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Research Interests
Research in the Moremen lab focuses on the structure, function, regulation, and localization of enzymes involved in the biosynthesis, recognition, and catabolism of mammalian glycoproteins. Carbohydrate structures on glycoproteins contribute to many biological recognition events during development, oncogenic transformation, and cell adhesion. In addition, protein-linked glycans can influence bioactivity, folding, localization, and immunogenicity of the attached polypeptide. Large numbers of intracellular and extracellular proteins contain covalently bound oligosaccharides, including enzymes, cell-surface receptors, hormones, immunoglobulins, and viral antigens. Alterations in the synthesis and degradation of these structures can also occur in human genetic diseases and cancer. Despite the ubiquity of glycoprotein structures, much is still unknown about the regulation of the glycosylation pathway and aspects of structure and function of the processing enzymes. Many questions also remain regarding oligosaccharide catabolism in different intracellular compartments as well as the specificity and regulation of protein-carbohydrate interactions during development.
Work in the Moremen lab is focused on four main areas: (1) characterization of mammalian glycoprotein biosynthesis and catabolism by the cloning, expression, and biochemical characterization of the enzymes involved in these processes (including structure-function studies), (2) identification of inhibitors of glycoprotein processing and maturation as potential therapeutics for protein misfolding disorders and anti-metastatic therapeutic agents, (3) determination of the structural and molecular basis for the interaction between glycosidases and glycosyltransferases and their corresponding substrates and (4) developing technologies for measuring transcript abundance for glycan-related genes. Each of these research programs is supported by grant funding by the National Institutes of Health.
Selected Recent Publications
- Akama, T.O., Nakagawa, H., Sugihara, K., Narisawa, S., Ohyama, C., Nishimura, S., O’Brien, D.A., Moremen, K.W., Millan, J.L., and Fukuda, M.N. (2002) Germ cell survival through carbohydrate-mediated interaction with Sertoli cells Science 295:124-127.
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Cabral, C.M., Liu, Y., Moremen, K.W., and Sifers, R.N. (2002) Organizational diversity among distinct glycoprotein ER-associated degradation programs Mol. Biol. Cell 13:2639-2650.
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Wu, Y., Moremen, K.W., Sifers, R.N. (2003) Elucidation of the molecular logic that preferentially targets misfolded a1-antitrypsin for intracellular degradation. Proc. Natl. Acad. Sci. USA 100:8229-8234.
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Tempel, W., Karaveg, K., Lui, Z. –J., Rose, J., Wang, B.-C. and Moremen, K.W. (2004) Structure of mouse Golgi alpha-mannosidase IA reveals the molecular basis for substrate specificity among Class I (family 47 glycosyl hydrolase) a1,2-mannosidases. J. Biol. Chem. 279:29774-29786.
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Li, B., Kawatkar, S.P., George, S., Strachan, H., Woods, R.J., Siriwardena, A., Moremen, K.W., Boons, G.J. (2004) Inhibition of Golgi mannosidase II with mannostatin A analogues: synthesis, biological evaluation, and structure-activity relationship studies. Chembiochem. 5:1220-1227.
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Mast, S.W., Diekman, K., Karaveg, K., Davis, A., Sifers, R.N., and Moremen, K.W. (2004) Human EDEM2, a novel homolog of family 47 glycosidases, is involved in the ER-associated degradation of glycoproteins. Glycobiology 15:421-436.
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Karaveg, K., Siriwardena, A., Tempel, W., Liu, Z.-J., Glushka, J., Wang, B.-C., and Moremen, K.W. (2005) Mechanism of Class 1 (glycosylhydrolase family 47) a-mannosidases involved in N-glycan processing and endoplasmic reticulum quality control. J. Biol Chem. 280:16197-16207.
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Siriwardena, A., Strachan, H., El-Daher, S., Way, G., Winchester, B., Glushka. J., Moremen, K., Boons, G.J. (2005) Potent and selective inhibition of Class II a-d-mannosidase activity by a bicyclic sulfonium salt. Chembiochem. 6:845-848.
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Karaveg, K. and Moremen, K.W. (2005) Energetics of substrate binding and catalysis by Class 1 (glycosylhydrolase family 47) a-mannosidases involved in N-glycan processing and endoplasmic reticulum quality control. J. Biol Chem. 280:29837-29848.
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Park, C., Meng, L. Stanton, L.H., Collins, R.E., Mast, S. W., Yi, X., Strachan, H., and Moremen, K.W. (2005) Characterization of a human core-specific lysosomal a1,6-mannosidase involved in N-glycan catabolism, J. Biol Chem. 280:37204-37216.
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Herring, K.W., Karaveg, K., Moremen, K.W., and Pearson, W.H. (2005) A practical synthesis of kifunensine analogues as inhibitors of endoplasmic reticulum a-mannosidase I J. Org. Chem. 70:9892-9904.
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Mast, S.W. and Moremen, K.W. (2006) Family 47 a-mannosidases in N-glycan processing. Meth. Enzymol. 415:31-45.
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Akama, T.O., Nakagawa, H., Wong, N.-K. Sutton-Smith, M., Dell, A., Nakayama, J., Nishimura, S., Pai, A., Moremen, K.W., Marth, J.D., and Fukuda, M.N. (2006) Essential and mutually compensatoryroles of a-mannosidase II and a-mannosidase IIx in N-glycan processing in vivo in mice. Proc. Natl. Acad. Sci. USA 103:8983-8988.
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Wu, Y., Termine, D.J., Swulius, M.T., Moremen, K.W., and Sifers, R.N. (2007) Human endoplasmic reticulum mannosidase I is subject to regulated proteolysis. J. Biol. Chem. 282, 4841-4849
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Liu, S., Venot, A., Meng, L., Tian, F., Moremen, K.W., Boons, G.-J., and Prestegard, J.H. (2007) Spin-Labeled Analogs of CMP-NeuAc as NMR probes of the α-2,6-sialyltransferase ST6Gal Ι, Chem. Biol., 14, 409-418.
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Nairn, A. V., Kinoshita-Toyoda, A., Toyoda, H., Xie, J., Harris, K., Dalton, S., Kulik, M., Pierce, J.M., Toida, T., Moremen, K.W., and Linhardt, R. J. (2007) Glycomics of proteoglycan biosynthesis in murine embryonic stem cell differentiation, J. Proteome Res., in press.
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