Professor of Medicinal Chemistry
Biological roles of Heparan Sulfate Proteoglycans in the CNS
Heparan sulfate (HS) is a ubiquitous molecular component of cell surfaces and the extracellular matrix. HS interacts with a wide variety of proteins such as growth factors, morphogens, chemokines, and many more. Their strategic location enables them to regulate many important biological processes through HS-protein interactions. Many of these interactions are essential for this class of proteins to transduce signals across the plasma membrane, which are implicated in human health and diseases. Furthermore, alterations in the biosynthesis or catabolism of HS chains are associated with various congenital and neurological disorders. The unique molecular sulfation pattern and flexibility of HS chains are essential for their ability to modulate cellular responses. However, it has been difficult to elucidate the rules that dictate such interactions that result in distinct biological responses.
We propose a chemical approach to spatiotemporally modulate biosynthetic enzymes to determine structure-function relationships. We design and synthesize a library of small molecules, and screen for their effect on the biosynthesis of HS and for the modulation of HS fine structures in model cellular systems with the aid of various analytical tools. The active molecules are then utilized in zebra fish through collaborations to decipher the role of HS in cell-signaling and in CNS development and disorders. We are also cloning and expressing various biosynthetic and catabolic enzymes to synthesize and deduce HS fine structures with a final goal to understand their biosynthetic and catabolic pathways, and their role in various physiological processes (axon guidance, regeneration, and learning and memory) and in human diseases (congenital defects, cerebral thrombosis, and CNS disorders). We anticipate that deciphering the enigmatic structures of HS and understanding their biosynthetic/catabolic pathways will lead to the development of HS-based molecular scaffolds to diagnose and tackle mental disorders.
Tsuzuki*, Y., Nguyen*, T.K.N., Garud, D.R., Kuberan, B., and Koketsu, M. (2010) Inhibitors of Glycosaminoglycan Biosynthesis. Bioorganic & Medicinal Chemistry Letters, in press. [*authors contributed equally] DOI: 10.1016/j.bmcl.2010.10.085
Tran, V.M., Nguyen, T.K.N., Raman, K., and Kuberan, B. (2010) Applications of Isotopes in Advancing Structural and Functional Heparanomics. Analytical and Bioanalytical Chemistry, in press. DOI: 10.1007/s00216-010-4166-x
Raman, K., and Kuberan, B. (2010) Differential Effects of Heparitinase I and Heparitinase III on Endothelial Cell Tube Formation In vitro. Biochemical and Biophysical Research Communications, 398:191-193.
Raman, K., and Kuberan, B. (2010) Click-Xylosides Mitigate Glioma Invasion In vitro. Molecular BioSystems, 6:1800-1802.
Nguyen, T.K.N., Tran, V.M., Victor, X., Skalicky, J., and Kuberan, B. (2010) Characterization of Uniformly and Atom-Specially 13C-Labeled Heparin and Heparan Sulfate Polysaccharide Precursors using 13C-NMR Spectroscopy and ESI-Mass Spectrometry. Carbohydrate Research, 345:2228-2232.
Tran, V.M., Victor, X.V., Yockman, J., and Kuberan, B. (2010) RGD-Xyloside Conjugates Prime Glycosminoglycans. Glycoconjugate Journal, 6:625-633.
Raman, K. and Kuberan, B. (2010) Chemical Tumor Biology of Heparan Sulfate Proteoglycans. Current Chemical Biology, 4(1):20-31.
Sigulinsky, C., Babu, P., Victor. X.V. and Kuberan, B. (2009) Preparation and Characterization of 15N-Enriched Size-Defined Heparan Sulfate Precursor Oligosaccharides. Carbohydrate Research, 345)2):250-256.
Babu, P., and Kuberan, B. (2009) Fluorescent Tagged Heparan Sulfate Precursor Oligosaccharides to Probe the Enzymatic Action of Heparitinase I. Analytical Biochemistry, 396(1):124-132.
Victor, X.V., Nguyen, T.K.N., Ethirajan, M., Tran, V.M., Nguyen, K.V., and Kuberan, B. (2009) Investigating the Elusive Mechanism of Glycosaminoglycan Biosynthesis. Journal of Biological Chemistry, 284:25842-25853.
Garud*, D.R, Tran*, V.M., Victor, X.V., Koketsu, M., Kuberan, B. (2008) Inhibition of Heparan Sulfate and Chondroitin Sulfate Proteoglycan Biosynthesis. Journal of Biological Chemistry, 283:28881-28887. (* contributed equally)
Kuberan, B., Ethirajan, M., Victor, X., Tran, V.M., Nguyen, K.V., and Do, A. (2008) "Click"- Xylosides Initiate Glycosaminoglycan Biosynthesis in a Mammalian Cell Line. ChemBioChem, 9:198-200.
Lawrence, R., Kuberan, B., Lech, M., Beeler, D.L., and Rosenberg, R.D. (2004) Mapping Critical Biological Motifs and Biosynthetic Pathways of Heparan Sulfate. Glycobiology, 14(5):467-479.
Kuberan, B., Lech, M., Borjigin, J., and Rosenberg, R.D. (2004) Light Induced 3-O-Sulfotransferase Expression Alters Pineal Heparan Sulfate Fine Structure: A Surprising Link to Circadian Rhythm. Journal of Biological Chemistry, 279(7):5053-5054.
Kuberan, B., Beeler, D.L., Lech, M., Wu, Z.L., and Rosenberg, R.D. (2003) Enzymatic Synthesis of Antithrombin III Binding Heparan Sulfate Pentasaccharide. Nature Biotechnology, 21(11):1343-1346.