Ancient Mechanism Aids Modern Enzyme

The enzyme inosine monophosphate dehydrogenase (IMPDH) catalyzes a critical two-part sequence in the synthesis of guanine nucleotides in prokaryotes and eukaryotes. First it dehydrogenates IMP to form an intermediate that is bound to a protein cysteine (Cys) residue, then the enzyme hydrolyzes the intermediate to form xanthosine monophosphate (XMP, reaction shown, R = ribose 5′-monophosphate). Now, a group led by Lizbeth Hedstrom of Brandeis University and Wei Yang of Florida State University has used a combination of computational simulations and experiments to study IMPDH's hydrolase activity and found that the enzyme likely works by transferring a proton from water to a neutral arginine residue (PLoS Biol., DOI: 10.1371/journal.pbio.0060206). When the arginine is protonated, however, the group found that the most likely mechanism involves a proton relay in which a threonine residue abstracts the proton from water while transferring its own proton to a nearby glutamate residue. The fact that the threonine and glutamate residues are conserved in a related enzyme, guanosine monophosphate reductase, led the group to propose that the threonine pathway was used in an ancestral enzyme and has been preserved in prokaryotes to satisfy nucleotide demand during proliferation.