Broken-Symmetry Density Functional Theory Analysis of the Ω Intermediate in Radical S-Adenosyl-l-methionine Enzymes: Evidence for a Near-Attack Conformer over an Organometallic Species
Abstract
Radical S-adenosyl-L-methionine (SAM) enzymes are found in all domains of life and catalyze a wide range of biochemical reactions. Recently, an organometallic intermediate, Ω, has been experimentally implicated in the 5'-deoxyadenosyl radical generation mechanism of the radical SAM superfamily. In this work, we employ broken-symmetry density functional theory to evaluate several structural models of Ω. The results show that the calculated hyperfine coupling constants (HFCCs) for the proposed organometallic structure of Ω are inconsistent with the experiment. In contrast, a near-attack conformer of SAM bound to the catalytic [4Fe–4S] cluster, in which the distance between the unique iron and SAM sulfur is ~3 Å, yields HFCCs that are all within 1 MHz of the experimental values. Furthermore, these results clarify the structure of the ubiquitous Ω intermediate and suggest a paradigm shift reversal regarding the mechanism of SAM cleavage by members of the radical SAM superfamily.
- Publication Date:
- Research Org.:
- Auburn Univ., AL (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC), Basic Energy Sciences (BES); National Science Foundation (NSF)
- OSTI Identifier:
- 1993829
- Alternate Identifier(s):
- OSTI ID: 1873905
- Grant/Contract Number:
- SC0018043
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Journal of the American Chemical Society
- Additional Journal Information:
- Journal Volume: 144; Journal Issue: 8; Journal ID: ISSN 0002-7863
- Publisher:
- American Chemical Society (ACS)
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; Chemical structure; Cluster chemistry; Cluster structure; Molecular structure; Peptides and proteins
Citation Formats
Donnan, Patrick H., and Mansoorabadi, Steven O. Broken-Symmetry Density Functional Theory Analysis of the Ω Intermediate in Radical S-Adenosyl-l-methionine Enzymes: Evidence for a Near-Attack Conformer over an Organometallic Species. United States: N. p., 2022.
Web. doi:10.1021/jacs.2c00678.
Donnan, Patrick H., & Mansoorabadi, Steven O. Broken-Symmetry Density Functional Theory Analysis of the Ω Intermediate in Radical S-Adenosyl-l-methionine Enzymes: Evidence for a Near-Attack Conformer over an Organometallic Species. United States. https://doi.org/10.1021/jacs.2c00678
Donnan, Patrick H., and Mansoorabadi, Steven O. Wed .
"Broken-Symmetry Density Functional Theory Analysis of the Ω Intermediate in Radical S-Adenosyl-l-methionine Enzymes: Evidence for a Near-Attack Conformer over an Organometallic Species". United States. https://doi.org/10.1021/jacs.2c00678. https://www.osti.gov/servlets/purl/1993829.
@article{osti_1993829,
title = {Broken-Symmetry Density Functional Theory Analysis of the Ω Intermediate in Radical S-Adenosyl-l-methionine Enzymes: Evidence for a Near-Attack Conformer over an Organometallic Species},
author = {Donnan, Patrick H. and Mansoorabadi, Steven O.},
abstractNote = {Radical S-adenosyl-L-methionine (SAM) enzymes are found in all domains of life and catalyze a wide range of biochemical reactions. Recently, an organometallic intermediate, Ω, has been experimentally implicated in the 5'-deoxyadenosyl radical generation mechanism of the radical SAM superfamily. In this work, we employ broken-symmetry density functional theory to evaluate several structural models of Ω. The results show that the calculated hyperfine coupling constants (HFCCs) for the proposed organometallic structure of Ω are inconsistent with the experiment. In contrast, a near-attack conformer of SAM bound to the catalytic [4Fe–4S] cluster, in which the distance between the unique iron and SAM sulfur is ~3 Å, yields HFCCs that are all within 1 MHz of the experimental values. Furthermore, these results clarify the structure of the ubiquitous Ω intermediate and suggest a paradigm shift reversal regarding the mechanism of SAM cleavage by members of the radical SAM superfamily.},
doi = {10.1021/jacs.2c00678},
journal = {Journal of the American Chemical Society},
number = 8,
volume = 144,
place = {United States},
year = {Wed Feb 16 00:00:00 EST 2022},
month = {Wed Feb 16 00:00:00 EST 2022}
}
Free Publicly Available Full Text
Publisher's Version of Record
Other availability
Search WorldCat to find libraries that may hold this journal
Save to My Library
You must Sign In or Create an Account in order to save documents to your library.
