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. 2020 Mar 19;180(6):1130-1143.e20.
doi: 10.1016/j.cell.2020.02.034. Epub 2020 Mar 10.

Discovery of a Regulatory Subunit of the Yeast Fatty Acid Synthase

Kashish Singh  1 , Benjamin Graf  1 , Andreas Linden  2 , Viktor Sautner  3 , Henning Urlaub  2 , Kai Tittmann  3 , Holger Stark  4 , Ashwin Chari  5
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Free article

Discovery of a Regulatory Subunit of the Yeast Fatty Acid Synthase

Kashish Singh et al. Cell. .
Free article

Abstract

Fatty acid synthases (FASs) are central to metabolism but are also of biotechnological interest for the production of fine chemicals and biofuels from renewable resources. During fatty acid synthesis, the growing fatty acid chain is thought to be shuttled by the dynamic acyl carrier protein domain to several enzyme active sites. Here, we report the discovery of a γ subunit of the 2.6 megadalton α6-β6S. cerevisiae FAS, which is shown by high-resolution structures to stabilize a rotated FAS conformation and rearrange ACP domains from equatorial to axial positions. The γ subunit spans the length of the FAS inner cavity, impeding reductase activities of FAS, regulating NADPH turnover by kinetic hysteresis at the ketoreductase, and suppressing off-pathway reactions at the enoylreductase. The γ subunit delineates the functional compartment within FAS. As a scaffold, it may be exploited to incorporate natural and designed enzymatic activities that are not present in natural FAS.

Keywords: FAS; FAS engineering; Tma17p; biotechnology; cryo-EM; energy landscape; enzyme kinetics; fatty acid synthase; inhibitor design; x-ray crystallography; γ subunit.

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Conflict of interest statement

Declaration of Interests A.C. and H.S. have filed a patent for the purification procedure described herein (EP16/17/3037, USSN 62/345,913). A.C., H.S., K.S., and B.G. have filed a patent for the exploitation of the γ subunit in a biotechnological and inhibitor development sense (EP19/16/3958).

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