title: Repositioning of a domain in a modular polyketide synthase to promote specific chain cleavage.
abstract: Macrocyclic polyketides exhibit an impressive range of medically useful activities, and there is great interest in manipulating the genes that govern their synthesis. The 6-deoxyerythronolide B synthase (DEBS) of Saccharopolyspora erythraea, which synthesizes the aglycone core of the antibiotic erythromycin A, has been modified by repositioning of a chain-terminating cyclase domain to the carboxyl-terminus of DEBS1, the multienzyme that catalyzes the first two rounds of polyketide chain extension. The resulting mutant markedly accelerates formation of the predicted triketide lactone, compared to a control in which the repositioned domain is inactive. Repositioning of the cyclase should be generally useful for redirecting polyketide synthesis to obtain polyketides of specified chain lengths.
authors.affiliation: Cambridge Centre for Molecular Recognition, University of Cambridge, UK.
authors.forename: J
authors.initials: J
authors.lastname: Cortes
authors.forename: K E
authors.initials: KE
authors.lastname: Wiesmann
authors.forename: G A
authors.initials: GA
authors.lastname: Roberts
authors.forename: M J
authors.initials: MJ
authors.lastname: Brown
authors.forename: J
authors.initials: J
authors.lastname: Staunton
authors.forename: P F
authors.initials: PF
authors.lastname: Leadlay
mesh_terms: D001483:Base Sequence; D001665:Binding Sites; D003001:Cloning, Molecular; D004917:Erythromycin / Q000096:biosynthesis; D005798:Genes, Bacterial; D005822:Genetic Vectors; D008969:Molecular Sequence Data; D009097:Multienzyme Complexes / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015202:Protein Engineering; D016930:Saccharopolyspora / Q000201:enzymology* / Q000235:genetics; D014170:Transformation, Genetic
chemical_list: D009097:Multienzyme Complexes; D004917:Erythromycin