title: Structural analysis of a 3-deoxy-D-arabino-heptulosonate 7-phosphate synthase with an N-terminal chorismate mutase-like regulatory domain.
abstract: 3-Deoxy-D-arabino-heptulosonate 7-phosphate synthase (DAHPS) catalyzes the first step in the biosynthesis of a number of aromatic metabolites. Likely because this reaction is situated at a pivotal biosynthetic gateway, several DAHPS classes distinguished by distinct mechanisms of allosteric regulation have independently evolved. One class of DAHPSs contains a regulatory domain with sequence homology to chorismate mutase-an enzyme further downstream of DAHPS that catalyzes the first committed step in tyrosine/phenylalanine biosynthesis-and is inhibited by chorismate mutase substrate (chorismate) and product (prephenate). Described in this work, structures of the Listeria monocytogenes chorismate/prephenate regulated DAHPS in complex with Mn(2+)  and Mn(2+)  + phosphoenolpyruvate reveal an unusual quaternary architecture: DAHPS domains assemble as a tetramer, from either side of which chorismate mutase-like (CML) regulatory domains asymmetrically emerge to form a pair of dimers. This domain organization suggests that chorismate/prephenate binding promotes a stable interaction between the discrete regulatory and catalytic domains and supports a mechanism of allosteric inhibition similar to tyrosine/phenylalanine control of a related DAHPS class. We argue that the structural similarity of chorismate mutase enzyme and CML regulatory domain provides a unique opportunity for the design of a multitarget antibacterial.
authors.affiliation: Center for Structural Genomics of Infectious Diseases, Department of Molecular Pharmacology and Biological Chemistry, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA.
authors.forename: Samuel H
authors.initials: SH
authors.lastname: Light
authors.forename: Andrei S
authors.initials: AS
authors.lastname: Halavaty
authors.forename: George
authors.initials: G
authors.lastname: Minasov
authors.forename: Ludmilla
authors.initials: L
authors.lastname: Shuvalova
authors.forename: Wayne F
authors.initials: WF
authors.lastname: Anderson
mesh_terms: D010723:3-Deoxy-7-Phosphoheptulonate Synthase / Q000737:chemistry* / Q000378:metabolism; D000494:Allosteric Regulation; D002826:Chorismate Mutase / Q000737:chemistry* / Q000378:metabolism; D018360:Crystallography, X-Ray; D055808:Drug Discovery; D008089:Listeria monocytogenes / Q000737:chemistry / Q000201:enzymology* / Q000378:metabolism; D008345:Manganese / Q000378:metabolism; D008958:Models, Molecular; D010728:Phosphoenolpyruvate / Q000378:metabolism; D017434:Protein Structure, Tertiary
chemical_list: D008345:Manganese; D010728:Phosphoenolpyruvate; D010723:3-Deoxy-7-Phosphoheptulonate Synthase; D002826:Chorismate Mutase