Troy, Frederic - University of California, Davis - Department of Biochemistry and Molecular Medicine

研究领域

Preferred Membrane Orientation of Dolichol (left) and Dolichylphosphate (right) in Model Phospholipid Membrane: Many glycosyltransferases contain contact amino acids within a transmembrane spanning domain that constitute a specific binding motif for interacting with dolichol and dolichylphosphate. These binding complexes may be important in biosynthetic and translocation processes that ferry glycoconjugates across cell membranes. The molecular details of this aspect of glycobiology is not understood in any biological system." Molecular medicine specializes in glycobiology, membrane chemistry and cancer metastasis. We study three overlapping problems in molecular medicine that focuses on glycobiology, membrane chemistry and cancer metastasis. A summary of these areas and relevant publications are described below. I. Glycobiology-The Polysialic Acid Glycotope: Structure, Function, Synthesis and Glycopathology. The landscape of the cell surface of normal and cancer cells is decorated with a bewildering array of informational-rich sugar molecules, usually attached to proteins (glycoproteins) and lipids (glycolipids). Surface expression of many of these complex sugars change dramatically during the developmental life of a cell and with the onset of cancer. Importantly, these sugars carry specific information that tell cells how to behave at different stages in their life cycle, when to detach, for example, and move to different locations within the body. They also signal to the cell when to stop dividing and become adherent. A specific example of one class of these surface carbohydrates in “polysialic acid” (polySia), the focus molecule for many of our studies. The references below summarize some of our studies. II. Role of the Polysialic Glycotope in Human Cancer Metastasis. The a2,8-ketosidically linked polySia on neural cell adhesion molecules (N-CAMs) is and oncodevelopmental, tumor-associated carbohydrate antigen. PolySia is an anti-adhesive glycotope that decreases N-CAM dependent cell adhesion in a variety of tissues. Based on correlative studies, we have shown that surface expression of polySia is positively correlated with increased metastasis in a number of human cancers. As such, polySia is postulated to be a metastatic factor than may help some tumors detach, invade and colonize distant sites, particularly brain. Two key mammalian CMP-Sia:a2,8-polysialyltransferase genes, designated PST and STX, have been cloned and shown to catalyze the polysialylation of N-CAM. One discovery-based aim of our studies seeks to determine the extent to which human cancers, including head and neck, breast, prostate, melanoma, and neuroblastomas overexpress polySia on their cell surfaces and to correlate this expression with their malignant potential and patient outcome. One such study is currently being carried out in collaboration with Professor Paul J. Donald, Director of the Skull Base Surgery Program, Department of Otolaryngology, UC Davis Medical Center. III. NMR Studies on the Preferred Membrane Orientation of Polyisoprenols (Dolichol) and How the Binding Complex of Polyisoprenol Recognition Peptides and Polyisoprenols Can Modulate Membrane Structure A problem of fundamental importance in glycobiology is how membrane-bound hydrophilic glycoconjugates are translocated across hydrophobic membranes. A number of our studies over the years have addressed the unresolved problem of how sugar chains attached to the polyisoprenol (PI) glycosyl carrier lipids, dolichylphosphate and undecapreylphosphate, are ferried across cell membranes. We have employed a combination of 1H- and 31P NMR spectroscopy, and energy minimized molecular modeling studies, to determine the preferred orientation of PIs in model phospholipids membranes. We have also shown how transmembrane glycosyltranferases that contain a PI recognition sequences (PIRS) uses this motif to mediate their binding to the PIs. Evidence in support of the hypothesis that a PI:PIRS binding complex may have the potential of forming a membrane channel that could potentially facilitate glycoconjugate translocation is also reviewed in our publications below.

