Enzyme inhibitor targets hidden site

Researchers at AstraZeneca facilities in Mölndal, Sweden, and Waltham, Mass., have characterized in several pathogenic bacteria a key enzyme-glutamate racemase-that is essential to the bacterial cell wall biosynthetic pathway (Nature 2007, 447, 817). The enzymes catalyze the conversion of L-glutamate to D-glutamate and are a target for antibiotic drug discovery. Led by Stewart L. Fisher in Waltham, the team found three distinct regulatory mechanisms within the enzyme family. They exploited these differences to identify an inhibitor (shown) that selectively targets the enzyme in Helicobacter pylori, the ulcer-causing bug. The inhibitor binds to a so-called cryptic, or hidden, allosteric binding site that exists only when the enzyme binds its glutamate substrate. Allosteric binding sites are ones where ligand binding changes the protein structure. The inhibitor locks the enzyme in a conformation that can't release the glutamate product. The authors state that this example of an uncompetitive inhibitor of a single-substrate enzyme is exceedingly rare.