Crystal Structure of Thioesterase SgcE10 Supporting Common Polyene Intermediates in 9- and 10-Membered Enediyne Core Biosynthesis
- Scripps Research Inst., Jupiter, FL (United States). Dept. of Chemistry
- Argonne National Lab. (ANL), Argonne, IL (United States). Midwest Center for Structural Genomics, Structural Biology Center, Biosciences Division
- Argonne National Lab. (ANL), Argonne, IL (United States). Midwest Center for Structural Genomics
- Rice Univ., Houston, TX (United States). BioSciences at Rice, Dept. of Chemistry
- Scripps Research Inst., Jupiter, FL (United States). Dept. of Chemistry, Dept. of Molecular Medicine, Natural Products Library Initiative
Enediynes are potent natural product anticancer antibiotics, and are classified as 9- or 10-membered according to the size of their enediyne core carbon skeleton. Both 9- and 10-membered enediyne cores are biosynthesized by the enediyne polyketide synthase (PKSE), thioesterase (TE), and PKSE-associated enzymes. Though the divergence between 9- and 10-membered enediyne core biosynthesis remains unclear, it has been observed that nascent polyketide intermediates, tethered to the acyl carrier protein (ACP) domain of PKSE, could be released by TE in the absence of the PKSE-associated enzymes. Here, we determined the crystal structure of SgcE10, the TE that participates in the biosynthesis of the 9-membered enediyne C-1027. Structural comparison of SgcE10 with CalE7 and DynE7, two TEs that participate in the biosynthesis of the 10-membered enediynes calicheamicin and dynemicin, respectively, revealed that they share a common α/β hot-dog fold. The amino acids involved in both substrate binding and catalysis are conserved among SgcE10, CalE7, and DynE7. The volume and the shape of the substrate-binding channel and active site in SgcE10, CalE7, and DynE7 confirm that TEs from both 9- and 10-membered enediyne biosynthetic machineries bind the linear form of similar ACP-tethered polyene intermediates. Taken together, our findings further support the proposal that the divergence between 9- and 10-membered enediyne core biosynthesis occurs beyond PKSE and TE catalysis.
- Research Organization:
- Argonne National Laboratory (ANL), Argonne, IL (United States)
- Sponsoring Organization:
- USDOE Office of Science (SC), Biological and Environmental Research (BER); National Institutes of Health (NIH); Arnold and Mabel Beckman Foundation; Scripps Research Institute
- Grant/Contract Number:
- AC02-06CH11357; AC02-06CH113; GM098248; CA078747; GM115575
- OSTI ID:
- 1393895
- Journal Information:
- ACS Omega, Vol. 2, Issue 8; ISSN 2470-1343
- Publisher:
- American Chemical Society (ACS)Copyright Statement
- Country of Publication:
- United States
- Language:
- English
Web of Science
Acyltransferases as Tools for Polyketide Synthase Engineering
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journal | July 2018 |
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