Regulation of the fungal fatty acid synthase through conformational selection.

Abstract

The fungal type 1 fatty acid synthase (FAS1) is a paradigm for multifunctional metabolic enzymes. The α6β6 heterododecamer is composed of six catalytic units, arranged in a barrel shaped hollow body. Each catalytic unit contains a copy of the six enzymatic domains required for de novo fatty acid synthesis and an integral acyl carrier protein (ACP), responsible for the transfer of reaction intermediates. It is assumed that stochastic diffusion of ACP drives fatty acid synthesis, whereas spatial organization of enzymatic domains facilitates productive encounter. In this model, the supramolecular structure of FAS1 acts as a rigid framework. However, it has recently been discovered that binding of a regulatory subunit causes substantial structural rearrangements of FAS1, concomitant with relocation of ACP. It is therefore conceivable that the catalytic activity is coupled to both the conformational dynamics of the FAS1 complex and the stochastic dynamics of the ACP. Here we use large-scale molecular dynamics simulations to contrast the conformational dynamics of the yeast FAS1 with and without regulatory subunit. We find that FAS1 can sample distinct conformations at the microsecond timescale. Binding of the regulatory regulatory subunit rigidifies the complex and attenuates the conformational dynamics. At the same time, the regulatory subunit stabilizes binding of ACP to the acetyltransferase domain. Overall, our results show, that the FAS1 is not a rigid framework, but cycles between distinct conformations. The conformational dynamics described here are akin the conformational cycling of the metazoan FAS1 that is correlated with distinct enzymatic activities. Further evidence is required to show if this correlation is also a general property of the fungal FAS1. However, binding of the regulatory subunit indeed suggests that subtle changes in conformational dynamics correlate with changes in enzymatic activity.