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Rates of competing fluoride elimination and iodination from a thiamin-derived Breslow intermediate
1Davenport Chemistry Laboratories, Department of Chemistry, University of Toronto, Toronto, Ontario M5S 3H6, Canada.
Bioorganic Chemistry
|January 14, 2022
Summary
This study quantifies competing reactions of the Breslow intermediate (BI), a key molecule in thiamin-dependent enzymes. Fluoride elimination from the BI occurs faster than protonation, revealing insights into enzyme mechanisms.
Area of Science:
- Biochemistry
- Enzyme kinetics
- Organic reaction mechanisms
Background:
- Thiamin diphosphate (TDP) dependent enzymes catalyze crucial metabolic reactions.
- The Breslow intermediate (BI) is a key reactive species in these enzymatic pathways.
- Understanding the reactivity of the BI is essential for elucidating enzyme mechanisms.
Purpose of the Study:
- To quantitatively assess competing reactions at the C2α position of the BI.
- To probe the intrinsic reactivity of the BI.
- To compare the reactivity of the enzymic BI with known reaction pathways.
Main Methods:
- Measuring rates of fluoride elimination from the BI.
- Measuring rates of iodination of the BI to estimate protonation rates.
- Determining the Brønsted β and pKA of the BI.
Main Results:
- Fluoride elimination from the BI occurs spontaneously at a rate of 7.5 ± 0.3 s-1.
- The rate of iodination provides an estimate for the competing protonation rate.
- The intrinsic reactivity of the BI was quantitatively assessed.
Conclusions:
- Spontaneous fluoride elimination from the enzymic BI has a lower activation barrier compared to enzyme-promoted pathways.
- This study provides key kinetic parameters for the BI, aiding in understanding thiamin enzyme mechanisms.
- The findings highlight the importance of intrinsic intermediate reactivity in enzyme catalysis.
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