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Mycocerosic acid synthase exemplifies the architecture of reducing polyketide synthases

Herbst, Dominik A. and Jakob, Roman P. and Zähringer, Franziska and Maier, Timm. (2016) Mycocerosic acid synthase exemplifies the architecture of reducing polyketide synthases. Nature, 531 (7595). pp. 533-537.

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Official URL: http://edoc.unibas.ch/42230/

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Abstract

Polyketide synthases (PKSs) are biosynthetic factories that produce natural products with important biological and pharmacological activities1, 2, 3. Their exceptional product diversity is encoded in a modular architecture. Modular PKSs (modPKSs) catalyse reactions colinear to the order of modules in an assembly line3, whereas iterative PKSs (iPKSs) use a single module iteratively as exemplified by fungal iPKSs (fiPKSs)3. However, in some cases non-colinear iterative action is also observed for modPKSs modules and is controlled by the assembly line environment4, 5. PKSs feature a structural and functional separation into a condensing and a modifying region as observed for fatty acid synthases6. Despite the outstanding relevance of PKSs, the detailed organization of PKSs with complete fully reducing modifying regions remains elusive. Here we report a hybrid crystal structure of Mycobacterium smegmatis mycocerosic acid synthase based on structures of its condensing and modifying regions. Mycocerosic acid synthase is a fully reducing iPKS, closely related to modPKSs, and the prototype of mycobacterial mycocerosic acid synthase-like7, 8 PKSs. It is involved in the biosynthesis of C20–C28 branched-chain fatty acids, which are important virulence factors of mycobacteria9. Our structural data reveal a dimeric linker-based organization of the modifying region and visualize dynamics and conformational coupling in PKSs. On the basis of comparative small-angle X-ray scattering, the observed modifying region architecture may be common also in modPKSs. The linker-based organization provides a rationale for the characteristic variability of PKS modules as a main contributor to product diversity. The comprehensive architectural model enables functional dissection and re-engineering of PKSs.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Structural Biology & Biophysics > Structural Biology (Maier)
UniBasel Contributors:Maier, Timm and Herbst, Dominik Alexander and Jakob, Roman Peter and Zähringer, Franziska Ursula
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Macmillan
ISSN:0028-0836
Note:Publication type according to Uni Basel Research Database: Journal article
Language:English
Identification Number:
Last Modified:10 Aug 2018 11:51
Deposited On:22 Nov 2016 07:30

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