Works referenced in this record:
Radical SAM, a novel protein superfamily linking unresolved steps in familiar biosynthetic pathways with radical mechanisms: functional characterization using new analysis and information visualization methods
journal, March 2001
- Sofia, H. J.
- Nucleic Acids Research, Vol. 29, Issue 5
The Radical SAM Superfamily
journal, January 2008
- Frey, Perry A.; Hegeman, Adrian D.; Ruzicka, Frank J.
- Critical Reviews in Biochemistry and Molecular Biology, Vol. 43, Issue 1
Radical S -Adenosylmethionine Enzymes
journal, January 2014
- Broderick, Joan B.; Duffus, Benjamin R.; Duschene, Kaitlin S.
- Chemical Reviews, Vol. 114, Issue 8
Radical S -Adenosylmethionine Enzymes in Human Health and Disease
journal, June 2016
- Landgraf, Bradley J.; McCarthy, Erin L.; Booker, Squire J.
- Annual Review of Biochemistry, Vol. 85, Issue 1
A Rich Man, Poor Man Story of S -Adenosylmethionine and Cobalamin Revisited
journal, June 2018
- Bridwell-Rabb, Jennifer; Grell, Tsehai A. J.; Drennan, Catherine L.
- Annual Review of Biochemistry, Vol. 87, Issue 1
Structure–function relationships of radical SAM enzymes
journal, April 2020
- Nicolet, Yvain
- Nature Catalysis, Vol. 3, Issue 4
Radical SAM catalysis via an organometallic intermediate with an Fe-[5'-C]-deoxyadenosyl bond
journal, May 2016
- Horitani, M.; Shisler, K.; Broderick, W. E.
- Science, Vol. 352, Issue 6287
Paradigm Shift for Radical S -Adenosyl- l -methionine Reactions: The Organometallic Intermediate Ω Is Central to Catalysis
journal, June 2018
- Byer, Amanda S.; Yang, Hao; McDaniel, Elizabeth C.
- Journal of the American Chemical Society, Vol. 140, Issue 28
Mechanism of Radical Initiation in the Radical S -Adenosyl- l -methionine Superfamily
journal, October 2018
- Broderick, William E.; Hoffman, Brian M.; Broderick, Joan B.
- Accounts of Chemical Research, Vol. 51, Issue 11
Organometallic and radical intermediates reveal mechanism of diphthamide biosynthesis
journal, March 2018
- Dong, Min; Kathiresan, Venkatesan; Fenwick, Michael K.
- Science, Vol. 359, Issue 6381
The Elusive 5′-Deoxyadenosyl Radical: Captured and Characterized by Electron Paramagnetic Resonance and Electron Nuclear Double Resonance Spectroscopies
journal, July 2019
- Yang, Hao; McDaniel, Elizabeth C.; Impano, Stella
- Journal of the American Chemical Society, Vol. 141, Issue 30
New Insight into the Mechanism of Anaerobic Heme Degradation
journal, October 2019
- Mathew, Liju G.; Beattie, Nathaniel R.; Pritchett, Clayton
- Biochemistry, Vol. 58, Issue 46
Trapping a cross-linked lysine–tryptophan radical in the catalytic cycle of the radical SAM enzyme SuiB
journal, May 2021
- Balo, Aidin R.; Caruso, Alessio; Tao, Lizhi
- Proceedings of the National Academy of Sciences, Vol. 118, Issue 21
Characterization and Mechanistic Study of the Radical SAM Enzyme ArsS Involved in Arsenosugar Biosynthesis
journal, February 2021
- Cheng, Jinduo; Ji, Wenjuan; Ma, Suze
- Angewandte Chemie International Edition, Vol. 60, Issue 14
S ‐Adenosyl‐ l ‐ethionine is a Catalytically Competent Analog of S ‐Adenosyl‐ l ‐methionine (SAM) in the Radical SAM Enzyme HydG
journal, January 2021
- Impano, Stella; Yang, Hao; Shepard, Eric M.
- Angewandte Chemie International Edition, Vol. 60, Issue 9
Radical SAM Enzyme Spore Photoproduct Lyase: Properties of the Ω Organometallic Intermediate and Identification of Stable Protein Radicals Formed during Substrate-Free Turnover
journal, September 2020
- Pagnier, Adrien; Yang, Hao; Jodts, Richard J.
- Journal of the American Chemical Society, Vol. 142, Issue 43
Analysis of Electrochemical Properties of S -Adenosyl- l -methionine and Implications for Its Role in Radical SAM Enzymes
journal, June 2019
- Miller, Sven A.; Bandarian, Vahe
- Journal of the American Chemical Society, Vol. 141, Issue 28
Photoinduced Electron Transfer in a Radical SAM Enzyme Generates an S -Adenosylmethionine Derived Methyl Radical
journal, September 2019
- Yang, Hao; Impano, Stella; Shepard, Eric M.
