Gerald Lackner, Markus Bohnert, Jonas Wick, Dirk Hoffmeister

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Presentation transcript:

Assembly of Melleolide Antibiotics Involves a Polyketide Synthase with Cross-Coupling Activity Gerald Lackner, Markus Bohnert, Jonas Wick, Dirk Hoffmeister Chemistry & Biology Volume 20, Issue 9, Pages 1101-1106 (September 2013) DOI: 10.1016/j.chembiol.2013.07.009 Copyright © 2013 Elsevier Ltd Terms and Conditions

Chemistry & Biology 2013 20, 1101-1106DOI: (10. 1016/j. chembiol. 2013 Copyright © 2013 Elsevier Ltd Terms and Conditions

Figure 1 Structure of Melleolides and ArmB (A) Chemical structures of OA and selected melleolides. (B) Domain structure of ArmB and proposed biosynthetic steps of orsellinic acid. SAT, starter unit: ACP transacylase; MAT, malonyl-CoA: ACP transacylase; PT, product template domain; KS, ketosynthase; TE, thioesterase. Chemistry & Biology 2013 20, 1101-1106DOI: (10.1016/j.chembiol.2013.07.009) Copyright © 2013 Elsevier Ltd Terms and Conditions

Figure 2 In Vitro Activity of ArmB (A) Organic extracts of in vitro reactions analyzed by HPLC (λ = 254 nm). I, synthetic OA standard; II, PKS reaction; III, negative control (vector). (B) Relative yields of cross-coupling activity of ArmB with selected alcohols (20 mM). Error bars indicate the standard deviation (n = 3). (C) HPLC profiles and proposed structures of OA esters formed with cyclic alcohol substrates. This panel has been composed out of three chromatograms, which are provided as Supplemental Information (see Figure S1 for data on ArmB identification and Figure S3 and Table S1). Chemistry & Biology 2013 20, 1101-1106DOI: (10.1016/j.chembiol.2013.07.009) Copyright © 2013 Elsevier Ltd Terms and Conditions

Figure 3 Melleolide Formation by ArmB (A) In vitro cross coupling of orsellinyl-ACP with PHP yielded a product exhibiting identical UV absorption and mass fragmentation as melledonol. (B) Proposed scheme of melleolide assembly in vitro. (C) Selected OA esters found in fungi. See Figure S2 for in vivo data. Chemistry & Biology 2013 20, 1101-1106DOI: (10.1016/j.chembiol.2013.07.009) Copyright © 2013 Elsevier Ltd Terms and Conditions

Figure 4 Phylogenetic Network of Thioesterase Domains of Fungal NR PKSs Monocyclic PKSs include TE domains with hydrolase (violet) or transferase (i.e., lactonization) (blue) or cross-coupling (bold species names) activity. Polycyclic PKSs from ascomycetes feature a CLC domain and can be further subdivided (Vagstad et al., 2012). Basidiomycete enzymes (green) are monophyletic (except Ustilago PKS2) and have diverged into two major subclades (light and dark green). The asterisk denotes the function is not verified. The scale bar indicates the uncorrected pairwise distance. For accession numbers, see Table S2. Chemistry & Biology 2013 20, 1101-1106DOI: (10.1016/j.chembiol.2013.07.009) Copyright © 2013 Elsevier Ltd Terms and Conditions