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<p>Metazoan fatty acid (FA) synthases (mFASs) facilitate the de novo synthesis of C16- and C18-FAs through iterative extensions within the FA cycle and hydrolytic release. Here we re-engineer mFAS to fine-tune the interplay between FA extension and FA hydrolytic release for the targeted production of short- and medium-chain fatty acids. Single amino acid exchanges in the ketosynthase domain can redirect FA product profiles from predominantly C8 (G113W) to C8/C10 (G113F) and C12/C14 (G113M). Integration of a thioreductase domain enables the production of medium-chain fatty aldehydes and alcohols. We apply our approach for controlling chain length in FA biosynthesis to the microbial production of C10- and C12-FAs, translate it into a yeast cell factory and achieve C10/C12-FAs titers of 674 mg l<sup>−1</sup> and 67% purity of total free FAs. Our work demonstrates a modular platform for programmable FA synthesis and paves the way toward sustainable bioproduction of valuable oleochemicals.</p><p></p>

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Engineering metazoan fatty acid synthase to control chain length applied in yeast

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年1月7日

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  • Damian L. Ludig,
  • Xiaoxin Zhai,
  • Alexander Rittner,
  • Christian Gusenda,
  • Maximilian Heinz,
  • Svenja Berlage,
  • Ning Gao,
  • Adrian J. Jervis,
  • Yongjin J. Zhou,
  • Martin Grininger

摘要

Metazoan fatty acid (FA) synthases (mFASs) facilitate the de novo synthesis of C16- and C18-FAs through iterative extensions within the FA cycle and hydrolytic release. Here we re-engineer mFAS to fine-tune the interplay between FA extension and FA hydrolytic release for the targeted production of short- and medium-chain fatty acids. Single amino acid exchanges in the ketosynthase domain can redirect FA product profiles from predominantly C8 (G113W) to C8/C10 (G113F) and C12/C14 (G113M). Integration of a thioreductase domain enables the production of medium-chain fatty aldehydes and alcohols. We apply our approach for controlling chain length in FA biosynthesis to the microbial production of C10- and C12-FAs, translate it into a yeast cell factory and achieve C10/C12-FAs titers of 674 mg l−1 and 67% purity of total free FAs. Our work demonstrates a modular platform for programmable FA synthesis and paves the way toward sustainable bioproduction of valuable oleochemicals.