skip to main content
DOE PAGES title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: A Biochemical Nickel(I) State Supports Nucleophilic Alkyl Addition: A Roadmap for Methyl Reactivity in Acetyl Coenzyme A Synthase

Abstract

Nickel-containing enzymes such as methyl coenzyme M reductase (MCR) and carbon monoxide dehydrogenase/acetyl coenzyme A synthase (CODH/ACS) play a critical role in global energy conversion reactions, with significant contributions to carbon-centered processes. These enzymes are implied to cycle through a series of nickel-based organometallic intermediates during catalysis, though identification of these intermediates remains challenging. In this work, we have developed and characterized a nickel-containing metalloprotein that models the methyl-bound organometallic intermediates proposed in the native enzymes. Using a nickel(I)-substituted azurin mutant, we demonstrate that alkyl binding occurs via nucleophilic addition of methyl iodide as a methyl donor. The paramagnetic Ni III-CH 3 species initially generated can be rapidly reduced to a high-spin Ni II-CH 3 species in the presence of exogenous reducing agent, following a reaction sequence analogous to that proposed for ACS. These two distinct bioorganometallic species have been characterized by optical, EPR, XAS, and MCD spectroscopy, and the overall mechanism describing methyl reactivity with nickel azurin has been quantitatively modeled using global kinetic simulations. A comparison between the nickel azurin protein system and existing ACS model compounds is presented. Ni III-CH 3 Az is only the second example of two-electron addition of methyl iodide to a Ni Imore » center to give an isolable species and the first to be formed in a biologically relevant system. These results highlight the divergent reactivity of nickel across the two intermediates, with implications for likely reaction mechanisms and catalytically relevant states in the native ACS enzyme.« less

Authors:
ORCiD logo [1];  [2];  [3]; ORCiD logo [3]; ORCiD logo [2]; ORCiD logo [1]
  1. The Ohio State Univ., Columbus, OH (United States). Dept. of Chemistry and Biochemistry
  2. Univ. of Michigan, Ann Arbor, MI (United States). Dept. of Chemistry
  3. Trinity Univ., San Antonio, TX (United States). Dept. of Chemistry
Publication Date:
Research Org.:
The Ohio State Univ., Columbus, OH (United States); Trinity Univ., San Antonio, TX (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22); ACS Petroleum Research Fund (ACS PRF) (United States); National Science Foundation (NSF); National Inst. of Health (NIH) (United States)
OSTI Identifier:
1495569
Alternate Identifier(s):
OSTI ID: 1508801
Grant/Contract Number:  
SC0018020; 57403-DNI6; CHE-1565766; GM120641
Resource Type:
Published Article
Journal Name:
Inorganic Chemistry
Additional Journal Information:
Journal Name: Inorganic Chemistry; Journal ID: ISSN 0020-1669
Publisher:
American Chemical Society (ACS)
Country of Publication:
United States
Language:
English

Citation Formats

Manesis, Anastasia C., Musselman, Bradley W., Keegan, Brenna C., Shearer, Jason, Lehnert, Nicolai, and Shafaat, Hannah S.. A Biochemical Nickel(I) State Supports Nucleophilic Alkyl Addition: A Roadmap for Methyl Reactivity in Acetyl Coenzyme A Synthase. United States: N. p., 2019. Web. doi:10.1021/acs.inorgchem.8b03546.
Manesis, Anastasia C., Musselman, Bradley W., Keegan, Brenna C., Shearer, Jason, Lehnert, Nicolai, & Shafaat, Hannah S.. A Biochemical Nickel(I) State Supports Nucleophilic Alkyl Addition: A Roadmap for Methyl Reactivity in Acetyl Coenzyme A Synthase. United States. doi:10.1021/acs.inorgchem.8b03546.
Manesis, Anastasia C., Musselman, Bradley W., Keegan, Brenna C., Shearer, Jason, Lehnert, Nicolai, and Shafaat, Hannah S.. Thu . "A Biochemical Nickel(I) State Supports Nucleophilic Alkyl Addition: A Roadmap for Methyl Reactivity in Acetyl Coenzyme A Synthase". United States. doi:10.1021/acs.inorgchem.8b03546.
@article{osti_1495569,
title = {A Biochemical Nickel(I) State Supports Nucleophilic Alkyl Addition: A Roadmap for Methyl Reactivity in Acetyl Coenzyme A Synthase},
author = {Manesis, Anastasia C. and Musselman, Bradley W. and Keegan, Brenna C. and Shearer, Jason and Lehnert, Nicolai and Shafaat, Hannah S.},
abstractNote = {Nickel-containing enzymes such as methyl coenzyme M reductase (MCR) and carbon monoxide dehydrogenase/acetyl coenzyme A synthase (CODH/ACS) play a critical role in global energy conversion reactions, with significant contributions to carbon-centered processes. These enzymes are implied to cycle through a series of nickel-based organometallic intermediates during catalysis, though identification of these intermediates remains challenging. In this work, we have developed and characterized a nickel-containing metalloprotein that models the methyl-bound organometallic intermediates proposed in the native enzymes. Using a nickel(I)-substituted azurin mutant, we demonstrate that alkyl binding occurs via nucleophilic addition of methyl iodide as a methyl donor. The paramagnetic NiIII-CH3 species initially generated can be rapidly reduced to a high-spin NiII-CH3 species in the presence of exogenous reducing agent, following a reaction sequence analogous to that proposed for ACS. These two distinct bioorganometallic species have been characterized by optical, EPR, XAS, and MCD spectroscopy, and the overall mechanism describing methyl reactivity with nickel azurin has been quantitatively modeled using global kinetic simulations. A comparison between the nickel azurin protein system and existing ACS model compounds is presented. NiIII-CH3 Az is only the second example of two-electron addition of methyl iodide to a NiI center to give an isolable species and the first to be formed in a biologically relevant system. These results highlight the divergent reactivity of nickel across the two intermediates, with implications for likely reaction mechanisms and catalytically relevant states in the native ACS enzyme.},
doi = {10.1021/acs.inorgchem.8b03546},
journal = {Inorganic Chemistry},
number = ,
volume = ,
place = {United States},
year = {2019},
month = {2}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record
DOI: 10.1021/acs.inorgchem.8b03546

Save / Share: