Research Topics
| LIZBETH K HEDSTROMSummaryAffiliation: Brandeis University Country: USA Publications
Research Grants
| Collaborators
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Detail Information
Publications
The dynamic determinants of reaction specificity in the IMPDH/GMPR family of (β/α)(8) barrel enzymesLizbeth Hedstrom
Departments of Biology and Chemistry, Brandeis University, Waltham, MA 02454, USA
Crit Rev Biochem Mol Biol 47:250-63. 2012..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...
Serine protease mechanism and specificityLizbeth Hedstrom
Department of Biochemistry, MS 009, Brandeis University, Waltham, Massachusetts 02454, USA
Chem Rev 102:4501-24. 2002- The antibiotic potential of prokaryotic IMP dehydrogenase inhibitorsL Hedstrom
Brandeis University, Departments of Biology, Waltham, MA 02454 9110, USA
Curr Med Chem 18:1909-18. 2011..A second generation inhibitor displays antibacterial activity against Helicobacter pylori, demonstrating the antibiotic potential of IMPDH inhibitors... 
IMP dehydrogenase-linked retinitis pigmentosaLizbeth Hedstrom
Department of Chemistry, Brandeis University, Waltham, Massachusetts, USA
Nucleosides Nucleotides Nucleic Acids 27:839-49. 2008..These observations suggest that IMPDH1 has a previously unappreciated role in RNA metabolism that is crucial for photoreceptor function...- IMP dehydrogenase: structural schizophrenia and an unusual baseLizbeth Hedstrom
Department of Biochemistry, Brandeis University, Waltham, MA 02454, USA
Curr Opin Chem Biol 10:520-5. 2006..How the balance between conformational states is maintained and how the various conformational states interconvert is only beginning to be understood... - The immunosuppressive agent mizoribine monophosphate forms a transition state analogue complex with inosine monophosphate dehydrogenaseLu Gan
Department of Biochemistry and Chemistry and the Rosenstiel Basic Medical Sciences Research Center, Brandeis University, Waltham, Massachusetts 02454, USA
Biochemistry 42:857-63. 2003..The closed conformation provides a structural explanation for the differences in drug selectivity and catalytic efficiency of IMPDH isozymes... - A twisted base? The role of arginine in enzyme-catalyzed proton abstractionsYollete V Guillen Schlippe
Department of Biochemistry, Brandeis University, Waltham, MA 02454, USA
Arch Biochem Biophys 433:266-78. 2005..The chemistry of the guanidine group suggests unique strategies to lower the pK(a) of Arg. Lastly, the presumption that general bases must be predominantly deprotonated is revisited... - Short-lived protease serpin complexes: partial disruption of the rat trypsin active siteLu Liu
Department of Chemistry, Graduate Program in Biochemistry, Brandeis University, Waltham, MA 02454, USA
Protein Sci 16:2403-11. 2007..These results also demonstrate that interactions between target proteases and the body of the serpin can hinder protease translocation leading to short-lived covalent complexes... - Substitution of the conserved Arg-Tyr dyad selectively disrupts the hydrolysis phase of the IMP dehydrogenase reactionYollete V Guillen Schlippe
Department of Biochemistry, Brandeis University, Waltham, Massachusetts 02454, USA
Biochemistry 43:4511-21. 2004..Moreover, since the effects of the Tyr419Phe mutation are comparatively small, these experiments suggest that Arg418 acts as the base to activate water... - Inosine 5'-monophosphate dehydrogenase binds nucleic acids in vitro and in vivoJeremy E McLean
Program in Biophysics and Structural Biology, Brandeis University, MS 009, 415 South St, Waltham, MA 02454, USA
Biochem J 379:243-51. 2004..These experiments indicate that IMPDH has a previously unappreciated role in replication, transcription or translation that is mediated by the subdomain... - Crystal structure of a ternary complex of Tritrichomonas foetus inosine 5'-monophosphate dehydrogenase: NAD+ orients the active site loop for catalysisLu Gan
Department of Biochemistry, Brandeis University, Waltham, Massachusetts 02454, USA
Biochemistry 41:13309-17. 2002..This site is adjacent to beta-Me-TAD, consistent with the link between the K(+) activation and NAD(+). However, contrary to the coupling model, the flap does not cover the adenosine subsite and remains largely disordered... - An overview of serine proteasesLizbeth Hedstrom
Brandeis University, Waltham, Massachusetts, USA
Curr Protoc Protein Sci . 2002..This unit summarizes the families of serine proteases and their mechanism of catalysis. Methods for assays and determining substrate specificity are briefly described. The mode of action of commonly available inhibitors is also included... - Is Arg418 the catalytic base required for the hydrolysis step of the IMP dehydrogenase reaction?Yollete V Guillen Schlippe
Department of Biochemistry, Brandeis University, Waltham, Massachusetts 02454, USA
Biochemistry 44:11700-7. 2005..The simplest explanation for these observations is that Arg418 serves as the base that activates water in the IMPDH reaction... - Autosomal dominant retinitis pigmentosa mutations in inosine 5'-monophosphate dehydrogenase type I disrupt nucleic acid bindingSarah E Mortimer
Department of Biochemistry, Brandeis University, 415 South St, Waltham, MA 02454-9110, USA
Biochem J 390:41-7. 2005..These observations suggest that nucleic acid binding provides a functional assay for adRP pathogenicity. The putative adRP-linked mutation V268I also disrupts nucleic acid binding, which suggests that this mutation is indeed pathogenic... - Targeting a prokaryotic protein in a eukaryotic pathogen: identification of lead compounds against cryptosporidiosisNwakaso N Umejiego
Department of Biochemistry, Brandeis University, 415 South Street, Waltham, MA 02454, USA
Chem Biol 15:70-7. 2008..We have identified four parasite-selective IMPDH inhibitors that display antiparasitic activity with greater potency than paromomycin, the current gold standard for anticryptosporidial activity... - Conformational distributions of protease-serpin complexes: a partially translocated complexLu Liu
Department of Chemistry, Brandeis University, 415 South Street, Waltham, Massachusetts 02454, USA
Biochemistry 45:10865-72. 2006..These results highlight the role of protease stability in determining the conformational distributions of protease-serpin covalent complexes and show that full translocation is not required for the formation of metastable complexes... - A kinetic alignment of orthologous inosine-5'-monophosphate dehydrogenasesThomas V Riera
Departments of Biochemistry and Chemistry, Brandeis University, Waltham, Massachusetts 02454, USA
Biochemistry 47:8689-96. 2008..This observation suggests that the closure of the flap simply sets the stage for catalysis rather than plays a more active role in the chemical transformation. This work provides the essential mechanistic framework for drug discovery... - The structural basis of Cryptosporidium -specific IMP dehydrogenase inhibitor selectivityIain S MacPherson
Departments of Biology, Brandeis University, MS009, 415 South Street, Waltham, Massachusetts 02454, USA
J Am Chem Soc 132:1230-1. 2010..Using this information, we have synthesized low-nanomolar inhibitors that display 10(3) selectivity for the parasite enzyme over human IMPDH2... - Triazole inhibitors of Cryptosporidium parvum inosine 5'-monophosphate dehydrogenaseSushil K Maurya
Department of Biology, Brandeis University, MS009, 415 South Street, Waltham, Massachusetts 02454, USA
J Med Chem 52:4623-30. 2009..The 1,2,3-triazole CpIMPDH inhibitors provide new tools for elucidating the role of IMPDH in C. parvum and may serve as potential therapeutics for treating cryptosporidiosis... - IMP dehydrogenase type 1 associates with polyribosomes translating rhodopsin mRNASarah E Mortimer
Department of Biochemistry, Brandeis University, Waltham, Massachusetts 02454 9110, USA
J Biol Chem 283:36354-60. 2008..We propose that IMPDH coordinates the translation of a set of mRNAs, perhaps by modulating localization or degradation... - Retinal isoforms of inosine 5'-monophosphate dehydrogenase type 1 are poor nucleic acid binding proteinsDong Xu
Department of Biochemistry, Brandeis University, 415 South Street, MS 009, Waltham, MA 02454, USA
Arch Biochem Biophys 472:100-4. 2008..This observation indicates that the C-terminal extension unique to the retinal isoforms blocks the nucleic acid binding site of IMPDH1, and thus uniquely regulates protein function within photoreceptors... - Guanidine derivatives rescue the Arg418Ala mutation of Tritrichomonas foetus IMP dehydrogenaseYollete V Guillen Schlippe
Department of Biochemistry, Brandeis University, Waltham, Massachusetts 02454, USA
Biochemistry 44:16695-700. 2005..These results suggest that proton transfer from water to guanidine is almost complete in the transition state...
Research Grants
- IMP DehydrogenaseLizbeth Hedstrom; Fiscal Year: 2009..Further, these motifs/factors will be new candidates for the 25% of hereditary retinal disease that is currently undefined. ..
- Development of IMPDH-Targeted Drugs against CrytosporidiumLizbeth Hedstrom; Fiscal Year: 2007..If successful, the work described in this proposal will develop an urgently needed drug for the management of cryptosporidiosis in epidemic outbreaks and AIDS patients that will be invaluable in the event of a bioterrorist attack. ..
- IMP DehydrogenaseLizbeth Hedstrom; Fiscal Year: 2007..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. ..
- The mechanism of IMPDH1-mediated retinitis pigmentosaLizbeth Hedstrom; Fiscal Year: 2007..Lastly, this work will provide important new insights into the biology of IMPDH, an important drug target for immunosuppressive, antiviral and cancer chemotherapy. ..
- IMP DehydrogenaseLizbeth Hedstrom; Fiscal Year: 2006..In addition to being crucial for the design of isozyme-specific inhibitors of IMPDH, this work will be an important contribution to understanding the relationship between structure and function in enzyme catalysis. ..
- INOSINE MONOPHOSPHATE DEHYDROGENASELizbeth Hedstrom; Fiscal Year: 2001..The structures of IMPDH complexed with inhibitors will also be solved. These experiments will utilize steady state kinetic, pre-steady state kinetic, site-directed mutagenesis and x-ray crystallography. ..
- IMP DehydrogenaseLIZBETH K HEDSTROM; Fiscal Year: 2010..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. ..