The University of Michigan (Ann Arbor, MI)
- PhD: Toxicology
- MPH: Epidemiology
- BS: Biopsychology and Cognitive Science (Behavioral Neuroscience)
I am a toxicologist with a research background in predictive toxicology, neuroscience, structural biology, and epidemiology. My research interests lie in applying the multi-disciplinary techniques to understand and identify the key steps and molecular initiating events that drive adverse biological outcomes following xenobiotic exposure.
I earned my PhD in Toxicology from the University of Michigan where I studied the interactions between organophosphorus compounds and the neuronal integral membrane protein neuropathy target esterase (NTE). NTE is a lysophospholipase that is thought to be the cellular target for certain classes of organophosphorus (OP) compounds that can cause a delayed axonopathy. This condition, termed OP compound-induced delayed toxicity (OPIDN) can result in permanent paralysis and a key feature of this affliction is the 7-14 day delay between exposure and the onset of symptoms. Currently, very little is known about the structure of NTE and the mechanism whereby interactions between neuropathic OP compounds and NTE initiate the cascade of events that result in OPIDN. To this end, I have used the plant-homologue of NTE (a protein called patatin found in the tubers of potatoes and related species) to study changes in its [patatin's] tertiary structure following interactions with OP compounds.
My prior research has focused on the role of periaqueductal grey region of the brain in learning and memory as well as the association between Type-2 diabetes mellitus and neurological markers of cognitive decline in a population of elderly Hispanic residents living in the Sacramento area. During the course of my undergraduate studies, I was involved in a set of research projects at the University of Michigan School of Dentistry, where we investigated the efficacy of condylotomy versus diskectomy in treating disorders of the temperomandibular joint (TMJ), the use of scalpel versus electrosurgery techniques in performing incisions during TMJ surgery as well as research into the prevalence of tinnitus in patents who have TMJ disorders.
My areas of expertise
- Cheminformatics and computational biology
- Organophosphorus compounds and cholinergic neurotoxicology
- Chaperones and protein folding
- Biophysical techniques: X-ray crystallography, bio-layer interferometry circular dichroism spectroscopy, calorimetry, etc.
- Protein expression in bacterial and eukaryotic (insect cell and mammalian cell) systems
- Biochemistry and molecular biology: Enzyme kinetics, mass spectroscopy, enzyme immunoassay (ELISA)
- Computer programming: C++, KNIME, Visual Basic, Java, BASIC
- Website development
Crystal structures I have solved
- Patatin in its native state to 1.96 A (PDB ID 4PK9) - Note: The selenomethionine pat17 structure was initially solved in 2003 by Tim Rydel at Monsanto to 2.2 A (PDB ID 1OXW)
- Patatin adducted to an aged diisopropyl fluorophosphate moiety (PDB ID 4PKA)
- Patatin adducted to an unaged methoxy arachidonyl fluorophosphonate moiety (PDB ID 4PKB)
- Wijeyesakere, S.J., Wilson, D.M., and Marty M.S. (2020). Prediction of cholinergic compounds by machine-learning. Published in Computational Toxicology.
- Richardson, R.J., Fink, J.K., Glynn, P., Hufnagel, R.B., Makhaeva, G.F., and Wijeyesakere, S. J. (2020). Neuropathy target esterase (NTE/PNPLA6) and organophosphorus compound-induced delayed neurotoxicity (OPIDN). In Neurotoxicity of Pesticides (1st ed., Vol. 4).
- Wijeyesakere, S.J., Wilson, D.M., Auernhammer, T.R., Parks, A.K., Kovacs, D., and Marty M.S. (2019). Hybrid machine-learning/SMARTS profiling model for mitochondrial inhibition. Published in Applied In Vitro Toxicology.
- Wijeyesakere, S.J., Wilson, D.M., Settivari, R., Auernhammer, T.R., Parks, A.K., and Marty M.S. (2018). Development of a Profiler for Facile Chemical Reactivity Using the Open-Source Konstanz Information Miner. Published in Applied In Vitro Toxicology.
- Wilson, D.M., Wijeyesakere, S.J., Parks, A.K., Auernhammer, T.R., Krieger, S., Hotchkiss, J.A., and Marty M.S. (2018). Profiling Acute Oral and Inhalation Toxicity Data Using a Computational Workflow to Screen for Facile Chemical Reactivity. Published in Applied In Vitro Toxicology.
- Wijeyesakere, S.J. and Richardson, R.J. (2017). In silico Chemical-Protein Docking and Molecular Dynamics. In Computational Systems Pharmacology and Toxicology. pp 174-190.
- Wijeyesakere, S.J., Bedi, S.K., Huynh, D., and Raghavan, M. (2016). The c-terminal acidic region of calreticulin mediates phosphatidylserine binding and apoptotic cell phagocytosis. Published in the Journal of Immunology.
- Wijeyesakere, S.J., Arora, K., Gagnon, J., and Raghavan, M. (2015). Regulation of calreticulin-major histocompatibility complex (MHC) class I interactions by ATP. Published in the Proceedings of the National Academy of Sciences of the United States of America (PNAS).
- Richardson, R.J., Worden, R.M., Wijeyesakere, S.J., Hein, N.D., Fink, J.K., and Makhaeva, G.F. (2015). Neuropathy target esterase as a biomarker and biosensor of delayed neuropathic agents. In Handbook of Toxicology of Chemical Warfare Agents, 2nd Ed. (R.C. Gupta, Ed.), Academic Press/Elsevier, Amsterdam. pp 935-952.
