title: Chemical and biosynthetic evolution of the antimycin-type depsipeptides.
abstract: Evolution of natural products, and particularly those resulting from microbial assembly line-like enzymes, such as polyketide (PK) and nonribosomal peptides (NRP), has resulted in a variety of pharmaceutically important and chemically diverse families of molecules. The antimycin-type depsipeptides are one such grouping, with a significant level of diversity and members that have noted activities against key targets governing human cellular apoptosis (e.g. Bcl-xL and GRP78). Chemical variance originates from ring size, with 9-, 12-, 15-, and 18-membered classes, and we show that such distinctions influence their molecular targeting. Further, we present here a systematic interrogation of the chemistry and assembly line evolution of antimycin-type analogues by conducting metabolomic profiling and biosynthetic gene cluster comparative analysis of the depsipeptide assembly lines for each member of the antimycin-group. Natural molecular evolution principles of such studies should assist in artificial re-combinatorializing of PK and NRP assembly lines.
authors.affiliation: Department Chemistry & Chemical Biology, McMaster University, M.G. DeGroote Institute for Infectious Disease Research, 1200 Main St. W, Hamilton, Ontario L8N 3Z5, Canada.
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Vanner
authors.forename: Xiang
authors.initials: X
authors.lastname: Li
authors.forename: Rostyslav
authors.initials: R
authors.lastname: Zvanych
authors.forename: Jonathon
authors.initials: J
authors.lastname: Torchia
authors.forename: Jing
authors.initials: J
authors.lastname: Sang
authors.forename: David W
authors.initials: DW
authors.lastname: Andrews
authors.forename: Nathan A
authors.initials: NA
authors.lastname: Magarvey
mesh_terms: D000595:Amino Acid Sequence; D000968:Antimycin A / Q000031:analogs & derivatives / Q000096:biosynthesis / Q000737:chemistry / Q000494:pharmacology; D001688:Biological Products / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D016000:Cluster Analysis; D019295:Computational Biology / Q000379:methods; D047630:Depsipeptides / Q000096:biosynthesis / Q000737:chemistry* / Q000494:pharmacology; D000091342:Endoplasmic Reticulum Chaperone BiP; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D019906:Nuclear Magnetic Resonance, Biomolecular; D011485:Protein Binding; D017433:Protein Structure, Secondary; D016415:Sequence Alignment; D051020:bcl-X Protein / Q000037:antagonists & inhibitors / Q000737:chemistry
chemical_list: D001688:Biological Products; D047630:Depsipeptides; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D051020:bcl-X Protein; C032456:antimycin; D000968:Antimycin A