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Title: Crystal Structures of SgcE6 and SgcC, the Two-Component Monooxygenase That Catalyzes Hydroxylation of a Carrier ProteinTethered Substrate during the Biosynthesis of the Enediyne Antitumor Antibiotic C-1027 in Streptomyces globisporus

C-1027 is a chromoprotein enediyne antitumor antibiotic produced by Streptomyces globisporus. In the last step of biosynthesis of the (S)-3-chloro-5-hydroxy-beta-tyrosine moiety of the C-1027 enediyne chromophore, SgcE6 and SgcC compose a two-component monooxygenase that hydroxylates the C-5 position of (S)-3-chloro-beta-tyrosine. This two-component monooxygenase is remarkable for two reasons. (i) SgcE6 specifically reacts with FAD and NADH, and (ii) SgcC is active with only the peptidyl carrier protein (PCP)-tethered substrate. To address the molecular details of substrate specificity, we determined the crystal structures of SgcE6 and SgcC at 1.66 and 2.63 A resolution, respectively. SgcE6 shares a similar β-barrel fold with the class I HpaC-like flavin reductases. A flexible loop near the active site of SgcE6 plays a role in FAD binding, likely by providing sufficient space to accommodate the AMP moiety of FAD, when compared to that of FMN-utilizing homologues. SgcC shows structural similarity to a few, other known FADH 2-dependent monooxygenases and sheds light on some biochemically but not structurally characterized homologues. In conclusion, the crystal structures reported here provide insights into substrate specificity, and comparison with homologues provides a catalytic mechanism of the two-component, FADH 2-dependent monooxygenase (SgcE6 and SgcC) that catalyzes the hydroxylation of a PCP-tethered substrate.
 [1] ;  [1] ;  [2] ;  [3] ;  [1] ;  [1] ;  [2] ;  [4] ;  [5] ;  [3] ;  [3] ;  [1] ;  [3] ;  [2] ;  [1]
  1. The Scripps Research Institute, Jupiter, FL (United States)
  2. Rice Univ., Houston, TX (United States)
  3. Argonne National Lab. (ANL), Argonne, IL (United States)
  4. Univ. of Wisconsin - Madison, Madison, WI (United States)
  5. Rice Univ., Houston, TX (United States); Jaypee Univ. of Information Technology, Pradesh (India)
Publication Date:
Grant/Contract Number:
Published Article
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Additional Journal Information:
Journal Volume: 55; Journal Issue: 36; Journal ID: ISSN 0006-2960
American Chemical Society (ACS)
Research Org:
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Org:
National Institutes of Health (NIH); USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23); Scripps Research Institute
Country of Publication:
United States
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Alternate Identifier(s):
OSTI ID: 1416000