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Sato, C., Fukuoka, H., Ohta, K., Matsuda, T., Koshino, R., Kobayashi, K., Troy, F.A., and Kitajima, K., “Frequent Occurrence of Pre-existing a2®8-linked Disialic and Oligosialic Acids with Chain Lengths Up to 7 Sia Residues in Mammalian Brain Glycoproteins: Prevalence Revealed by Highly Sensitive Chemical Methods and Anti-Di-, Oligo- and PolySia Antibodies Specific for Defined Chain Lengths”. J. Biol. Chem. (2000) 275; 15422-15431. Zhou, G-P., and Troy, F.A. “Characterization by NMR and Molecular Modeling of the Binding of Polyisoprenols and Polyisoprenyl Recognition Sequence Peptides: 3D Structure of the Complexes Reveals Sites of Specific Interactions”. Glycobiology (2003) 13; 51-71. Troy, F.A. “Polysialic Acid in Molecular Medicine”. Encyclopedia of Biological Chemistry (2004) 3; 407-414. Zhou, G-P., and Troy, F.A. “NMR Study of the Preferred Membrane Orientation of Polyisoprenols (dolichol) and the Impact of Their Complex With Polyisoprenyl Recognition Sequence Peptides on Membrane Structure”. Glycobiology (2005) 15; 347-359. Zhou, G-P., and Troy, F.A. “NMR Studies on How the Binding Complex of Polyisoprenol Recognition Sequence Peptides and Polyisoprenols Can Modulate Membrane Structure”. Current Protein and Peptide Science. (2005) 6; 399-411. Park, H. H., Nakata, D., P. J. Donald and Troy II, F. A. “Expression of Polysialylated Neural Cell Adhesion Molecules in Human Head and Neck Cancer”. Glycobiology 15; (2005) 1251 (254). Nakata, D. and Troy II, F.A. “Degree of Polymerization (DP) of Polysialic Acid (PolySia) on Neural Cell Adhesion Molecules (N-CAMs): Development and Application of a New Strategy to Accurately Determine the DP of PolySia Chains on NCAMs”. J. Biol. Chem. (2005) 280; 38305-38316. Cong, X., Czerwieniec, G. McJimpsey, E., Ahn, S., Troy II, F. A. and Lebrilla, C. B. “Structural Relationships in Small Molecule Interactions Governing Gas- Phase Enantioselectivity and Zwitterionic Formation”. J. Am. Soc. Mass Spectrometry. Mar; (2006) 17(3):442-452 Nakata, D., Zhang, L. and Troy II, F. A. “Molecular Basis for Polysialylation: A Novel Polybasic Polysialyltransferase Domain (PSTD) of 32 Amino Acids Unique to the a2,8-polysialyltransferases is Essential for Polysialylation”. Glycoconjugate Jour. (2006) 23;423-436. Park, K.H., Jang, K.H., Yeo, S. W., Rask-Anderson, H. and Troy II, F.A., “Expression of Neural Cell Adhesion Molecule and Polysialic Acid in Cultured Spiral Ganglion Neurons”, Skull Base (2007) 17;1055 Wang, B., Hu, H., Yu, B., and Troy II, F. A.,“Molecular Characterization of Pig UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine Kinase (Gne) Gene: Effect of Dietary Sia Supplementation on Gene Expression in Piglets”. Curr. Topics in Nutraceutical Res. (2008) 5,(4). 