Crystal structure of the erythromycin polyketide synthase dehydratase |
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Authors: | Keatinge-Clay Adrian |
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Institution: | Department of Biochemistry and Biophysics, University of California, San Francisco, 600 16th Street, San Francisco, CA 94158, USA |
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Abstract: | The dehydratases (DHs) of modular polyketide synthases (PKSs) catalyze dehydrations that occur frequently in the biosynthesis of complex polyketides, yet little is known about them structurally or mechanistically. Here, the structure of a DH domain, isolated from the fourth module of the erythromycin PKS, is presented at 1.85 Å resolution. As with the DH of the highly related animalian fatty acid synthase, the DH monomer possesses a double-hotdog fold. Two symmetry mates within the crystal lattice make a contact that likely represents the DH dimerization interface within an intact PKS. Conserved hydrophobic residues on the DH surface indicate potential interfaces with two other PKS domains, the ketoreductase and the acyl carrier protein. Mutation of an invariant arginine at the hypothesized acyl carrier protein docking site in the context of the erythromycin PKS resulted in decreased production of the erythromycin precursor 6-deoxyerythronolide B. The structure elucidates how the α-hydrogen and β-hydroxyl group of a polyketide substrate interact with the catalytic histidine and aspartic acid in the DH active site prior to dehydration. |
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Keywords: | ACP acyl carrier protein AT acyltransferase CoA coenzyme A DH dehydratase ER enoylreductase FAS fatty acid synthase KR ketoreductase KS ketosynthase PKS polyketide synthase TE thioesterase Asc ascomycin Rap rapamycin Rif rifamycin Tyl tylosin 6-dEB 6-deoxyerythronolide B LC/MS liquid chromatography/mass spectrometry TFA trifluoroacetic acid |
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