page_title: Tylactone synthase
section_title: Engineering applications
hierarchical_section_title: Tylactone synthase / Engineering applications
caption_attribution_description: English: Loading Module loop highlighted that facilitates intermodular interaction.
context_page_description: Tylactone synthase or TYLS is a Type 1 polyketide synthase. TYLS is found in strains of Streptomyces fradiae and responsible for the synthesis of the macrolide ring, tylactone, the precursor of an antibiotic, tylosin. TYLS is composed of five large multi-functional proteins, TylGI-V. Each protein contains either one or two modules. Each module consists of a minimum of a Ketosynthase, an Acyltransferase, and an Acyl carrier protein but may also contain a Ketoreductase, Dehydrotase, and Enoyl Reductase for additional reduction reactions. The domains of TYLS have similar activity domains to those found in other Type I polyketide synthase such as 6-Deoxyerythronolide B synthase. The TYLS system also contains a loading module consisting of a ketosynthase‐like decarboxylase domain, an acyltransferase, and acyl carrier protein. The terminal Thioesterase terminates tylactone synthesis by cyclizing the macrolide ring. After the TYLS completes tylactone synthesis, the tylactone molecule is modified by oxidation at C-20 and C-23 and glycosylation of mycaminose, mycinose, and mycarose to produce tylosin.
context_section_description: Because polyketide synthases catalyze stereospecific reactions, there is interest in engineering new molecules via PKS engineering. Efforts to engineer a hybrid PKS have met with some success. A team from Lilly Research Laboratories designed a hybrid tylactone/platenolide synthase that was able to accept the propionate substrate from the TYLS loading module instead of acetate, the natural precursor in the platenolide synthase system. This led to the production of a novel hybrid macrolactone. Other efforts have engineered systems by expressing a chalcomycin synthase genes along with the TYLS system. This points to the potential of coexpressing homologous PKS systems for the production of new products, however the high specificity of protein-protein interactions limits chimeric PKS engineering.
  Biosynthesis reactions that interchange the KR domain from TYLS with the KR domain from DEBS lead to products with different stereochemistry. Other studies have elucidated the stereospecificity of the DEBS DH domain by co-incubating the DEBS DH domain with the TYLS KR from module 1 and comparing the product to that produced by the DEBS system.
caption: TYLS KR1 with Loading Module loop indicated. The loop facilitates intermodular interaction.[18]
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