protein residues and one from the substrate) in enabling C—S bond formation in OvoA from Methyloversatilis thermotoleran, which represents the first experimentally observed intermediate spin iron(IV) species in non-heme iron enzymes. Results reported in this study thus set the stage to further dissect the mechanism of enzymatic oxidative C—S bond formation in the OSHA biosynthesis pathway. They also afford new opportunities to study the structure-function relationship of high-valent iron intermediates supported by a histidine rich ligand environment.

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Research Organization:: SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States)

Sponsoring Organization:: National Science Foundation (NSF); USDOE Office of Science (SC), Basic Energy Sciences (BES)

Grant/Contract Number:: AC02-76SF00515

OSTI ID:: 2308799

Journal Information:: Angewandte Chemie (International Edition), Journal Name: Angewandte Chemie (International Edition) Journal Issue: 43 Vol. 62; ISSN 1433-7851

Publisher:: WileyCopyright Statement

Country of Publication:: United States

Language:: English

References (50)

Structure of the Sulfoxide Synthase EgtB from the Ergothioneine Biosynthetic Pathway Goncharenko, Kristina V.; Vit, Allegra; Blankenfeldt, Wulf Angewandte Chemie International Edition, Vol. 54, Issue 9 https://doi.org/10.1002/anie.201410045	journal	January 2015
Anaerobic Origin of Ergothioneine Burn, Reto; Misson, Laëtitia; Meury, Marcel Angewandte Chemie International Edition, Vol. 56, Issue 41 https://doi.org/10.1002/anie.201705932	journal	September 2017
Coordination Switch Drives Selective C−S Bond Formation by the Non‐Heme Sulfoxide Synthases** Wu, Peng; Gu, Yang; Liao, Langxing Angewandte Chemie International Edition, Vol. 61, Issue 50 https://doi.org/10.1002/anie.202214235	journal	November 2022
Dioxygen activation by nonheme iron enzymes with the 2-His-1-carboxylate facial triad that generate high-valent oxoiron oxidants Kal, Subhasree; Que, Lawrence JBIC Journal of Biological Inorganic Chemistry, Vol. 22, Issue 2-3 https://doi.org/10.1007/s00775-016-1431-2	journal	January 2017
Ergothioneine; antioxidant potential, physiological function and role in disease Cheah, Irwin K.; Halliwell, Barry Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, Vol. 1822, Issue 5 https://doi.org/10.1016/j.bbadis.2011.09.017	journal	May 2012
Peroxo and oxo intermediates in mononuclear nonheme iron enzymes and related active sites Solomon, Edward I.; Wong, Shaun D.; Liu, Lei V. Current Opinion in Chemical Biology, Vol. 13, Issue 1 https://doi.org/10.1016/j.cbpa.2009.02.011	journal	February 2009
Structure and function of atypically coordinated enzymatic mononuclear non-heme-Fe(II) centers Buongiorno, Daniela; Straganz, Grit D. Coordination Chemistry Reviews, Vol. 257, Issue 2 https://doi.org/10.1016/j.ccr.2012.04.028	journal	January 2013
High-valent nonheme iron-oxo complexes: Synthesis, structure, and spectroscopy McDonald, Aidan R.; Que, Lawrence Coordination Chemistry Reviews, Vol. 257, Issue 2 https://doi.org/10.1016/j.ccr.2012.08.002	journal	January 2013
Stalking intermediates in oxygen activation by iron enzymes: Motivation and method Bollinger, J. Martin; Krebs, Carsten Journal of Inorganic Biochemistry, Vol. 100, Issue 4 https://doi.org/10.1016/j.jinorgbio.2006.01.022	journal	April 2006
Amazing Diversity in Biochemical Roles of Fe(II)/2-Oxoglutarate Oxygenases Herr, Caitlyn Q.; Hausinger, Robert P. Trends in Biochemical Sciences, Vol. 43, Issue 7 https://doi.org/10.1016/j.tibs.2018.04.002	journal	July 2018
