title: The dynamic determinants of reaction specificity in the IMPDH/GMPR family of (β/α)(8) barrel enzymes.
abstract: The inosine monophosphate dehydrogenase (IMPDH)/guanosine monophosphate reductase (GMPR) family of (β/α)(8) enzymes presents an excellent opportunity to investigate how subtle changes in enzyme structure change reaction specificity. IMPDH and GMPR bind the same ligands with similar affinities and share a common set of catalytic residues. Both enzymes catalyze a hydride transfer reaction involving a nicotinamide cofactor hydride, and both reactions proceed via the same covalent intermediate. In the case of IMPDH, this intermediate reacts with water, while in GMPR it reacts with ammonia. In both cases, the two chemical transformations are separated by a conformational change. In IMPDH, the conformational change involves a mobile protein flap while in GMPR, the cofactor moves. Thus reaction specificity is controlled by differences in dynamics, which in turn are controlled by residues outside the active site. These findings have some intriguing implications for the evolution of the IMPDH/GMPR family.
authors.affiliation: Departments of Biology and Chemistry, Brandeis University, Waltham, MA 02454, USA. hedstrom@brandeis.edu
authors.forename: Lizbeth
authors.initials: L
authors.lastname: Hedstrom
mesh_terms: D000641:Ammonia / Q000737:chemistry; D020134:Catalytic Domain; D002414:Cations, Monovalent / Q000737:chemistry; D050899:GMP Reductase / Q000737:chemistry*; D006157:Guanosine Monophosphate / Q000737:chemistry*; D006801:Humans; D007168:IMP Dehydrogenase / Q000737:chemistry*; D007700:Kinetics; D008024:Ligands; D011485:Protein Binding; D017510:Protein Folding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D013379:Substrate Specificity; D014867:Water / Q000737:chemistry
chemical_list: D002414:Cations, Monovalent; D008024:Ligands; D014867:Water; D000641:Ammonia; D006157:Guanosine Monophosphate; D007168:IMP Dehydrogenase; C501687:IMPDH2 protein, human; D050899:GMP Reductase; C469406:GMPR2 protein, human