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Insights into the function of trans-acyl transferase polyketide synthases from the SAXS structure of a complete module

Abstract : The modular polyketide synthases (PKS) are gigantic multienzymes which synthesize diverse secondary metabolites of therapeutic value. Although structural information is increasingly available for the `cis-AT' class of modular PKS, almost nothing is known about the evolutionarily divergent `trans-AT' PKS, which characteristically incorporate an iteratively-acting acyl transferase. We report here the SAXS solution structure of a complete apo module from the virginiamycin trans-AT PKS, which is fundamentally different to structural models proposed for the cis-AT PKS based on the crystal structure of animal fatty acid synthase. The module, which serves as a platform for the beta-modification of the polyketide intermediate, consists of a ketosynthase (KS) and two acyl carrier protein (ACP) domains. In our solved structure, the homodimeric KS, which is flanked by well-folded linker regions, occupies the center of the module. While the first ACP is located close to the KS, the second is situated at the end of a flexible linker, and mobile. Taken together, these data provide a physical explanation for the functional non-equivalence previously observed for certain tandem ACPs of trans-AT PKS. Furthermore, the overall open shape of the module renders the second ACP highly accessible, which may be critical for its interaction with multiple in trans catalytic partners. Finally, our analysis redefines the function of a putative dimerization motif of tandem ACPs as a docking domain, suggesting that the module likely adopts a more closed form in order to affect transfer of the chain extension intermediate to the subsequent module.
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Submitted on : Thursday, February 2, 2017 - 4:12:47 PM
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Jack Davison, Jonathan Dorival, Hery Rabeharindranto, Hortense Mazon, Benjamin Chagot, et al.. Insights into the function of trans-acyl transferase polyketide synthases from the SAXS structure of a complete module. Chemical Science , 2014, 5 (8), pp.3081-3095. ⟨10.1039/c3sc53511h⟩. ⟨hal-01453210⟩



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