Crystal Structure of Thioesterase SgcE10 Supporting Common Polyene Intermediates in 9- and 10-Membered Enediyne Core Biosynthesis
journal contributionposted on 2017-08-30, 12:03 authored by Thibault Annaval, Jeffrey D. Rudolf, Chin-Yuan Chang, Jeremy R. Lohman, Youngchang Kim, Lance Bigelow, Robert Jedrzejczak, Gyorgy Babnigg, Andrzej Joachimiak, George N. Phillips, Ben Shen
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. Although 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. In this study, 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, these findings further support the proposal that the divergence between 9- and 10-membered enediyne core biosynthesis occurs beyond PKSE and TE catalysis.
10- Membered Enediyne Core Biosynthesis Enediynesenediyne core carbon skeletonPKSE-associated enzymes10- membered enediyne core biosynthesisDynE10- membered enediyne coresproduct anticancer antibioticsCommon Polyene IntermediatesThioesterase SgcE 10enediyne polyketide synthaseACP-tethered polyene intermediates9- membered enediyne C -1027. Structural comparisonTECalE10- membered enediyne biosynthetic machineries bind10- membered enediynes calicheamicinacyl carrier protein