- Journal of the American Chemical Society, Vol. 141, Issue 40
Trapping and Electron Paramagnetic Resonance Characterization of the 5′dAdo • Radical in a Radical S -Adenosyl Methionine Enzyme Reaction with a Non-Native Substrate
journal, September 2019
- Sayler, Richard I.; Stich, Troy A.; Joshi, Sumedh
- ACS Central Science, Vol. 5, Issue 11
Active-Site Controlled, Jahn–Teller Enabled Regioselectivity in Reductive S–C Bond Cleavage of S -Adenosylmethionine in Radical SAM Enzymes
journal, December 2020
- Impano, Stella; Yang, Hao; Jodts, Richard J.
- Journal of the American Chemical Society, Vol. 143, Issue 1
A Synthetic Model of Enzymatic [Fe 4 S 4 ]–Alkyl Intermediates
journal, August 2019
- Ye, Mengshan; Thompson, Niklas B.; Brown, Alexandra C.
- Journal of the American Chemical Society, Vol. 141, Issue 34
Reversible Formation of Alkyl Radicals at [Fe 4 S 4 ] Clusters and Its Implications for Selectivity in Radical SAM Enzymes
journal, July 2020
- Brown, Alexandra C.; Suess, Daniel L. M.
- Journal of the American Chemical Society, Vol. 142, Issue 33
Mechanistic Dichotomy in the Activation of SAM by Radical SAM Enzymes: QM/MM Modeling Deciphers the Determinant
journal, November 2020
- Zhao, Chengxin; Li, Yao; Wang, Chao
- ACS Catalysis, Vol. 10, Issue 22
A model for the spin states of high-potential iron-sulfur [Fe4S4]3+ proteins
journal, October 1988
- Noodleman, Louis
- Inorganic Chemistry, Vol. 27, Issue 20
Exchange coupling and resonance delocalization in reduced iron-sulfur [Fe4S4]+ and iron-selenium [Fe4Se4]+ clusters. 2. A generalized nonlinear model for spin-state energies and EPR and hyperfine properties
journal, January 1991
- Noodleman, Louis
- Inorganic Chemistry, Vol. 30, Issue 2
Density Functional and Reduction Potential Calculations of Fe 4 S 4 Clusters
journal, February 2003
- Torres, Rhonda A.; Lovell, Timothy; Noodleman, Louis
- Journal of the American Chemical Society, Vol. 125, Issue 7
Broken-Symmetry DFT Computations for the Reaction Pathway of IspH, an Iron–Sulfur Enzyme in Pathogenic Bacteria
journal, June 2015
- Blachly, Patrick G.; Sandala, Gregory M.; Giammona, Debra Ann
- Inorganic Chemistry, Vol. 54, Issue 13
Density Functional Calculations of 55Mn, 14N and 13C Electron Paramagnetic Resonance Parameters Support an Energetically Feasible Model System for the S2 State of the Oxygen-Evolving Complex of Photosystem II
journal, July 2010
- Schinzel, Sandra; Schraut, Johannes; Arbuznikov, Alexei V.
- Chemistry - A European Journal, Vol. 16, Issue 34
Two Interconvertible Structures that Explain the Spectroscopic Properties of the Oxygen-Evolving Complex of Photosystem II in the S 2 State
journal, August 2012
- Pantazis, Dimitrios A.; Ames, William; Cox, Nicholas
- Angewandte Chemie International Edition, Vol. 51, Issue 39
A Comparison of Experimental and Broken Symmetry Density Functional Theory (BS-DFT) Calculated Electron Paramagnetic Resonance (EPR) Parameters for Intermediates Involved in the S 2 to S 3 State Transition of Nature’s Oxygen Evolving Complex
journal, January 2018
- Beal, Nathan J.; Corry, Thomas A.; O’Malley, Patrick J.
- The Journal of Physical Chemistry B, Vol. 122, Issue 4
Is Deprotonation of the Oxygen-Evolving Complex of Photosystem II during the S 1 → S 2 Transition Suppressed by Proton Quantum Delocalization?
journal, May 2021
- Yang, Ke R.; Lakshmi, K. V.; Brudvig, Gary W.
