title: Discovery and assembly-line biosynthesis of the lymphostin pyrroloquinoline alkaloid family of mTOR inhibitors in Salinispora bacteria.
abstract: The pyrroloquinoline alkaloid family of natural products, which includes the immunosuppressant lymphostin, has long been postulated to arise from tryptophan. We now report the molecular basis of lymphostin biosynthesis in three marine Salinispora species that maintain conserved biosynthetic gene clusters harboring a hybrid nonribosomal peptide synthetase-polyketide synthase that is central to lymphostin assembly. Through a series of experiments involving gene mutations, stable isotope profiling, and natural product discovery, we report the assembly-line biosynthesis of lymphostin and nine new analogues that exhibit potent mTOR inhibitory activity.
authors.affiliation: Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California at San Diego, La Jolla, California 92093-0204, United States.
authors.forename: Akimasa
authors.initials: A
authors.lastname: Miyanaga
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Janso
authors.forename: Leonard
authors.initials: L
authors.lastname: McDonald
authors.forename: Min
authors.initials: M
authors.lastname: He
authors.forename: Hongbo
authors.initials: H
authors.lastname: Liu
authors.forename: Laurel
authors.initials: L
authors.lastname: Barbieri
authors.forename: Alessandra S
authors.initials: AS
authors.lastname: Eustáquio
authors.forename: Elisha N
authors.initials: EN
authors.lastname: Fielding
authors.forename: Guy T
authors.initials: GT
authors.lastname: Carter
authors.forename: Paul R
authors.initials: PR
authors.lastname: Jensen
authors.forename: Xidong
authors.initials: X
authors.lastname: Feng
authors.forename: Margaret
authors.initials: M
authors.lastname: Leighton
authors.forename: Frank E
authors.initials: FE
authors.lastname: Koehn
authors.forename: Bradley S
authors.initials: BS
authors.lastname: Moore
mesh_terms: D000192:Actinomycetales / Q000737:chemistry / Q000378:metabolism*; D000470:Alkaloids / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D011758:Pyrroles / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D011804:Quinolines / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000470:Alkaloids; D004791:Enzyme Inhibitors; D011758:Pyrroles; D011804:Quinolines; C410406:pyrroloquinoline; D058570:TOR Serine-Threonine Kinases