November 28
PROGRAM

09

Glycoscience : diversity and integration

Glycosylation in the metabolic originsof common grievous disease
Jamey D. Marth, Ph.D.
Director, Center for Nanomedicine,
Professor, Sanford-Burnham Medical Research Institute andUniversity of California Santa Barbara, USA

Jamey D. Marth
ProfileMy laboratory combines molecular, cellular, and physiological research to investigate the roles of mammalian glycans inbiology and disease. Modern literature including the current widely used cell biology textbook by Alberts et al., states that glycans are one of the four fundamental components of cells, along with lipids, proteinsand nucleic acids. All four of these macromolecules and structural components consist of a defined set of building blocks thatare used to produce their diverse structuralrepertoires. The glycan repertoire, termed
the glycome, consists of saccharides linked
by glycosidic bonds to proteins, lipids, andother saccharides. Considering their abundance and diversity, relatively few laboratories incorporate them into an integrated
research program. Because glycans are notdirectly encoded by the genome, defining
their structure and function is more difficult and not amenable to template-based
biology and its associated current highthroughput technologies. With combinations of genetic, biochemical and physiological approaches, including Cre-loxP
conditional mutagenesis developed by thislaboratory, the biological roles of protein
glycosylation have been increasingly revealed. The functions ascribed to glycans
discovered by this laboratory, span roles in
apoptosis, autoimmune disease, the complications of sepsis, and as the appended
revised R01 A1 proposal includes – theorigins of diet- and obesity-associateddiabetes. Studies over the past two decadesindicate that glycans contribute to some of
the most important missing pieces in thepuzzles of disease, and their involvement
presents opportunities for rational approaches to disease prevention and treatment. Our research spans the enzymes ofglycosylation and the proteinaceous lectinsthat exist to decode the biological information contained in glycans. By doing so, we
hope to achieve a more holistic and rigorous understanding of cell biology and themechanisms that govern health and disease.

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Glycosyltransferases and glycosidases
represent most of the enzymatic machinery that participates in determining thestructural repertoires of glycans producedby cells and organisms. Changes in theglycome can be observed in both genetic
and acquired disease states. While some
genetic diseases have been linked directly
to DNA sequence variation that then alters
the enzymes of glycosylation, multiple
common diseases and syndromes appear
to originate from metabolic changes inglycosylation in the absence of detectable
inherited genomic variation. From studies
over the past two decades, this laboratory
has identified environmental triggers thatalter mammalian and human glycosylation, and which represent metabolic origins of common grievous disease. These
metabolic factors include dietary stressand microbial interactions/infections withthe host organism. The disease pathways
induced by such metabolic processes
include, for example, the pathogenesisof Type 2 diabetes in response to obesity,
primary insulin resistance, and high levelsof free fatty acids. In this disease pathway, an acquired change in glycosylationis responsible for disabling the first stepof glycolysis among pancreatic beta cells,
which then causes beta cell dysfunctionthat provokes disease onset. In anotherexample, the altered metabolism of glycans
has been found to determine the outcomesthe 20th Anniversary of the Mizutani Foundation for Glycoscienceof infection among pathogens and theirhosts bearing normal genomes. Examples
of such microbial interactions have been
identified among our studies of the common mammalian pathogens Streptococcus
pneumoniae and Salmonella typhimurium.
Infections by these bacteria cause metabolic changes in host glycans that aresensed by host receptor systems residing
in various tissues. The outcomes of suchinteractions determine the course of disease, including the severity of host tissue
damage and the frequencies of host survival. From these and other studies to be
described, we are developing and combining high-throughput detection approaches
to simultaneously interrogate the four
macromolecules and structural components of cells, namely the nucleic acids,
the proteins, the lipids, and the glycans.
By observing both the inherited biologicalresponses governed by the expression ofgenes and proteins, and the acquired biological responses governed by the metabolism of glycans and lipids, such combined
studies may further reveal the origins andpathways of common mysterious diseases
that arise from metabolic triggers. Almost
all diseases originate from a combinationof inherited and environmental factorsthat when considered together will be able
to explain the roles of nature and nurture
in disease pathogenesis.

