Thermodynamic and Mechanistic Aspects of Small-Ring Formation Mediated by Nonheme-Iron and 2‑Oxoglutarate Dependent Enzymes.
- 1Division of Chemical Biology & Medicinal Chemistry, College of Pharmacy, University of Texas at Austin, Austin, Texas 78712, United States.
- 2Department of Chemistry, North Carolina State University, Raleigh, North Carolina 27607, United States.
Abstract
The biological formation of three-membered rings catalyzed by nonheme-iron and 2-oxoglutarate dependent (Fe/2OG) enzymes incurs a thermodynamic cost paid by the four-electron reduction of molecular oxygen. Inspection, however, suggests that this chemistry is closely related to the Fenton reaction, where the central ferryl complex serves as a more reactive surrogate for hydrogen peroxide. While this sacrifices some of the oxidative power of O₂ to heat, sufficient chemical potential is retained to make small-ring cyclization strongly exergonic while also reducing kinetic barriers to reaction. At the same time, mechanistic features must be introduced that raise the relative activation energies for alternative reaction pathways. Current study of Fe/2OG catalyzed small ring cyclization is helping to identify these features including substrate-cofactor disposition, ferric stabilization and active site preorganization among others that likely work together to define reaction channels and thus determine the reaction outcome.
Related
- Computational Mechanistic Analysis of Olefin Formation in Ketyl Radical-Mediated Photoexcited Palladium Catalysis
- Mechanistic Elucidation of the Acidic Hydrolysis of Triazolobenzodiazepines: Integration of Kinetic, Thermodynamic, and Quantum Chemical Analyses
- Thermodynamic principles governing MXene formation by molten salt etching
- Mechanistic Insights into Light-Alkane Formation from Photoexcited Uranyl complexes
- Probing Benzoxazine Dimer Formation Using Methyl-Blocked Derivatives as Mechanistic Probes
BibTeX
@article{ruszczycky2026thermodynamic,
title = {{Thermodynamic and Mechanistic Aspects of Small-Ring Formation Mediated by Nonheme-Iron and 2‑Oxoglutarate Dependent Enzymes.}},
author = {Mark W Ruszczycky and Wei-Chen Chang},
journal = {ACS bio \& med chem Au},
year = {2026},
month = jul,
doi = {10.1021/acsbiomedchemau.6c00102},
url = {https://europepmc.org/article/MED/42921253},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Thermodynamic and Mechanistic Aspects of Small-Ring Formation Mediated by Nonheme-Iron and 2‑Oxoglutarate Dependent Enzymes.
AU - Mark W Ruszczycky
AU - Wei-Chen Chang
PY - 2026
DA - 2026/07/25
JO - ACS bio & med chem Au
DO - 10.1021/acsbiomedchemau.6c00102
UR - https://europepmc.org/article/MED/42921253
AB - The biological formation of three-membered rings catalyzed by nonheme-iron and 2-oxoglutarate dependent (Fe/2OG) enzymes incurs a thermodynamic cost paid by the four-electron reduction of molecular oxygen. Inspection, however, suggests that this chemistry is closely related to the Fenton reaction, where the central ferryl complex serves as a more reactive surrogate for hydrogen peroxide. While this sacrifices some of the oxidative power of O₂ to heat, sufficient chemical potential is retained to make small-ring cyclization strongly exergonic while also reducing kinetic barriers to reaction. At the same time, mechanistic features must be introduced that raise the relative activation energies for alternative reaction pathways. Current study of Fe/2OG catalyzed small ring cyclization is helping to identify these features including substrate-cofactor disposition, ferric stabilization and active site preorganization among others that likely work together to define reaction channels and thus determine the reaction outcome.
SN - 2694-2437
ER -