STRUCTURE OF DEHYDROQUINATE SYNTHASE REVEALS AN ACTIVE-SITE CAPABLE OF MULTISTEP CATALYSIS

Dehydroquinate synthase (DHQS) has long been regarded as a catalytic m arvel because of its ability to perform several consecutive chemical r eactions in one active site(1-7). There has been considerable debate a s to whether DHQS is actively involved in all these steps(1,2), or whe ther several steps occur spontaneously, making DHQS a spectator in its own mechanism(3-5). DHQS performs the second step in the shikimate pa thway, which is required for the synthesis of aromatic compounds in ba cteria, microbial eukaryotes and plants(8). This enzyme is a potential target for new antifungal and antibacterial drugs(9,10) as the shikim ate pathway is absent from mammals and DHQS is required for pathogen v irulence(11). Here we report the crystal structure of DHQS, which has several unexpected features, including a previously unobserved mode fo r NAD(+)-binding and an active-site organization that is surprisingly similar to that of alcohol dehydrogenase, in a new protein fold, The s tructure reveals interactions between the active site and a substrate- analogue inhibitor, which indicate how DHQS can perform multistep cata lysis without the formation of unwanted by-products.