FIgure 1. The molecular building block of life.
We have further defined 70 basic building blocks of life in all cells, yet we can only see a small portion, less than half….
By developing the means to interrogate and modulate all of these cellular components…our research at the CNM can address multiple grievous andmysterious diseases, many of which are escalating in the human population

References1) 	Orban, P.C., Chui, D., and Marth, J.D. (1992). Tissue - and site-specific DNA
recombination in transgenic mice. Proc. Natl. Acad. Sci. USA 89, 6861-6865.
2) 	Gu, H., Marth, J.D., Orban, P.C., Mossmann, H., and Rajewsky, K. (1994).
Deletion of the DNA polymerase beta gene in T cells using tissue-specificgene targeting. Science 265, 103-106.
3) 	Hennet, T., Hagen, F.K., Tabak, L.A., and Marth, J.D. (1995). T cell-specificdeletion of a polypeptide Nacetylgalactosaminyltransferasegene by site-directed recombination. Proc. Natl. Acad. Sci. USA 92, 12070-12074.
4) 	Chui, D., Oh-Eda, M., Liao, Y.F., Panneerselvam, K., Lal, A., Marek, K.W.,Freeze, H.H., Moremen, K.W., Fukuda, M.N., and Marth, J.D. (1997). Alphamannosidase-II deficiency results in dyserythropoiesis and unveils an alternate pathway in oligosaccharide biosynthesis. Cell 90, 157-167.
5) 	Hennet, T., Chui, D., Paulson, J.C., and Marth, J.D. (1998). Immune regulation by the ST6Gal sialyltransferase. Proc. Natl. Acad. Sci. USA 95, 45044509.
6) 	Ellies, L.G., Tsuboi, S., Petryniak, B., Lowe, J.B., Fukuda, M., and Marth, J.D.
(1998). Core 2 Oglycan biosynthesis distinguishes between selectin ligands
essential for leukocyte homing and inflammation. Immunity 9, 881-890.
7) 	Priatel, J.J., Chui, D., Hiraoka, N., Simmons, C.J.T., Richardson, K.B., Page,D.M., Fukuda, M., Varki, N.M., and Marth, J.D. (2000). The ST3Gal-I sialyltransferase controls CD8+ T cell homeostasis by modulating O-glycan biosynthesis. Immunity 12, 273-283.
8) 	Shafi, R., Iyler, S.P.N., O’Donnell, N., Ellies, L.G., Marek, K.W., Chui, D.,
Hart, G.W., and Marth, J.D. (2000). The O-GlcNAc transferase gene resides
on the X chromosome and is essential for embryonic stem cell viability andmouse ontogeny. Proc. Natl. Acad. Sci. USA 97, 5735-5739.

9) 	Chui, D., Sellakumar, G., Green, R.S., Sutton-Smith, M., McQuistan, T.,Marek, K.W., Morris, H.R., Dell, A., and Marth, J.D. (2001). Genetic remodeling of protein glycosylation in vivo induces autoimmune disease. Proc.
Natl. Acad. Sci. USA 98, 1142-1147.
10) 	Ellies, L.E., D. Ditto, D., Levy, G.G., Wahrenbock, M., Ginsburg, D., Varki,A., Le, D., and Marth, J.D. (2002). Sialyltransferase ST3Gal-IV operates as adominant modifier of hemostasis by concealing asialoglycoprotein receptor
ligands. Proc. Natl. Acad.Sci. USA 99, 10042-10047.
11) 	Ohtsubo, K., Takamatsu, S., Minowa, M.T., Yoshida, A., Takeuchi, M., andMarth, J.D. (2005). Dietary and genetic control of glucose transporter glycosylation promotes insulin secretion in suppressing diabetes. Cell 123, 13071321.
12) 	Grewal, P.K., Boton, M., Rameriz, K., Collins, B.E., Chui, D., Paulson, J.C.,and Marth, J.D. (2006). ST6Gal-I restrains CD22-dependent antigen receptor endocytosis and Shp-1 recruitment in normal and pathogenic immune
signaling. Mol. Cell. Biol. 26, 4970-4981.
13) 	Green, R.S., Stone, E.L., Tenno, M., Lehtonen, E., Farquhar, M.G., and Marth,J.D. (2007). Mammalian N-glycan branching protects against innate immune
self-recognition and inflammation in autoimmune disease pathogenesis. Immunity 27, 308-320.
14) 	Grewal, P.K., Uchiyama, S., Ditto, D., Varki, N., Le, D.T., Nizet, V., and Marth,J.D. (2008). The Ashwell receptor mitigates the lethal coagulopathy of sepsis.
Nat. Med., 14, 648-655. NIHMSID: NIHMS183221
15) 	Ohtsubo, K., Chen, M.Z., Olefsky, J.M., and Marth, J.D. (2011). Pathway todiet- and obesity-associated diabetes through attenuation of pancreatic beta
cell glycosylation and glucose transport. Nat. Med., 17, 1067-1075.

Commemorative Symposium

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