Journal Article

Structural dynamics of human fatty acid synthase in the condensing cycle

Cheng, Yifan, Choi, Wooyoung, Li, Chengmin, Chen, Yifei, Wang, YongQiang

2025

Overview

Long-chain fatty acids are the building blocks of fat in human bodies. In mammals, fatty acid synthase (FASN) contains multiple enzymatic domains to catalyse all chemical reactions needed for de novo fatty acid synthesis 1 . Although the chemical reactions carried out by these enzymatic domains are well defined, how the dimeric FASN with an open architecture continuously catalyses such reactions to synthesize a complete fatty acid remains elusive. Here, using a strategy of tagging and purifying endogenous FASN in HEK293T cells for single-particle cryo-electron microscopy studies, we characterized the structural dynamics of endogenous human FASN. We captured conformational snapshots of various functional substates in the condensing cycle and developed a procedure to analyse the particle distribution landscape of FASN with different orientations between its condensing and modifying wings. Together, our findings reveal that FASN function does not require a large rotational motion between its two main functional domains during the condensing cycle, and that the catalytic reactions in the condensing cycle carried out by the two monomers are unsynchronized. Our data thus provide a new composite view of FASN dynamics during the fatty acid synthesis condensing cycle. A study examines functional human endogenous fatty acid synthase and characterizes its structural dynamics using single-particle cryo-electron microscopy, providing insights into its dynamics during the fatty acid synthesis condensing cycle.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 101/28 / 631/45/607/1167 / 631/535/1258/1259 / Biocatalysis / Chemical reactions / Chemical synthesis / Cryoelectron Microscopy / Datasets / Electron microscopy / Enzymes / Fatty Acid Synthase, Type I - chemistry / Fatty Acid Synthase, Type I - genetics / Fatty Acid Synthase, Type I - metabolism / Fatty Acid Synthase, Type I - ultrastructure / Fatty Acid Synthases - chemistry / Fatty Acid Synthases - metabolism / Fatty Acid Synthases - ultrastructure / Fatty acids / Fatty Acids - biosynthesis / Fatty-acid synthase / HEK293 Cells / Humanities and Social Sciences / Humans / Microscopy / Models, Molecular / multidisciplinary / Open architectures / Protein Domains / Protein Multimerization / Proteins / Rotation / Science / Science (multidisciplinary)