Resveratrol synthase uncovered: Cyclization specificity of type III polyketide...( A group from the Salk institute illumin...)

Plant natural products called stilbenes can confer antifungal resistance to host plants and have been shown to possess health benefits for humans and other animals when present in their diet. The best known stilbene is resveratrol, which is found in grapes and is believed to be a major contributor to the "French Paradox," which refers to the health benefits associated with the moderate consumption of red wine. The mechanism of stilbene synthesis is therefore of great pharmaceutical and medical interest. Much is already understood about the enzymatic features of type III polyketide synthases, the enzyme family that generates stilbenes, but until now one mystery remained: How are stilbene synthases regulated to conduct the specific cyclization reaction required to produce stilbenes? For example, stilbene synthase (STS) and chalcone synthase (CHS) share 75%90% amino acid sequence identity and generate the same tetraketide, but STS enzymes cyclize this tetraketide via an intramolecular C2 to C7 aldol condensation to make stilbene, whereas the CHS cyclize via C2 to C6 condensation reaction to make chalcone. A group of researchers led by Joseph Noel at the Salk Institute has revealed the structural basis for the specificity of this critical reaction. To do this, the Noel group generated the first crystal structure of a STS and identified how STS evolved from its CHS ancestor by comparing the two at the structural and molecular levels. To prove their hypothesis, the Noel group used this information to convert alfalfa CHS into a functional STS by structure-guided engineering. Their work reveals an unexpected mechanism for functional divergence of the STS from the CHS. Specificity of cyclization is not regulated by the shape of the active site, as was believed prev
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Contact: Heidi Hardman
hhardman@cell.com
617-397-2879
Cell Press
17-Sep-2004