Structure and function of fatty acid synthases

by M Grininger

The mammalian FAS is a homodimeric complex composed of two multifunctional polypeptides of approximately 270 kDa each. It catalyzes, in a highly coordinated manner, a cascade of 16 substrate transfer reactions, 7 condensations, 21 processing steps of three different types, and a final hydrolysis step that releases the fatty acid product. This complex choreography is enabled by the acyl carrier protein (ACP), which covalently tethers intermediates via its phosphopantetheine prosthetic group and shuttles them between catalytic domains.

In contrast, the fungal FAS (fFAS) adopts a markedly different architectural principle. Instead of existing as a dimer of large, multifunctional polypeptides, the fungal system is organized as a barrel-shaped α₆β₆ complex, where the catalytic domains are distributed over two distinct polypeptides. Despite these structural differences, both systems perform the same fundamental sequence of reactions — a striking example of how evolution has developed different structural solutions for the same biochemical task.

The Grininger Lab has made significant contributions to the structural understanding of both fungal and mammalian fatty acid synthases. We determined the structure of the FAS from baker’s yeast inhibited by cerulenin (1) and analyzed its assembly pathway (2) as well as its post-translational phosphopantetheinylation (3). Key contributions were also achieved in collaboration with the Kühlbrandt Lab (6).

For mammalian FAS, we determined structures of the ketosynthase (KS) and malonyl/acetyltransferase (MAT) domains with bound substrates (4,5). These studies provide fundamental groundwork for our current efforts in chain-length engineering and FAS re-engineering.

1. Johansson, P. et al. Inhibition of the fungal fatty acid synthase type I multienzyme complex. Proc Natl Acad Sci U A 105, 12803–12808 (2008).
2. Fischer, M. et al. Analysis of the co-translational assembly of the fungal fatty acid synthase (FAS). Sci. Rep. 10, 895 (2020).
3. Johansson, P. et al. Multimeric options for the auto-activation of the Saccharomyces cerevisiae FAS type I megasynthase. Structure 17, 1063–1074 (2009).
4. Rittner, A., Paithankar, K. S., Huu, K. V. & Grininger, M. Characterization of the Polyspecific Transferase of Murine Type I Fatty Acid Synthase (FAS) and Implications for Polyketide Synthase (PKS) Engineering. ACS Chem. Biol. 13, 723–732 (2018).
5. Rittner, A., Paithankar, K. S., Himmler, A. & Grininger, M. Type I fatty acid synthase trapped in the octanoyl-bound state. Protein Sci 29, 589–605 (2020).
6. Gipson, P. et al. Direct structural insight into the substrate-shuttling mechanism of yeast fatty acid synthase by electron cryomicroscopy. Proc Natl Acad Sci U A 107, 9164–9169 (2010).