165-176. Drake, P., Nathan, J., Stock, C., Chang, P., Muench, M., Nakata, D., Reader, R., Gip, P., Golden, K., Weinhold, B., Gerardy-Schahn, R., Troy II, F.A. and Bertozzi, C., “The Highly Restricted Glycan, Polysialic Acid, is Differentially Expressed on Human and Murine Leukocytes and Modulated Immune Response”. J..Immunology, (2008) 181; 6850-6858). Wong, J., Nakata, D., Troy II, F. A. and Gervay-Hague, J. “Synthesis of Neutral CMP-Sialic Acid Analogs as Polysialyltransferase Inhibitors”. ACS San Francisco Mtg. Abst. (2009) Kyoung Ho Park ,Sang Won Yeo, Frederic A. Troy II “Polysialylated Neural Cell Adhesion Molecules Mediates Neuronal Differentiation in Adult Neural Stem Cells from Guinea Pig Spiral Ganglion Neurons” Glycobiology (2009)19;1367 (266) Troy, F.A. and Nakata, D. “Kinetic Parameters of N-CAM Polysialylation Catalyzed by Purified Constructs of STX & PST and Their Differential Sensitivity to Detergents. Glycobiology (2009) 19; No. 11, 1341 (Abst.180). Troy II, Frederic A.. Park, Kyoung Ho and Yeo, Sang-Won. Polysialic Acid and Neural Cell Adhesion Molecule Expression in Adult Stem Cells Cultured from Spiral Ganglion Neurons. Glycobiology (2009) 19; No. 11, 1367 (Abst. 266). Bum Jung Park, Paul J Donald, and Troy, F.A. II, “Expression of Polysialylated Neural Cell Adhesion Molecules: Potential Role as a Prognostic Indicator for Squamous Cell Carcinoma in Head and Neck Cancers”. J. Otolaryngology-Head and Neck Surgery (2010) Wang, F., Xia.B., Wang, B. and Troy II, F.A. “HPLC MS/MS Analyses of Free Neu5Ac, Neu5Gc and KDN (2-Keto-3-deoxy-D-glycero-D-galacto-nononic Acid) in Head & Neck Tumors of the Throat” (Glycobiology 21; No.11, Nov. 2011 (Abst.). Shan, Y., Yu, H., Wang, B., and Troy II, F.A. “Expression of TriSia & PolySia in Human Cancers: Potential Role for Diagnostic & Prognostic Biomarkers for Cancer Screening”. Glycobiology (2011) Vol.11, No. 10 (Abst). Wang, F., Xia.B., Wang, B. and Troy II, F.A. “LC MS/MS Analyses of Free Neu5Ac, Neu5Gc and KDN (2-Keto-3-deoxy-D-glycero-D-galacto-nononic Acid) in Head & Neck Tumors of the Throat” Glycobiology 21; No.11, Nov. 2011(Abst.). Chen HJ, Wang, P., Han, Y., Ma, J., Troy II FA, Wang B. “Evaluation of Dietary Intake of Lactating Women in China and its Potential Impact on the Health of Mothers and Infants”. BMC Women's Health 12;(18) 1-10. DOI:10.1186/1472-6874-12-18. Chen, Y., Pan, L. Liu, N. Troy II, F. A. and Wang, B. “LC-MS/MS Quantification of N-actylneuraminic acid, N-glycolylneuraminic acid and ketodeoxynonulosonic acid Levels in the Urine and Potential Relationship with Dietary Sialic Acid Intake and Disease in 3- to 5-year old Children”. British Jour. of Nutrition. (2013) 5:1-10. Doi:10.1017/S0007114513002468. Chen, Y., Zheng Z., Xi Zhu, X., Shi , Y., Tian , D., Huppi, P., Troy II, F.A. and Wang, B. “Lactoferrin Promotes Early Brain Development and Cognition in Postnatal Piglets by Up-regulating the BDNF Signaling Pathway and Polysialylation”. Molecular Neurobiology (2014) 52; (1) 256-269 . doi10.1007/s12035-014-8856-9. Park, K-P, Yeo, S-W and Troy, II, F.A. “Expression of Polysialylated Neural Cell Adhesion Molecules on Adult Stem Cells After Neuronal Differentiation of Inner Ear Spiral Ganglion Neurons”. Biochemical and Biophysical Research Communications. doi:http://dx.doi.org/10.1016/j.bbrc.2014.05.035. Gan, HA, Zhang, QZ, Zhang, H. Chen, Y., Lin, JZ., Kang, TS, Zhang, JX, Troy II, FA, Wang, B. “Development of New Population-averaged Standard Template for Spatial Normalization and Segmentation of MR Images for Postnatal Piglet Brains”. Magnetic Resonance Imaging (2014), http://dx.doi.org/10.1016/j.mri.2014.08.036.