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Epimerization and desaturation by carbapenem synthase (CarC). A hybrid DFT study
Tomasz Borowski1, Ewa Broclawik, Christopher J Schofield
1Department of Physics, Stockholm Center for Physics, Astronomy and Biotechnology, Stockholm University, S-10691 Stockholm, Sweden. borowski@physto.se
Journal of Computational Chemistry
|March 8, 2006
Summary
Computational methods reveal carbapenem synthase
Area of Science:
- Biochemistry
- Computational Chemistry
- Enzymology
Background:
- Carbapenem synthases are crucial enzymes in antibiotic biosynthesis.
- Understanding their reaction mechanisms is key to developing novel therapeutics.
- Unusual epimerization and desaturation reactions present a mechanistic challenge.
Purpose of the Study:
- To elucidate the catalytic mechanism of carbapenem synthase.
- To investigate the roles of the iron cofactor and tyrosine residues in catalysis.
- To computationally model the epimerization and desaturation reactions.
Main Methods:
- Hybrid density functional theory (DFT) calculations using the B3LYP functional.
- Exploration of multiple computational models, including protonated and deprotonated substrates.
- Analysis of reaction energetics and transition state barrier heights.
Main Results:
- The study identified key steps in the epimerization and desaturation pathways.
- Calculations suggest a tyrosine residue (potentially Tyr67) assists in hydrogen abstraction.
- The proposed mechanism is consistent with experimental data for CarC and related enzymes.
Conclusions:
- The computational findings provide a detailed mechanistic insight into carbapenem synthase activity.
- The involvement of a tyrosine residue in hydrogen abstraction is supported by energetic calculations.
- This study enhances our understanding of 2-oxoglutarate dependent dioxygenases.
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