- Wijeyesakere, S.J., Richardson, R.J., and Stuckey, J.A. (2014). Crystal structure of patatin-17 in complex with aged and non-aged organophosphorus compounds. Published in PLOS One.
- Wijeyesakere, S.J., Rizvi, S.M., and Raghavan M. (2013). Glycan-Dependent and Independent Interactions Contribute to Cellular Substrate Recruitment by Calreticulin. Published in J. Biol. Chem.
- Raghavan, M. Wijeyesakere, S.J., Peters, L.R., and Del Cid, N. (2012). Calreticulin in the immune system: ins and outs. Invited review published in Trends in Immunology.
- Richardson, R.J., Hein, N.D., Wijeyesakere, S.J., Fink, J.K., and Makhaeva, G.F. (2012). Neuropathy target esterase (NTE): overview and future. Review article published in Chemico-Biological Interactions.
- Wijeyesakere, S.J., Gafni, A.A., and Raghavan, M. (2011). Calreticulin is a thermostable protein with distinct structural responses to different divalent cation environments. Published in J. Biol. Chem.
- Wang, Y., Liu, X., Schneider, B., Zverina, E.A., Russ, K., Wijeyesakere, S.J., Fierke, C.A., Richardson, R.J., and Philbert, M.A. (2011). Mixed Inhibition of Adenosine Deaminase Activity by 1,3-Dinitrobenzene: A Model for Understanding Cell-Selective Neurotoxicity in Chemically Induced Energy Deprivation Syndromes in Brain. Published in Toxicol. Sci.
- Wijeyesakere, S.J. and Richardson, R.J. (2010). Neuropathy target esterase. In The Hayes Handbook of Pesticide Toxicity (3rd ed). pp 1435-1455.
- Wijeyesakere, S.J. (2009). Enzyme aging: structural insights from NTE and patatin. PhD Dissertation. The University of Michigan, Ann Arbor. (Link in Mirlyn).
- Makhaeva, G.F., Aksinenko, A.Y., Sokolov, V.B., Baskin, I.I., Palyulin, V.A., Zefirov, N.S., Hein, N.D., Kampf, J.W., Wijeyesakere, S.J., and Richardson, R.J. (2009). Kinetics and mechanism of inhibition of serine esterases by fluorinated aminophosphonates. Published in Chem. Biol. Interact.
- Wijeyesakere, S.J. et al. (2008). Diethyl [2,2,2-trifluoro-1-phenylsulfonylamino-1-(trifluoromethyl)ethyl]phosphonate. Published in Acta Crystallographica Section E. (The full paper (including the PDF version with supplementary material) may be downloaded free of charge).
- Wijeyesakere, S.J., Richardson, R,J,, and Stuckey J.A. (2007). Modeling the Patatin Domain of Neuropathy Target Esterase. Published in the Protein Journal.
- Upton, L.G., and Wijeyesakere, S.J. (2004). Occurrence of Tinnitus in the TMD Population. Published in the International Tinnitus Journal.
- Wijeyesakere, S.J., Gagnon, J., Arora, K., Brooks, C.L III., and Raghavan, M. (2015). ATP regulates interactions between calreticulin and monoglucosylated substrates. Poster presentation given at the 20th Annual Midwest Stress Response and Molecular Chaperone Meeting. Northwestern University, Evanston, IL.
- Wijeyesakere, S.J., Rizvi, S., and Raghavan M. (2014). Modes of interaction between the chaperone calreticulin (CRT) and protein substrates. Poster presentation given at the Society of Toxicology's annual meeting in Phoenix, AZ.
- Wijeyesakere, S.J., Rizvi, S., and Raghavan M. (2012). Glycan dependent and independent modes of calreticulin-substrate binding. Poster presentation given at the “Molecular Chaperones and the Heat Response” meeting in Cold Spring Harbor, NY.
- Wijeyesakere, S.J. (2010). Modeling the Esterase Domain of Neuropathy Target Esterase. Platform presentation given at the Society of Toxicology's annual meeting in Salt Lake City, UT.
- Wijeyesakere, S.J. (2009). Structural insights into the Calcium-Binding Chaperone Calreticulin. Platform presentation given at the Department of Microbiology and Immunology (University of Michigan) retreat in Augusta, MI.
- Wijeyesakere, S.J. (2009). Structural Insight into Inhibition and Aging of Organophosphorus Compounds (OPs) and Patatin-17, a Homologue of Neuropathy Target Esterase's (NTE) Catalytic Domain. Platform presentation given at the Society of Toxicology's annual meeting in Baltimore, MD.
- Wijeyesakere, S.J. (2008). Dangerous Dyads: The NTE-Patatin Connection. Platform presentation given at the University of Michigan Life Sciences Institute (XTAL Seminar Series) in Ann Arbor, MI.
- Wijeyesakere, S.J. (2006). Patatin as a model for Neuropathy Target Esterase. Platform presentation given at the Great Lakes Bioinformatics Retreat in Grand Rapids, MI.
- Complete list of my published work in MyBibliography (NCBI)
- My research profile on Google Scholar
- My profile on LinkedIn