title: An aldol switch discovered in stilbene synthases mediates cyclization specificity of type III polyketide synthases.
abstract: Stilbene synthase (STS) and chalcone synthase (CHS) each catalyze the formation of a tetraketide intermediate from a CoA-tethered phenylpropanoid starter and three molecules of malonyl-CoA, but use different cyclization mechanisms to produce distinct chemical scaffolds for a variety of plant natural products. Here we present the first STS crystal structure and identify, by mutagenic conversion of alfalfa CHS into a functional stilbene synthase, the structural basis for the evolution of STS cyclization specificity in type III polyketide synthase (PKS) enzymes. Additional mutagenesis and enzymatic characterization confirms that electronic effects rather than steric factors balance competing cyclization specificities in CHS and STS. Finally, we discuss the problematic in vitro reconstitution of plant stilbenecarboxylate pathways, using insights from existing biomimetic polyketide cyclization studies to generate a novel mechanistic hypothesis to explain stilbenecarboxylate biosynthesis.
authors.affiliation: Structural Biology Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Austin
authors.forename: Marianne E
authors.initials: ME
authors.lastname: Bowman
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Ferrer
authors.forename: Joachim
authors.initials: J
authors.lastname: Schröder
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Noel
mesh_terms: D000217:Acyltransferases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000595:Amino Acid Sequence; D018360:Crystallography, X-Ray; D003500:Cyclization; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D000077185:Resveratrol; D013267:Stilbenes / Q000378:metabolism; D013379:Substrate Specificity
chemical_list: D013267:Stilbenes; D000217:Acyltransferases; C022674:stilbene synthase; C020141:flavanone synthetase; D000077185:Resveratrol