title: Stereochemistry and conformation of skyllamycin, a non-ribosomally synthesized peptide from Streptomyces sp. Acta 2897.
abstract: Skyllamycin is a non-ribosomally synthesized cyclic depsipeptide from Streptomyces sp. Acta 2897 that inhibits PDGF-signaling. The peptide scaffold contains an N-terminal cinnamoyl moiety, a β-methylation of aspartic acid, three β-hydroxylated amino acids and one rarely occurring α-hydroxy glycine. With the exception of α-hydroxy glycine, the stereochemistry of the amino acids was assigned by comparison to synthetic reference amino acids applying chiral GC-MS and Marfey-HPLC analysis. The stereochemistry of α-hydroxy glycine, which is unstable under basic and acidic conditions, was determined by conformational analysis, employing a combination of data from NOESY-NMR spectroscopy, simulated annealing and free MD simulations. The simulation procedures were applied for both R- and S-configured α-hydroxy glycine of the skyllamycin structure and compared to the NOESY data. Both methods, simulated annealing and free MD simulations independently support S-configured α-hydroxy glycine thus enabling the assignment of all stereocenters in the structure of skyllamycin and devising the role of two-component flavin dependent monooxygenase (Sky39) as S-selective.
authors.affiliation: Institut für Chemie, TU Berlin, Straße des 17, Juni 124, 10623 Berlin (Germany).
authors.forename: Vivien
authors.initials: V
authors.lastname: Schubert
authors.forename: Florent
authors.initials: F
authors.lastname: Di Meo
authors.forename: Pierre-Loïc
authors.initials: PL
authors.lastname: Saaidi
authors.forename: Stefan
authors.initials: S
authors.lastname: Bartoschek
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Fiedler
authors.forename: Patrick
authors.initials: P
authors.lastname: Trouillas
authors.forename: Roderich D
authors.initials: RD
authors.lastname: Süssmuth
mesh_terms: D047630:Depsipeptides / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D056004:Molecular Dynamics Simulation; D010456:Peptides, Cyclic / Q000737:chemistry*; D010982:Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013302:Streptomyces / Q000737:chemistry*
chemical_list: D047630:Depsipeptides; D010456:Peptides, Cyclic; D010982:Platelet-Derived Growth Factor; C433003:skyllamycins
keywords: NOESY-NMR spectroscopy; conformational analysis; peptide antibiotics; skyllamycin; structure elucidation