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.

Polymer amide in the Allende and Murchison meteorites

“…; Schubert et al. ). However, once incorporated in a protein, or polymer amide, it shows very good stability.…”

Total Synthesis of Skyllamycins A–C

“…The stereochemistry of the amino acids present in 1 – 3 was not assigned during the initial isolation; however further work by Süssmuth and co‐workers confirmed the absolute configuration of the amino acids through a combination of chiral HPLC/GC and Marfey's analysis. Owing to the instability of the α‐OH‐Gly residue, the configuration could not be confirmed experimentally.…”

New WS9326A Derivatives and One New Annimycin Derivative with Antimalarial Activity are Produced by Streptomyces asterosporus DSM 41452 and Its Mutant

“…Another prominent feature of WS9326A is the N ‐acyl group, consisting of a ( Z )‐pentenylcinnamoyl moiety; similar side chains are also found in depsipeptide skyllamycin, pepticinnamins, and the dimeric peptides mohangamide A and B . Structure and bioactivity relationships have shown that the ( Z )‐pentenylcinnamoyl moiety is essential for activity .…”

“…Within the putative SAS gene cluster, 18 genes are predicted to be involved in the biosynthesis of the PKS‐derived acyl side chain. Very similar genes were also found in the skyllmycin gene cluster (Table S5). In contrast to the skyllmycin gene cluster, SKY11 encoding a putative carboxyltransferase is absent in our cluster.…”

“…Thus, malonyl‐coenzyme A as the starting building block is most likely derived from the primary metabolism in our strain. Further bioinformatic analysis of the genes within this locus revealed that six genes (i.e., sas7 , sas8 , sas30 , sas31 , sas32 , and sas33 ) were predicted to encode 3‐oxoacyl‐ACP synthases for fatty acid biosynthesis, which might be involved in a series of condensation reactions with acetyl‐CoA and malonyl‐CoA units to form the N ‐acyl C14‐polyene before aromatic ring formation occurs . The terminal C12=C13 bond in this C14‐polyene intermediate might be further reduced by a reductase encoded by sas21 , which shows significant homology (96 % amino‐acid identity) to an oxidoreductase from Streptomyces griseoflavus .…”