Abstract
Acyl carrier proteins (ACPs) are highly conserved protein domains involved in the synthesis of polyketides, natural products essential to pharmaceutical drug development. ACPs are part of a multicomponent modular system known as polyketide synthases (PKSs). Understanding these systems permits the manipulation of PKSs to produce “unnatural” natural compounds essential for combating health issues. ACPs interact with PKS domains through a flexible 4′phosphopantetheine (4′-Ppant) prosthetic arm that undergoes important and fast conformational changes difficult to track with NMR and X-ray crystallography. We installed a thiocyanate (-SCN) probe on the terminal thiol of a 4′ Ppant arm to observe these conformations on a picosecond time scale. The method enables the identification of factors affecting 4′ Ppant arm movement. We observed the effects on 6-deoxyerythronolide B synthase (DEBS) and fatty acid synthase (FAS) ACP conformation when titrated with their respective catalytic ketosynthase (KS) partners. Vibrational spectroscopy reveals that dynamic protein-protein interactions as well as substrate chain length perturb the conformation and location of the 4′ Ppant arm.
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