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Reveromycin A biosynthesis uses RevG and RevJ for stereospecific spiroacetal formation.

Abstract
Spiroacetal compounds are ubiquitous in nature, and their stereospecific structures are responsible for diverse pharmaceutical activities. Elucidation of the biosynthetic mechanisms that are involved in spiroacetal formation will open the door to efficient generation of stereospecific structures that are otherwise hard to synthesize chemically. However, the biosynthesis of these compounds is poorly understood, owing to difficulties in identifying the responsible enzymes and analyzing unstable intermediates. Here we comprehensively describe the spiroacetal formation involved in the biosynthesis of reveromycin A, which inhibits bone resorption and bone metastases of tumor cells by inducing apoptosis in osteoclasts. We performed gene disruption, systematic metabolite analysis, feeding of labeled precursors and conversion studies with recombinant enzymes. We identified two key enzymes, dihydroxy ketone synthase and spiroacetal synthase, and showed in vitro reconstruction of the stereospecific spiroacetal structure from a stable acyclic precursor. Our findings provide insights into the creation of a variety of biologically active spiroacetal compounds for drug leads.
AuthorsShunji Takahashi, Atsushi Toyoda, Yasuyo Sekiyama, Hiroshi Takagi, Toshihiko Nogawa, Masakazu Uramoto, Ryuichiro Suzuki, Hiroyuki Koshino, Takuto Kumano, Suresh Panthee, Tohru Dairi, Jun Ishikawa, Haruo Ikeda, Yoshiyuki Sakaki, Hiroyuki Osada
JournalNature chemical biology (Nat Chem Biol) Vol. 7 Issue 7 Pg. 461-8 (Jun 05 2011) ISSN: 1552-4469 [Electronic] United States
PMID21642985 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Pyrans
  • Spiro Compounds
  • reveromycin A
  • Polyketide Synthases
Topics
  • Biosynthetic Pathways
  • Chromatography, High Pressure Liquid
  • Cyclization
  • Mass Spectrometry
  • Molecular Structure
  • Polyketide Synthases (genetics, metabolism)
  • Pyrans (chemistry)
  • Spiro Compounds (chemistry)
  • Stereoisomerism
  • Streptomyces (enzymology, genetics)

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