Inosine monophosphate dehydrogenase (IMPDH) catalyzes the oxidation of inosine monophosphate (IMP) to xanthosine monophosphate (XMP) with the concomitant reduction of NAD+. This reaction controls the entry of purines into the guanine nucleotide pool, making IMPDH a billion-dollar target for immunosuppressive, antiviral and anticancer drugs. The IMPDH reaction involves two different chemical transformations: hydride transfer and hydrolysis of a covalent intermediate, and thus provides unique opportunity to investigate how proteins efficiently change conformations to accommodate multiple substrate binding events, transition states and product release steps. This enzyme displays several remarkable mechanistic features, including a large conformational change in mid-catalytic stream, an Arg residue that acts as a general base catalyst and a K+ that acts as a molecular lubricant. Lastly, IMPDH contains two CBS domains of unknown function (named for the related domains in cystathionine (3 synthase). Mutations in the CBS domains of IMPDH1 cause autosomal dominant retinitis pigmentosa, an inherited blindness, yet have no effect on the enzymatic activity of IMPDH. Thus IMPDH must have another cellular function. We propose to address the following questions:
Aim 1. How is water activated? Aim 2. How does IMPDH remodel to accommodate different transition states? Aim 3. What is the mechanism of K+ activation? Aim 4. What is the function of the CBS domains? This work will provide important new insights into IMPDH function that will be invaluable in the design of new cancer, viral and immunosuppressive therapy. Elucidation of the function of the CBS domains is critical for the development of chemotherapy of retinitis pigmentosa and other inherited diseases involving CBS domains.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Special Emphasis Panel (ZRG1-BCMB-B (02))
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Anderson, Vernon
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Brandeis University
Schools of Arts and Sciences
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Wei, Yang; Kuzmi?, Petr; Yu, Runhan et al. (2016) Inhibition of Inosine-5'-monophosphate Dehydrogenase from Bacillus anthracis: Mechanism Revealed by Pre-Steady-State Kinetics. Biochemistry 55:5279-88
Wu, D; Fajer, M I; Cao, L et al. (2016) Generalized Ensemble Sampling of Enzyme Reaction Free Energy Pathways. Methods Enzymol 577:57-74
Rosenberg, Masha M; Redfield, Alfred G; Roberts, Mary F et al. (2016) Substrate and Cofactor Dynamics on Guanosine Monophosphate Reductase Probed by High Resolution Field Cycling 31P NMR Relaxometry. J Biol Chem 291:22988-22998
Cao, Liaoran; Lv, Chao; Yang, Wei (2013) Hidden Conformation Events in DNA Base Extrusions: A Generalized Ensemble Path Optimization and Equilibrium Simulation Study. J Chem Theory Comput 9:
Long, Marcus J C; Hedstrom, Lizbeth (2012) Mushroom tyrosinase oxidizes tyrosine-rich sequences to allow selective protein functionalization. Chembiochem 13:1818-25
Hansen, Bjarne G; Sun, Xin E; Genee, Hans J et al. (2012) Adaptive evolution of drug targets in producer and non-producer organisms. Biochem J 441:219-26
Hedstrom, Lizbeth (2012) The dynamic determinants of reaction specificity in the IMPDH/GMPR family of (*/*)(8) barrel enzymes. Crit Rev Biochem Mol Biol 47:250-63
Long, Marcus J C; Gollapalli, Deviprasad R; Hedstrom, Lizbeth (2012) Inhibitor mediated protein degradation. Chem Biol 19:629-37
MacPherson, Iain S; Temme, J Sebastian; Habeshian, Sevan et al. (2011) Multivalent glycocluster design through directed evolution. Angew Chem Int Ed Engl 50:11238-42
Riera, Thomas V; Zheng, Lianqing; Josephine, Helen R et al. (2011) Allosteric activation via kinetic control: potassium accelerates a conformational change in IMP dehydrogenase. Biochemistry 50:8508-18

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