Involvement of Lipocalin-like CghA in Decalin-Forming Stereoselective Intramolecular [4+2] Cycloaddition

Details

• Alternative Title:
  Chembiochem
• Personal Author:
  Sato, Michio ; Yagishita, Fumitoshi ; Mino, Takashi ; Uchiyama, Nahoko ; Patel, Ashay ; Chooi, Yit-Heng ; Goda, Yukihiro ; Xu, Wei ; Noguchi, Hiroshi ; Yamamoto, Tsuyoshi ; Hotta, Kinya ; Houk, Kendall N. ; Tang, Yi ; Watanabe, Kenji
• Description:
  Understanding enzymatic Diels-Alder (DA) reactions that can form complex natural product scaffolds is of considerable interest. Sch 210972 1, a potential anti-HIV fungal natural product, contains a decalin core that is proposed to form through a DA reaction. We identified the gene cluster responsible for the biosynthesis of 1 and heterologously reconstituted the biosynthetic pathway in Aspergillus nidulans to characterize the enzymes involved. Most notably, deletion of cghA resulted in a loss of stereoselective decalin core formation, yielding both an endo (1) and a diastereomeric exo adduct of the proposed DA reaction. Complementation with cghA restored the sole formation of 1. Density functional theory computation of the proposed DA reaction provided a plausible explanation of the observed pattern of product formation. Based on our study, we propose that lipocalin-like CghA is responsible for the stereoselective intramolecular [4+2] cycloaddition that forms the decalin core of 1.
• Subjects:
  Article Aspergillus Nidulans Cycloaddition Cycloaddition Reaction Decalin Natural Product Density Functional Calculations Fungal Metabolite Fungal Proteins Lipocalins Molecular Conformation Naphthalenes Stereoisomerism Tetramic Acid Thermodynamics

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• Source:
  Chembiochem. 16(16):2294-2298
• Pubmed ID:
  26360642
• Pubmed Central ID:
  PMC4915928
• Document Type:
  Journal Article
• Funding:
  1R01M097200/PHS HHSUnited States/ ; R01 GM097200/GM/NIGMS NIH HHSUnited States/ ; DP1 GM106413/GM/NIGMS NIH HHSUnited States/ ; T32GM008496/GM/NIGMS NIH HHSUnited States/ ; 1DP1M106413/DP/NCCDPHP CDC HHSUnited States/ ; T32 GM008496/GM/NIGMS NIH HHSUnited States/ ; R01 GM085128/GM/NIGMS NIH HHSUnited States/
• Volume:
  16
• Issue:
  16
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:b3fb4526f50b526d379c96795d8c0443dadf4d48dfcc15d3ca28fa5a48077c4e
• Download URL:
  https://stacks.cdc.gov/view/cdc/40002/cdc_40002_DS1.pdf
• File Type:
  [PDF - 720.42 KB ]