Molecular basis for chloronium-mediated meroterpene cyclization: cloning, sequencing, and heterologous expression of the napyradiomycin biosynthetic gene cluster.
Structural inspection of the bacterial meroterpenoid antibiotics belonging to the napyradiomycin family of chlorinated dihydroquinones suggests that the biosynthetic cyclization of their terpenoid subunits is initiated via a chloronium ion. The vanadium-dependent haloperoxidases that catalyze such reactions are distributed in fungi and marine algae and have yet to be characterized from bacteria. The cloning and sequence analysis of the 43-kb napyradiomycin biosynthetic cluster (nap) from Streptomyces aculeolatus NRRL 18422 and from the undescribed marine sediment-derived Streptomyces sp. CNQ-525 revealed 33 open reading frames, three of which putatively encode vanadium-dependent chloroperoxidases. Heterologous expression of the CNQ-525-based nap biosynthetic cluster in Streptomyces albus produced at least seven napyradiomycins, including the new analog 2-deschloro-2-hydroxy-A80915C. These data not only revealed the molecular basis behind the biosynthesis of these novel meroterpenoid natural products but also resulted in the first in vivo verification of vanadium-dependent haloperoxidases.
Winter
Jaclyn M
JM
Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California at San Diego, La Jolla, California 92093-0204, USA.
Moffitt
Michelle C
MC
Zazopoulos
Emmanuel
E
McAlpine
James B
JB
Dorrestein
Pieter C
PC
Moore
Bradley S
BS
D000900:Anti-Bacterial Agents / Q000096:biosynthesis*; D001426:Bacterial Proteins / Q000096:biosynthesis* / Q000235:genetics; D001483:Base Sequence; D002384:Catalysis; D003001:Cloning, Molecular; D015870:Gene Expression; D008969:Molecular Sequence Data; D005810:Multigene Family / Q000502:physiology*; D009285:Naphthoquinones / Q000378:metabolism*; D016366:Open Reading Frames / Q000502:physiology; D010544:Peroxidases / Q000096:biosynthesis* / Q000235:genetics; D017422:Sequence Analysis, DNA; D013302:Streptomyces / Q000201:enzymology* / Q000235:genetics; D013729:Terpenes / Q000378:metabolism*; D014639:Vanadium / Q000378:metabolism
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D009285:Naphthoquinones; D013729:Terpenes; D014639:Vanadium; D010544:Peroxidases