The chemical defensome: Environmental sensing and response genes in the Strongylocentrotus purpuratus genome Goldstone, J. V.; Hamdoun, A.; Cole, B. J. Developmental Biology, Vol. 300, Issue 1 https://doi.org/10.1016/j.ydbio.2006.08.066	journal	December 2006
Toward the Synthesis of More Reactive S = 2 Non-Heme Oxoiron(IV) Complexes Puri, Mayank; Que, Lawrence Accounts of Chemical Research, Vol. 48, Issue 8 https://doi.org/10.1021/acs.accounts.5b00244	journal	July 2015
Mini-Review: Ergothioneine and Ovothiol Biosyntheses, an Unprecedented Trans-Sulfur Strategy in Natural Product Biosynthesis Naowarojna, Nathchar; Cheng, Ronghai; Chen, Li Biochemistry, Vol. 57, Issue 24 https://doi.org/10.1021/acs.biochem.8b00239	journal	March 2018
Electronic State of the His/Tyr-Ligated Heme of BthA by Mössbauer and DFT Analysis Weitz, Andrew C.; Biswas, Saborni; Rizzolo, Kim Inorganic Chemistry, Vol. 59, Issue 14 https://doi.org/10.1021/acs.inorgchem.0c01349	journal	June 2020
Theoretical Study of the Mechanism of the Nonheme Iron Enzyme EgtB Wei, Wen-Jie; Siegbahn, Per E. M.; Liao, Rong-Zhen Inorganic Chemistry, Vol. 56, Issue 6 https://doi.org/10.1021/acs.inorgchem.6b03177	journal	March 2017
In Vitro Reconstitution of the Remaining Steps in Ovothiol A Biosynthesis: C–S Lyase and Methyltransferase Reactions Naowarojna, Nathchar; Huang, Pei; Cai, Yujuan Organic Letters, Vol. 20, Issue 17 https://doi.org/10.1021/acs.orglett.8b02332	journal	August 2018
Single-Step Replacement of an Unreactive C–H Bond by a C–S Bond Using Polysulfide as the Direct Sulfur Source in the Anaerobic Ergothioneine Biosynthesis Cheng, Ronghai; Wu, Lian; Lai, Rui ACS Catalysis, Vol. 10, Issue 16 https://doi.org/10.1021/acscatal.0c01809	journal	July 2020
Mechanism of Sulfoxidation and C–S Bond Formation Involved in the Biosynthesis of Ergothioneine Catalyzed by Ergothioneine Synthase (EgtB) Tian, Ge; Su, Hao; Liu, Yongjun ACS Catalysis, Vol. 8, Issue 7 https://doi.org/10.1021/acscatal.8b01473	journal	May 2018
Mechanistic Studies of a Nonheme Iron Enzyme OvoA in Ovothiol Biosynthesis Using a Tyrosine Analogue, 2-Amino-3-(4-hydroxy-3-(methoxyl) phenyl) Propanoic Acid (MeOTyr) Chen, Li; Naowarojna, Nathchar; Chen, Bin ACS Catalysis, Vol. 9, Issue 1 https://doi.org/10.1021/acscatal.8b03903	journal	December 2018
A Theory for Bioinorganic Chemical Reactivity of Oxometal Complexes and Analogous Oxidants: The Exchange and Orbital-Selection Rules Usharani, Dandamudi; Janardanan, Deepa; Li, Chunsen Accounts of Chemical Research, Vol. 46, Issue 2 https://doi.org/10.1021/ar300204y	journal	December 2012
Non-Heme Fe(IV)–Oxo Intermediates Krebs, Carsten; Galonić Fujimori, Danica; Walsh, Christopher T. Accounts of Chemical Research, Vol. 40, Issue 7 https://doi.org/10.1021/ar700066p	journal	July 2007
Moessbauer and electron paramagnetic resonance studies of horseradish peroxidase and its catalytic intermediates Schulz, C. E.; Rutter, R.; Sage, J. T. Biochemistry, Vol. 23, Issue 20 https://doi.org/10.1021/bi00315a033	journal	September 1984
The First Direct Characterization of a High-Valent Iron Intermediate in the Reaction of an α-Ketoglutarate-Dependent Dioxygenase: A High-Spin Fe(IV) Complex in Taurine/α-Ketoglutarate Dioxygenase (TauD) from Escherichia coli ^† Price, John C.; Barr, Eric W.; Tirupati, Bhramara Biochemistry, Vol. 42, Issue 24 https://doi.org/10.1021/bi030011f	journal	June 2003
