Frederic A. Troy II, Ph.D.
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.
Graduate Group Affiliations
- Biochemistry, Molecular, Cellular and Developmental Biology
- Cell and Developmental Biology
Si-Ming Liao,Bo Lu, Xue-Hui Liu , Zhi-Long Lu, Shi-Jie Liang Dong Chen, Frederic A. Troy II*, Ri-Bo Huang* and Guo-Ping Zhou* "Molecular Interactions of the Polysialytransferase Domain (PSTD) in ST8Sia IV with CMP-Sialic Acid and Polysialic Acid Required for Polysialylation of the Neural Cell Adhesion Molecule Proteins: An NMR Study. Intl. Jour. Molec. Sci. (2020) 21, 1590doi:1,3390/ijms21051590 Pub..Feb. 26, 2020.(*Corresp. AU's).
Yue Chen, Yujie Shi, Xi Zhu, Ni Liu, Hexia Gan, Changwei Yang, Kevin Wang, Frederic A. Troy II and Bing Wang. (2019). "Functional Correlates and Impact of Dietary Lactoferrin Intervention and its Concentration-dependence on Neurodevelopment and Cognition in Neonatal Piglets: A Molecular Transcriptome Analysis" (Prepared for submission, Jour. Nut. Biochem.)
Changwei Yang, Panwang Zhang, Wang Fang, Yue Chen, Nai Zhang, Zhiliang Qiao, Frederic A. Troy II, Bing Wang. "Molecular Mechanisms Underlying How Sialyllactose Intervention Promotes Intestinal Maturity by Up-regulating GDNF Through a CREB-dependent Pathway in Neonatal Piglets (2019) Jour. Molecular Neurobiolog ISSN 0893-7648 DOI: 10.1007/s12035-019-1628-9 (Pub. June 5, 2019)
Li-Xin Peng, Xue-Hui Liu, Bo Lu, S-Ming Liao, Feng Zhou, Ji-Min Huang, Dong Chen, Frederic A. Troy II, Guo-Ping Zhou, "The Inhibition of Polysialyltranseferase ST8SiaIV through Heparin binding to Polysialyltransferase Domain (PSTD)" (2018) Medicinal Chemistry 15 DOI: 10.2174/157340641566618121810162134.
Bo Lu, Xue-Hui Liu, Ri-Bo Huang, Frederic A. Troy II, and Guo-Ping Zhou "The Interaction between Polysialic Acid and Polysialyltransferase Domain (PSTD) in ST8Sia IV and the Cooperative Effect of the PSTD and the Polybasic Region". (2018) Journal of Cheminformatics (2018)CHIN-D-18-00140
Yue Chen, He Ren, Nai Zhang, Frederic A. Troy II and Bing Wang. "Biochemical Characterization and Analyses of Polysialic Acid-Associated Carrier Proteins and Genes in Piglets During Neonatal Brain Development". ChemBioChem 18;1270-1278 (10.1002/cbic.201700029 [June, 2017).
Ri-Bo Huang , D. Cheng, Bo Lu, Si-Ming Liao, Frederic A. Troy II and Guo-Ping Zhou. "The Intrinsic Relationship Between Structure and Function of the Sialyltransferase ST8Sia Family Members". Current Topics in Medicinal Chemistry (2017), 17, 2465-2475.
Ji, SA.,Wang, F., Yang, CW., Zhang, PW., Zhang, XB., Troy II, FA., and Wang, B. Developmental Changes in the Level of Free and Conjugated Sialic Acids, Neu5Ac, Neu5Gc and KDN in Different Organs of Pig: A LC-MS/MS Quantitative Analyses. Glycoconjugate J (2016). Doi:10.1007/s10719-016-9724-9.
Wang, F., Xie, BY,.Wang, B., and Troy II, F.A. LC-MS/MS Glycomic Analyses of Free and Conjugated Forms of the Sialic Acids, Neu5Ac, Neu5Gc and KDN in Human Throat Cancers. Glycobiology (2015) 25; 1362-1374.
Zhou, Guo-Ping, Huang, Ri-Bo, and Troy II, Frederic A. 3D Structural Conformation and Functional Domains of Polytransferase ST8Sia IV Required for Polysialylation of Neural Cell Adhesion Molecules, Protein & Peptide Letters, 22; 137-148 (2015).
Xi Zhu, Zhiqiang Zheng, Nai Zhang, Yue Chen, Ni Liu, Frederic A Troy II and Bing Wang. Molecular Characterization and Expression Analyses of ST8Sia II and IV in Piglets During Postnatal Development: Lack of Correlation Between Transcription and Posttranslational Levels. Glycoconjugate Jour. (2015) 32; 715-728
Fang, F., Wang, F. Xie., Wang, B. and Troy II, F.A. LC-MS/MS Glycomic Analyses of Free and Conjugated Forms of the Sialic Acids, Neu5Ac, Neu5Gc and KDN in Human Throat Cancers. Glycobiology (2015) 10.1093/glycob/cwv051 (Published on-line August 2015).
Yang, C.W, Zhu, X, Liu, N, Chen, Y, Gan, H.A., Troy II, F.A, and Wang, B. Lactoferrin up-regulates intestinal gene expression of brain-derived neurotrophic factors BDNF, UCHL1 and alkaline phosphatase activity to alleviate early weaning diarrhea in postnatal piglets. Jour. Nutr. Biochem. (2014) 25; 834-42. Doi.org/10.1016/j.jnutbio.2014.03.015.
Troy II, F.A., Zhu, Xi, Z., Z., Zhang, N,. Chen, Y., Liu, N., and Wang, B., Molecular Characterization and Expression Analyses of ST8Sia II, III and IV in Piglets During Postnatal Development: Lack of Correlation Between Transcription and Posttranslational Levels. Glycobiology (2014) 24; No. 1155-1156 (Abst. 191).
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.
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.
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.
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 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.
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.).
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. 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.).
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)
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).
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).
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)
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)
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).
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.
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
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.
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
- “Polysialic Acid: From Microbes to Man” (1993) Jurgen Roth, Urs Rutishauser and Frederic A. Troy II (Editors). Birkhauser Varlag, Basel, Switzerland. ISBN 3-7643-2803-7; ISBN 0-8176-2803-7.
- “Sialobiology and Other Novel Forms of Glycosylation” (1999) Yasuo Inoue, Yuan C. Lee and Frederic A. Troy II (Editors). Gakushin Publishing Company, Osaka, Japan. ISBN 4-907773-00-5.
Upper Division Courses
- 192 Internship in Biological Chemistry
- 198 Group Study
- 199 Special Study for Advanced Undergraduates
- 209 Prostaglandins/Leukotrienes and Related Lipids (offered even years)
- 214 Molecular Medicine
- 217 Molecular Genetics of Fungi (odd years)
- 222 Mechanisms of Translational Control (even years)
- 230 Practical NMR
- 231 Biomedical NMR (same as BPH 231)
- 291 Human Genetics Seminar
- 298 Group Study
- 299 Research
Professional Courses for Medical Students
- 410A Molecular and Cell Biology
- 499 Research