Biosynthetic Gene Cluster of the Non-ribosomally Synthesized Cyclodepsipeptide Skyllamycin: Deciphering Unprecedented Ways of Unusual Hydroxylation Reactions
- 1 April 2011
- journal article
- Published by American Chemical Society (ACS) in Journal of the American Chemical Society
- Vol. 133 (16), 6194-6205
- https://doi.org/10.1021/ja108971p
Abstract
The cyclic depsipeptide skyllamycin A is a potent inhibitor of the platelet-derived growth factor (PDGF) signaling pathway by inhibiting binding of homodimeric PDGF BB to the PDGF β-receptor. Its structure contains a cinnamoyl side chain and shows a high amount of β-hydroxylated amino acids as well as an unusual α-hydroxyglycine moiety as a rare structural modification. The skyllamycin biosynthetic gene cluster was cloned and sequenced from Streptomyces sp. Acta 2897. Its analysis revealed the presence of open reading frames encoding proteins for fatty acid precursor biosynthesis, non-ribosomal peptide synthetases, regulators, and transporters along with other modifying enzymes. Specific in-frame mutagenesis of these tailoring enzymes resulted in the production of novel skyllamycin derivatives revealing that β-hydroxy groups in skyllamycin A are introduced by a promiscuous cytochrome P450 monooxygenase, whereas a two-component flavin-dependent monooxygenase is involved in α-hydroxylation.Keywords
This publication has 67 references indexed in Scilit:
- Activation of the Pacidamycin PacL Adenylation Domain by MbtH-like ProteinsBiochemistry, 2010
- MbtH-Like Proteins as Integral Components of Bacterial Nonribosomal Peptide SynthetasesBiochemistry, 2010
- Functional Dissection of Surfactin Synthetase Initiation Module Reveals Insights into the Mechanism of LipoinitiationCell Chemical Biology, 2010
- The Actinomycin Biosynthetic Gene Cluster ofStreptomyces chrysomallus: a Genetic Hall of Mirrors for Synthesis of a Molecule with Mirror SymmetryJournal of Bacteriology, 2010
- The Pfam protein families databaseNucleic Acids Research, 2009
- Protein kinase inhibitors: contributions from structure to clinical compoundsQuarterly Reviews of Biophysics, 2009
- Role of platelet-derived growth factors in physiology and medicineGenes & Development, 2008
- Cloning and characterization of the biosynthetic gene cluster for kutzneridesProceedings of the National Academy of Sciences of the United States of America, 2007
- Cloning, Sequencing, and Characterization of a Gene Cluster Involved in EDTA Degradation from the Bacterium BNC1Applied and Environmental Microbiology, 2001
- Gapped BLAST and PSI-BLAST: a new generation of protein database search programsNucleic Acids Research, 1997