O ₂ -Evolving Chlorite Dismutase as a Tool for Studying O ₂ -Utilizing Enzymes Dassama, Laura M. K.; Yosca, Timothy H.; Conner, Denise A. Biochemistry, Vol. 51, Issue 8 https://doi.org/10.1021/bi201906x	journal	February 2012
Model Iron–Oxo Species and the Oxidation of Imidazole: Insights into the Mechanism of OvoA and EgtB? Bushnell, Eric A. C.; Fortowsky, Grant B.; Gauld, James W. Inorganic Chemistry, Vol. 51, Issue 24 https://doi.org/10.1021/ic3021172	journal	December 2012
Evidence for Two Ferryl Species in Chloroperoxidase Compound II Stone, Kari L.; Hoffart, Lee M.; Behan, Rachel K. Journal of the American Chemical Society, Vol. 128, Issue 18 https://doi.org/10.1021/ja057876w	journal	May 2006
Spectroscopic and Computational Evaluation of the Structure of the High-Spin Fe(IV)-Oxo Intermediates in Taurine: α-Ketoglutarate Dioxygenase from Escherichia coli and Its His99Ala Ligand Variant Sinnecker, Sebastian; Svensen, Nina; Barr, Eric W. Journal of the American Chemical Society, Vol. 129, Issue 19 https://doi.org/10.1021/ja067899q	journal	May 2007
Identification and Characterization of the First Ovothiol Biosynthetic Enzyme Braunshausen, Andrea; Seebeck, Florian P. Journal of the American Chemical Society, Vol. 133, Issue 6 https://doi.org/10.1021/ja109378e	journal	February 2011
Spectroscopic Evidence for the Two C–H-Cleaving Intermediates of Aspergillus nidulans Isopenicillin N Synthase Tamanaha, Esta; Zhang, Bo; Guo, Yisong Journal of the American Chemical Society, Vol. 138, Issue 28 https://doi.org/10.1021/jacs.6b04065	journal	July 2016
Sulfoxide Synthase versus Cysteine Dioxygenase Reactivity in a Nonheme Iron Enzyme Faponle, Abayomi S.; Seebeck, Florian P.; de Visser, Sam P. Journal of the American Chemical Society, Vol. 139, Issue 27 https://doi.org/10.1021/jacs.7b04251	journal	June 2017
Use of a Tyrosine Analogue To Modulate the Two Activities of a Nonheme Iron Enzyme OvoA in Ovothiol Biosynthesis, Cysteine Oxidation versus Oxidative C–S Bond Formation Chen, Li; Naowarojna, Nathchar; Song, Heng Journal of the American Chemical Society, Vol. 140, Issue 13 https://doi.org/10.1021/jacs.7b13628	journal	March 2018
An Alternative Active Site Architecture for O₂ Activation in the Ergothioneine Biosynthetic EgtB from Chloracidobacterium thermophilum Stampfli, Anja R.; Goncharenko, Kristina V.; Meury, Marcel Journal of the American Chemical Society, Vol. 141, Issue 13 https://doi.org/10.1021/jacs.8b13023	journal	March 2019
Discovery and Characterization of the Metallopterin-Dependent Ergothioneine Synthase from Caldithrix abyssi Beliaeva, Mariia A.; Seebeck, Florian P. JACS Au, Vol. 2, Issue 9 https://doi.org/10.1021/jacsau.2c00365	journal	August 2022
A widely distributed diheme enzyme from Burkholderia that displays an atypically stable bis-Fe(IV) state Rizzolo, Kimberly; Cohen, Steven E.; Weitz, Andrew C. Nature Communications, Vol. 10, Issue 1 https://doi.org/10.1038/s41467-019-09020-4	journal	March 2019
An iron–oxygen intermediate formed during the catalytic cycle of cysteine dioxygenase Tchesnokov, E. P.; Faponle, A. S.; Davies, C. G. Chemical Communications, Vol. 52, Issue 57 https://doi.org/10.1039/C6CC03904A	journal	January 2016
Recent examples of α-ketoglutarate-dependent mononuclear non-haem iron enzymes in natural product biosyntheses Gao, Shu-Shan; Naowarojna, Nathchar; Cheng, Ronghai Natural Product Reports, Vol. 35, Issue 8 https://doi.org/10.1039/C7NP00067G	journal	January 2018
