title: Tryptophan synthase: a multienzyme complex with an intramolecular tunnel.
abstract: Tryptophan synthase is a classic enzyme that channels a metabolic intermediate, indole. The crystal structure of the tryptophan synthase alpha2beta2 complex from Salmonella typhimurium revealed for the first time the architecture of a multienzyme complex and the presence of an intramolecular tunnel. This remarkable hydrophobic tunnel provides a likely passageway for indole from the active site of the alpha subunit, where it is produced, to the active site of the beta subunit, where it reacts with L-serine to form L-tryptophan in a pyridoxal phosphate-dependent reaction. Rapid kinetic studies of the wild type enzyme and of channel-impaired mutant enzymes provide strong evidence for the proposed channeling mechanism. Structures of a series of enzyme-substrate intermediates at the alpha and beta active sites are elucidating enzyme mechanisms and dynamics. These structural results are providing a fascinating picture of loops opening and closing, of domain movements, and of conformational changes in the indole tunnel. Solution studies provide further evidence for ligand-induced conformational changes that send signals between the alpha and beta subunits. The combined results show that the switching of the enzyme between open and closed conformations couples the catalytic reactions at the alpha and beta active sites and prevents the escape of indole.
authors.affiliation: Section on Enzyme Structure and Function, Laboratory of Biochemistry and Genetics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda Maryland 20892-0830, USA. EdithM@intra.niddk.nih.gov
authors.forename: E W
authors.initials: EW
authors.lastname: Miles
mesh_terms: D001692:Biological Transport; D002384:Catalysis; D007211:Indoles / Q000378:metabolism / Q000494:pharmacology; D007700:Kinetics; D009097:Multienzyme Complexes / Q000737:chemistry / Q000378:metabolism; D011487:Protein Conformation / Q000187:drug effects; D011732:Pyridoxal Phosphate / Q000737:chemistry; D012486:Salmonella typhimurium / Q000201:enzymology; D014367:Tryptophan Synthase / Q000737:chemistry* / Q000378:metabolism
chemical_list: D007211:Indoles; D009097:Multienzyme Complexes; D011732:Pyridoxal Phosphate; C030374:indole; D014367:Tryptophan Synthase