- Journal of the American Chemical Society, Vol. 143, Issue 22
FeMo Cofactor of Nitrogenase: A Density Functional Study of States M N , M OX , M R , and M I
journal, December 2001
- Lovell, Timothy; Li, Jian; Liu, Tiqing
- Journal of the American Chemical Society, Vol. 123, Issue 49
Ligand-Bound S = 1 / 2 FeMo-Cofactor of Nitrogenase: Hyperfine Interaction Analysis and Implication for the Central Ligand X Identity
journal, July 2008
- Pelmenschikov, Vladimir; Case, David A.; Noodleman, Louis
- Inorganic Chemistry, Vol. 47, Issue 14
QM/MM Study of the Nitrogenase MoFe Protein Resting State: Broken-Symmetry States, Protonation States, and QM Region Convergence in the FeMoco Active Site
journal, October 2017
- Benediktsson, Bardi; Bjornsson, Ragnar
- Inorganic Chemistry, Vol. 56, Issue 21
Critical computational analysis illuminates the reductive-elimination mechanism that activates nitrogenase for N 2 reduction
journal, October 2018
- Raugei, Simone; Seefeldt, Lance C.; Hoffman, Brian M.
- Proceedings of the National Academy of Sciences, Vol. 115, Issue 45
Orbital interactions, electron delocalization and spin coupling in iron-sulfur clusters
journal, October 1995
- Noodleman, L.; Peng, C. Y.; Case, D. A.
- Coordination Chemistry Reviews, Vol. 144
A New Quantum Chemical Approach to the Magnetic Properties of Oligonuclear Transition-Metal Complexes: Application to a Model for the Tetranuclear Manganese Cluster of Photosystem II
journal, May 2009
- Pantazis, Dimitrios A.; Orio, Maylis; Petrenko, Taras
- Chemistry - A European Journal, Vol. 15, Issue 20
The ORCA program system: The ORCA program system
journal, June 2011
- Neese, Frank
- Wiley Interdisciplinary Reviews: Computational Molecular Science, Vol. 2, Issue 1
Software update: the ORCA program system, version 4.0: Software update
journal, July 2017
- Neese, Frank
- Wiley Interdisciplinary Reviews: Computational Molecular Science, Vol. 8, Issue 1
Density-functional exchange-energy approximation with correct asymptotic behavior
journal, September 1988
- Becke, A. D.
- Physical Review A, Vol. 38, Issue 6
Comparative assessment of a new nonempirical density functional: Molecules and hydrogen-bonded complexes
journal, December 2003
- Staroverov, Viktor N.; Scuseria, Gustavo E.; Tao, Jianmin
- The Journal of Chemical Physics, Vol. 119, Issue 23
Balanced basis sets of split valence, triple zeta valence and quadruple zeta valence quality for H to Rn: Design and assessment of accuracy
journal, January 2005
- Weigend, Florian; Ahlrichs, Reinhart
- Physical Chemistry Chemical Physics, Vol. 7, Issue 18, p. 3297-3305
Accurate Coulomb-fitting basis sets for H to Rn
journal, January 2006
- Weigend, Florian
- Physical Chemistry Chemical Physics, Vol. 8, Issue 9
Development and validation of reliable quantum mechanical approaches for the study of free radicals in solution
journal, December 1996
- Rega, Nadia; Cossi, Maurizio; Barone, Vincenzo
- The Journal of Chemical Physics, Vol. 105, Issue 24
Prediction and interpretation of the 57Fe isomer shift in Mössbauer spectra by density functional theory
journal, September 2002
- Neese, Frank
- Inorganica Chimica Acta, Vol. 337
Efficient, approximate and parallel Hartree–Fock and hybrid DFT calculations. A ‘chain-of-spheres’ algorithm for the Hartree–Fock exchange
journal, February 2009
- Neese, Frank; Wennmohs, Frank; Hansen, Andreas
- Chemical Physics, Vol. 356, Issue 1-3
Structural basis for glycyl radical formation by pyruvate formate-lyase activating enzyme
journal, October 2008
- Vey, J. L.; Yang, J.; Li, M.
- Proceedings of the National Academy of Sciences, Vol. 105, Issue 42
Chemical Basis for Enzyme Catalysis
journal, May 2000
- Bruice, Thomas C.; Benkovic, Stephen J.
- Biochemistry, Vol. 39, Issue 21
Crystal Structure of the [FeFe]-Hydrogenase Maturase HydE Bound to Complex-B
journal, May 2021
- Rohac, Roman; Martin, Lydie; Liu, Liang
- Journal of the American Chemical Society, Vol. 143, Issue 22
Direct FeS Cluster Involvement in Generation of a Radical in Lysine 2,3-Aminomutase †
journal, December 2000
- Cosper, Nathaniel J.; Booker, Squire J.; Ruzicka, Frank
- Biochemistry, Vol. 39, Issue 51