OvoA_MthtfromMethyloversatilis thermotoleransovothiol biosynthesis is a bifunction enzyme: thiol oxygenase and sulfoxide synthase activities Cheng, Ronghai; Weitz, Andrew C.; Paris, Jared Chemical Science, Vol. 13, Issue 12 https://doi.org/10.1039/D1SC05479A	journal	January 2022
Prediction of high-valent iron K-edge absorption spectra by time-dependent Density Functional Theory Chandrasekaran, P.; Stieber, S. Chantal E.; Collins, Terrence J. Dalton Transactions, Vol. 40, Issue 42 https://doi.org/10.1039/c1dt11331c	journal	January 2011
Mössbauer spectroscopic determination of the electronic structure of highly oxidized iron in hemoproteins Harami, T.; Maeda, Y.; Morita, Y. The Journal of Chemical Physics, Vol. 67, Issue 3 https://doi.org/10.1063/1.434969	journal	August 1977
Discovery of the ergothioneine transporter Gründemann, Dirk; Harlfinger, Stephanie; Golz, Stefan Proceedings of the National Academy of Sciences, Vol. 102, Issue 14 https://doi.org/10.1073/pnas.0408624102	journal	March 2005
X-ray absorption spectroscopic characterization of a cytochrome P450 compound II derivative Newcomb, M.; Halgrimson, J. A.; Horner, J. H. Proceedings of the National Academy of Sciences, Vol. 105, Issue 24 https://doi.org/10.1073/pnas.0708299105	journal	January 2008
A catalytic di-heme bis-Fe(IV) intermediate, alternative to an Fe(IV)=O porphyrin radical Li, X.; Fu, R.; Lee, S. Proceedings of the National Academy of Sciences, Vol. 105, Issue 25 https://doi.org/10.1073/pnas.0801643105	journal	June 2008
Trapping and spectroscopic characterization of an FeIII-superoxo intermediate from a nonheme mononuclear iron-containing enzyme Mbughuni, M. M.; Chakrabarti, M.; Hayden, J. A. Proceedings of the National Academy of Sciences, Vol. 107, Issue 39 https://doi.org/10.1073/pnas.1010015107	journal	September 2010
Prolonging healthy aging: Longevity vitamins and proteins Ames, Bruce N. Proceedings of the National Academy of Sciences, Vol. 115, Issue 43 https://doi.org/10.1073/pnas.1809045115	journal	October 2018
Identification of a major low‐molecular‐mass thiol of the trypanosomatid Crithidia fasciculata as ovothiol A Steenkamp, Daniel J.; Spies, Hendrik S. C. European Journal of Biochemistry, Vol. 223, Issue 1 https://doi.org/10.1111/j.1432-1033.1994.tb18964.x	journal	July 1994
Thiols of Intracellular Pathogens. Identification of Ovothiol A in Leishmania Donovani and Structural Analysis of a Novel Thiol from Mycobacterium Bovis Spies, Hendrik S. C.; Steenkamp, Daniel J. European Journal of Biochemistry, Vol. 224, Issue 1 https://doi.org/10.1111/j.1432-1033.1994.tb20013.x	journal	August 1994
A Thiolate-Ligated Nonheme Oxoiron(IV) Complex Relevant to Cytochrome P450 Bukowski, M. R. Science, Vol. 310, Issue 5750 https://doi.org/10.1126/science.1119092	journal	November 2005
Crystallographic and Spectroscopic Characterization of a Nonheme Fe(IV)&cjs0811;O Complex Rohde, J. -U. Science, Vol. 299, Issue 5609 https://doi.org/10.1126/science.299.5609.1037	journal	February 2003
Could Ergothioneine Aid in the Treatment of Coronavirus Patients? Cheah, Irwin K.; Halliwell, Barry Antioxidants, Vol. 9, Issue 7 https://doi.org/10.3390/antiox9070595	journal	July 2020
Ovothiol Isolated from Sea Urchin Oocytes Induces Autophagy in the Hep-G2 Cell Line Russo, Gian; Russo, Maria; Castellano, Immacolata Marine Drugs, Vol. 12, Issue 7 https://doi.org/10.3390/md12074069	journal	July 2014

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Title: An S=1 Iron(IV) Intermediate Revealed in a Non-Heme Iron Enzyme-Catalyzed Oxidative C—S Bond Formation

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