Molecular mechanisms of the mammalian fatty acid cycle

Mammalian fatty acid synthase (mFAS) supplies cells with saturated fatty acids for energy storage, membrane formation, and protein modifications. Structural studies over the past two decades have identified conformational variability as a hallmark feature of the multidomain mFAS, but how does this structural flexibility influence fatty acid synthesis? Cryo-electron microscopy (cryo-EM) snapshots of human FAS (hFAS) and a homologous polyketide synthase (PKS) reveal that efficiency is governed less by large-scale flexibility and more by the precise docking choreography of the acyl carrier protein (ACP). Three principles appear to influence the propagation of the fatty acid cycle: inherent conformational variability, scaffolding that steers ACP towards productive interactions, and ACP:domain interface complementarity.