Refined structures of beta-ketoacyl-acyl carrier protein synthase III

beta -Ketoacyl-acyl carrier protein synthase III (FabH) is a condensing enz yme that plays central roles in fatty acid biosynthesis. Three-dimensional structures of E. coli FabH in the presence and absence of ligands have been refined to 1.46 Angstrom resolution The structures of improved accuracy re vealed detailed interactions involved in ligand binding. These structures a lso provided new insights into the FabH mechanism, e.g. the possible role o f a water or hydroxyl anion in Cys112 deprotonation. A structure of the apo enzyme uncovered large conformational changes in the active site, exemplif ied by the disordering of four essential loops (84-86, 146-152, 185-217 and 305-307) and the movement of catalytic residues (Cys112 and His244). The d isordering of the loops leads to greater than 50 % reduction in the FabH di mer interface, suggesting a dynamic nature for an unusually large portion o f the dimer interface. The existence of a large solvent-accessible channel in the dimer interface as well as two cis-peptides (cis-Pro88 and cis-Phe30 8) in two of the disordered loops may explain the observed structural insta bilities. (C) 2001 Academic Press.