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Templating effects in aristolochene synthase catalysis: elimination versus cyclisation.
Juan A Faraldos1, Verónica González, Michael Senske
1School of Chemistry, Cardiff University, Main Building, Park Place, Cardiff, CF10 3AT, United Kingdom.
Organic & Biomolecular Chemistry
|August 27, 2011
Summary
Aristolochene synthase mutants show that Leu 108 is crucial for farnesyl diphosphate conformation, enabling ring-closure and (+)-aristolochene production.
Area of Science:
- Biochemistry
- Enzymology
- Natural Product Synthesis
Background:
- Aristolochene synthase (PR-AS) from P. roqueforti catalyzes a key step in sesquiterpenoid biosynthesis.
- Understanding enzyme structure-function relationships is vital for metabolic engineering and drug discovery.
Purpose of the Study:
- To investigate the structural role of specific residues in PR-AS activity.
- To elucidate the mechanism of farnesyl diphosphate cyclization catalyzed by PR-AS.
Main Methods:
- Site-directed mutagenesis of PR-AS to alter specific amino acid residues.
- Analysis of enzymatic products generated by wild-type and mutant PR-AS.
- Biochemical characterization of mutant enzyme activity.
Main Results:
- The aliphatic residue Leu 108 was identified as critical for maintaining the enzyme's active conformation.
- Mutations at Leu 108 disrupted the productive binding of farnesyl diphosphate.
- This disruption impaired the C1-C10 ring-closure essential for (+)-aristolochene formation.
Conclusions:
- Leu 108 plays a prominent structural role in PR-AS function.
- The precise conformation of farnesyl diphosphate is essential for the catalytic cyclization reaction.
- These findings provide insights into the mechanism of aristolochene biosynthesis.
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