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Exploring the Molecular Determinants of Heterocycle Formation in Hybrid Nonribosomal Peptides/Polyketides
Author(s) -
Dowling Daniel P.,
Kung Yan,
Croft Anna,
Taghizadeh Koli,
Kelly Wendy,
Walsh Christopher T.,
Drennan Catherine L.
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.796.24
Subject(s) - nonribosomal peptide , oxazole , chemistry , stereochemistry , amino acid , polyketide , computational biology , biochemistry , combinatorial chemistry , biology , biosynthesis , gene
Many secondary metabolites from natural sources contain thiazole or oxazole derivatives that stem from the precursor amino acids cysteine, serine or threonine, and how Nature generates these azolines depends on the biosynthetic strategy used by that organism. Here, we explore azoline formation within hybrid nonribosomal peptide (NRP) and polyketide (PK) compounds, a class of molecules that are extremely beneficial for drug discovery. Epothilones are example hybrid NRP/PK products that demonstrate antitumor activity by stabilizing microtubules. They are biosynthesized through the action of EpoA‐F from Sorangium cellulosum , in which the EpoA and EpoB proteins act as the starter unit to generate the 2‐methylthiazole functionality. EpoB contains a cyclization (Cy) domain capable of catalyzing both chain extension and cyclization reactions to yield a heterocycle. We report crystal structures for a didomain of the EpoB Cy domain tethered to its N‐terminal docking domain, which have implications in locating carrier protein binding sites, identifying phosphopantetheine binding tunnels, and determining residues involved in catalysis. Site‐directed mutagenesis of active site residues have identified key amino acids required for catalysis. X‐ray crystal structures of the EpoB Cy domain and related systems provide an opportunity to analyze critical similarities and differences that may guide future bioengineering efforts for green chemistry applications. Support or Funding Information U.S. National Institutes of Health [1R15GM123425‐01 to D.P.D.]. C.L.D. is a Howard Hughes Medical Institute Investigator. Support for this research was provided by National Institute of Environmental Health Sciences, NIH Core Center Grant P30‐ES002109. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .