Modifying the Thioester Linkage Affects the Structure of the Acyl Carrier Protein

• DOI: 10.1002/anie.201903815
• Publication Date: 2019-05-29T02:04:32Z
• Authors: Terra Sztain; Ashay Patel; D. John Lee; Tony D. Davis; J. Andrew McCammon; Michael D. Burkart
• Keywords: 0301 basic medicine; 570; 0303 health sciences; Magnetic Resonance Spectroscopy; Molecular Structure; Organic Chemistry; Esters; Hydrogen Bonding; Biological Sciences; Molecular Dynamics Simulation; 540; protein interactions; molecular dynamics; NMR; 03 medical and health sciences; Chemical sciences; protein structures; Chemical Sciences; Acyl carrier protein; Biochemistry and Cell Biology; Sulfhydryl Compounds; Carrier Proteins

AbstractAt the center of many complex biosynthetic pathways, the acyl carrier protein (ACP) shuttles substrates to appropriate enzymatic partners to produce fatty acids and polyketides. Carrier proteins covalently tether their cargo via a thioester linkage to a phosphopantetheine cofactor. Due to the labile nature of this linkage, chemoenzymatic methods have been developed that involve replacement of the thioester with a more stable amide or ester bond. We explored the importance of the thioester bond to the structure of the carrier protein by using solution NMR spectroscopy and molecular dynamics simulations. Remarkably, the replacement of sulfur with other heteroatoms results in significant structural changes, thus suggesting more rigorous selections of isosteric substitutes is needed.