Mechanism of Thioesterase-Catalyzed Chain Release in the Biosynthesis of the Polyether Antibiotic Nanchangmycin Tiangang Liu, Xin Lin, Xiufen Zhou, Zixin.

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Presentation transcript:

Mechanism of Thioesterase-Catalyzed Chain Release in the Biosynthesis of the Polyether Antibiotic Nanchangmycin Tiangang Liu, Xin Lin, Xiufen Zhou, Zixin Deng, David E. Cane Chemistry & Biology Volume 15, Issue 5, Pages 449-458 (May 2008) DOI: 10.1016/j.chembiol.2008.04.006 Copyright © 2008 Elsevier Ltd Terms and Conditions

Figure 1 Polyether Ionophores Nanchangmycin, 1, Monensin A, 2, and Salinomycin, 3 Chemistry & Biology 2008 15, 449-458DOI: (10.1016/j.chembiol.2008.04.006) Copyright © 2008 Elsevier Ltd Terms and Conditions

Figure 2 Proposed Pathway of Nanchangmycin Biosynthesis in S. nanchangensis NS3226 The parent polyketide is first assembled from a malonyl-CoA primer plus four malonyl-CoA and 10 methylmalonyl-CoA extension units, mediated by the 14 modules of the modular PKS NanA1-NanA10. The initially generated unsaturated pentadecaketide acyl-ACP ester is then thought to undergo NanO-catalyzed epoxidation, followed by a cascade of epoxide ring openings and acetalizations, catalyzed by NanI to generate the pentacylic ether. Oxidation of the terminal methyl group by the P450 NanP generates the ACP-bound nanchangmycin aglycone, which is glycosylated at the C-19 hydroxyl under the control of NanG5, before final hydrolytic release by the NanE TE. Chemistry & Biology 2008 15, 449-458DOI: (10.1016/j.chembiol.2008.04.006) Copyright © 2008 Elsevier Ltd Terms and Conditions

Figure 3 Hydrolysis of Polyether and Polyketide-SNAC Substrates by the NanE TE N.R. indicates no reaction. Chemistry & Biology 2008 15, 449-458DOI: (10.1016/j.chembiol.2008.04.006) Copyright © 2008 Elsevier Ltd Terms and Conditions

Figure 4 Sequence Comparison of the Type II TEs Encoded by the Nanchangmycin, Monensin, and Nigericin Biosynthetic Gene Clusters The asterisk indicates the Ser/His/Asp catalytic triad, the solid line designates the conserved GXSXG motif surrounding the active site Ser, and the black dot marks the conserved Trp residue in this motif that corresponds to an Ala in the type I TEs of polyketide biosynthesis. MonCII = monensin; NanE = nanchangmycin; NigCII = nigericin. Chemistry & Biology 2008 15, 449-458DOI: (10.1016/j.chembiol.2008.04.006) Copyright © 2008 Elsevier Ltd Terms and Conditions

Figure 5 Deletion of the nanG5 Glycosyl Transferase Gene of S. nanchangensis NS3226 Abolishes Nanchangmycin Production and Leads to Accumulation of the Nanchangmycin Aglycone, 6, in the Deletion Mutant S. nanchangensis LTΔnanG5 (A) Replacement of nanG5 by the apramycin resistance gene cassette aac(3)IV by PCR-directed mutagenesis and homologous recombination to generate S. nanchangensis LTΔnanG5. (B) The genomic DNA in the LTΔnanG5-19 mutant was checked by PCR amplification with primers NanG5-check-1 and NanG5-check-2. In the wild-type, the PCR product is 1,588 bp, while in the mutant the PCR product it is 1,671 bp. Digestion of each fragment with SacI (S) and PvuII (P) gave fragments of different sizes. (C) LC-ESI-MS of nanchangmycin aglycone (6), retention time of 2.89 min isolated from S. nanchangensis LTΔnanG5-4. Chemistry & Biology 2008 15, 449-458DOI: (10.1016/j.chembiol.2008.04.006) Copyright © 2008 Elsevier Ltd Terms and Conditions