title: New Stetter reactions catalyzed by thiamine diphosphate dependent MenD from E. coli.
abstract: The intermolecular asymmetric Stetter reaction is a rarely found biocatalysts transformation. MenD, the second enzyme of the menaquinone biosynthetic pathway, catalyzes as a physiological reaction a Stetter-like addition of α-ketoglutarate to isochorismate. The substrate range of MenD for similar 1,4-additions is highly restricted. All other thiamine diphosphate dependent enzymes known to act as stetterases are members of the PigD enzyme subfamily, which accept aliphatic and aromatic α,β-unsaturated ketones and thioesters as Michael acceptor substrates. Here, we describe the unexpected activity of MenD with short-chain α,β-unsaturated acids and derivatives as substrates in Stetter reactions. MenD possesses a characteristic substrate range with respect to Michael acceptor substrates which is distinctly different from the classical stetterases. This provides biocatalytic access to new types of products which are not related to the products currently accessible by thiamine diphosphate dependent enzyme catalysis.
authors.affiliation: Institute of Pharmaceutical Sciences, Albert-Ludwigs-Universität Freiburg, Albertstrasse 25, 79104 Freiburg, Germany.
authors.forename: Maryam
authors.initials: M
authors.lastname: Beigi
authors.affiliation: Institute of Pharmaceutical Sciences, Albert-Ludwigs-Universität Freiburg, Albertstrasse 25, 79104 Freiburg, Germany.
authors.forename: Simon
authors.initials: S
authors.lastname: Waltzer
authors.affiliation: Center for Biological Systems Analysis, Albert-Ludwigs-Universität Freiburg, Habsburgerstrasse 49, 79104 Freiburg, Germany.
authors.forename: Mostafa
authors.initials: M
authors.lastname: Zarei
authors.affiliation: Institute of Pharmaceutical Sciences, Albert-Ludwigs-Universität Freiburg, Albertstrasse 25, 79104 Freiburg, Germany. Electronic address: michael.mueller@pharmazie.uni-freiburg.de.
authors.forename: Michael
authors.initials: M
authors.lastname: Müller
mesh_terms: D000595:Amino Acid Sequence; D053898:Biosynthetic Pathways; D002384:Catalysis; D004926:Escherichia coli / Q000201:enzymology* / Q000235:genetics; D029968:Escherichia coli Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D007659:Ketones / Q000737:chemistry; D011771:Pyruvate Oxidase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013379:Substrate Specificity; D013440:Sulfides / Q000737:chemistry; D013835:Thiamine Pyrophosphate / Q000737:chemistry / Q000378:metabolism*
chemical_list: D029968:Escherichia coli Proteins; D007659:Ketones; D013440:Sulfides; C534108:2-succinyl-5-enolpyruvyl-6-hydroxy-3-cyclohexadiene-1-carboxylate synthase, E coli; D011771:Pyruvate Oxidase; D013835:Thiamine Pyrophosphate
keywords: 1,4-Carboligation; Biocatalysis; CC coupling; Chemoenzymatic synthesis; Umpolung