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Theoretical studies on farnesyltransferase: the distances paradox explained
Sérgio Filipe Sousa1, Pedro Alexandrino Fernandes, Maria João Ramos
1REQUIMTE, Departamento de Química, Faculdade de Ciências, Universidade do Porto, 4169-007 Porto, Portugal.
Proteins
|October 28, 2006
Summary
Farnesyltransferase (FTase) enzyme mechanism clarified: FPP rotation, not cysteine thiolate activation, overcomes the catalytic distance paradox. This finding advances understanding of the farnesylation reaction.
Area of Science:
- Biochemistry
- Enzymology
- Computational Chemistry
Background:
- The enzyme farnesyltransferase (FTase) plays a crucial role in biological processes.
- Its catalytic mechanism, particularly the "distances paradox," remains incompletely understood.
- This paradox involves a significant spatial gap between reactive substrates.
Purpose of the Study:
- To investigate the mechanism by which FTase overcomes the large distance between its reactive sites.
- To evaluate two proposed hypotheses for resolving the "distances paradox" in FTase catalysis.
- To elucidate the chemical step of the farnesylation reaction.
Main Methods:
- Combined molecular mechanics (AMBER) and quantum chemical calculations (B3LYP).
- Evaluated substrate activation and molecular rotation as potential mechanisms.
- Analyzed crystallographic data of ternary complexes.
Main Results:
- Cysteine thiolate activation and displacement is an unlikely mechanism to overcome the 8-Å distance.
- Rotation of the farnesyldiphosphate (FPP) molecule provides a viable pathway.
- FPP rotation brings reactive atoms closer with a moderate energetic cost.
Conclusions:
- Farnesylation reaction mechanism is better explained by FPP rotation.
- This study resolves a fundamental dilemma in FTase enzyme mechanism.
- Provides a clearer understanding of the chemical step in farnesylation.
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