Skipping in a Hybrid Polyketide Synthase

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Presentation transcript:

Skipping in a Hybrid Polyketide Synthase Iain Thomas, Christine J Martin, Christopher J Wilkinson, James Staunton, Peter F Leadlay Chemistry & Biology Volume 9, Issue 7, Pages 781-787 (July 2002) DOI: 10.1016/S1074-5521(02)00164-3

Figure 1 The Lactone Products Produced by the Truncated Model PKS DEBS1-TE and by the Tetraketide Synthase LM-Ery1-Rap2-Ery2-TE (A) The lactone products produced by the truncated model PKS DEBS1-TE. (B) Those products produced by the tetraketide synthase LM-Ery1-Rap2-Ery2-TE. Abbreviations are as follows: LM, loading module; KS, ketosynthase; AT, acyltransferase; KR, ketoreductase; ACP, acylcarrier protein; and TE, thioesterase/cyclase. Chemistry & Biology 2002 9, 781-787DOI: (10.1016/S1074-5521(02)00164-3)

Figure 2 Alternative Proposed Mechanisms for Skipping of an Interpolated Module in a Hybrid Polyketide Synthase In mechanism 1, the polyketide chain is passed between modules Ery1 and Ery2 via the KS and ACP active sites of the inserted Rap2 module; in mechanism 2, the chain is passed via the Rap2 ACP active site only; in mechanism 3, the chain is passed via the Rap2 KS active site only; and in mechanism 4, the chain is passed between modules Ery1 and Ery2 without any involvement of the Rap2 KS and ACP active sites (perhaps via a carrier molecule). The inserted Rap2 module is shown in red. Chemistry & Biology 2002 9, 781-787DOI: (10.1016/S1074-5521(02)00164-3)

Figure 3 The Lactone Products Produced by Mutagenized Versions of the Tetraketide Synthase LM-Ery1-Rap2-Ery2-TE A cross indicates the replacement of a single essential active site residue within a Rap2 domain. Chemistry & Biology 2002 9, 781-787DOI: (10.1016/S1074-5521(02)00164-3)

Figure 4 A Model for ACP(Ery1)-to-ACP(Rap2) Transfer Mediated by the Intervening KS(Rap2) Domain The polyketide acyl chain (represented by R-CH2-CO-) can be transferred to the 4′-phosphopantetheine “swinging arm” ACP(Rap2) within the KS(Rap2) site, even when the active site cysteine residue is replaced by alanine. Chemistry & Biology 2002 9, 781-787DOI: (10.1016/S1074-5521(02)00164-3)