Sanjeeva Wijeyesakere

Education

The University of Michigan (Ann Arbor, MI)

Professional background

I am a toxicologist with a research background in cheminformatics / predictive toxicology, neuroscience, and epidemiology. My research interests lie in applying new approach methods to understand and predict the key steps and molecular initiating events that drive adverse human-health outcomes following xenobiotic [chemical] exposure.

Ingalls Mall at the UM Ann Arbor

Ingalls Mall at the University of Michigan, Ann Arbor. The Burton Memorial Tower is seen in the center.

I earned my PhD in Toxicology from the University of Michigan where I studied interactions between organophosphorus (OP) compounds and the neuronal integral membrane protein neuropathy target esterase (NTE). NTE (also known as patatin-like phospholipase domain-containing protein 6 (PNPLA6)) is a lysophospholipase that is thought to be the cellular target for certain classes of OP compounds that can cause a delayed axonopathy. This condition, termed OP compound-induced delayed toxicity (OPIDN), can result in permanent paralysis. A key feature of this affliction is the 7-14 day delay between exposure and onset of symptoms. Currently, very little is known about the structure of NTE and the mechanism whereby interactions between neuropathic OP compounds (OPs that can cause OPIDN) and NTE initiate the cascade of subcellular events that result in pathology. To this end, I have used patain (the plant-homologue of NTE that is expressed in the tubers of potatoes and related species and is the eponymous member of the PNPLA family of enzymes) to study changes in its [patatin's] tertiary structure following interactions with both neuropathic and non-neuropathic OP compounds.

My prior research focused on the role of periaqueductal grey region of the brain in the acquisition od 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

Protein crystal structures I have solved

  1. 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 Å (PDB ID 1OXW)
  2. Patatin adducted to an aged diisopropyl fluorophosphate moiety (PDB ID 4PKA)
  3. Patatin adducted to an unaged methoxy arachidonyl fluorophosphonate moiety (PDB ID 4PKB)

Publications

  1. Firman, J.W., Boobis, A., Hollnagel, H.M., Kaiser, S., Lovell, D.P., Moretto, A., Mueller, S., Rider, C.V., Schmidt, F., Stice, S., Wijeyesakere, S.J., Borja, G., and Patlewicz, G. (2024). Evaluating the consistency of judgments derived through both in silico and expert application of the Cramer classification scheme. Published in Food and Chemical Toxicology.
  2. Settivari, R.S., Martini, A., Wijeyesakere, S.J., Toltin, A., and LeBaron, M.J. (2024). Application of Evolving New Approach Methodologies for Chemical Safety Assessment. In A Comprehensive Guide to Toxicology in Nonclinical Drug Development (Third Edition) (Faqi, A.S., ed), Academic Press. pp 977-1015.
  3. Wijeyesakere, S.J., and Richardson, R.J. (2023). Computational Toxicology. In Patty's Toxicology (eds E. Bingham, B. Cohrssen and C.H. Powell), Wiley. pp 1-18.
  4. Wijeyesakere, S.J., Auernhammer, T., Parks, A., and Wilson, D. (2023). Profiling mechanisms that drive acute oral toxicity in mammals and its prediction via machine learning. Published in Toxicological Sciences.
  5. Wijeyesakere, S.J., Wilson, D., Auernhammer, T., Parks, A., and Marty M.S. (2022). Machine-Learning Model Predicts Interaction with γ-Amino Butyric Acid (GABA)ergic Neurotransmission. Published in Applied In Vitro Toxicology.
  6. Venkatesan, A., Geng, J., Kandarpa, M., Wijeyesakere, S.J., et al. (2021). Mechanism of mutant calreticulin-mediated activation of the thrombopoietin receptor in cancers . Published in Journal of Cell Biology.
  7. Mansouri, K., Karmaus, A.L., Fitzpatrick, J., Patlewicz, G., Pradeep, P., Alberga, D., Alepee, N., Allen, T.E.H., Allen, D., Alves, V.M., Andrade, C.H., Auernhammer, T.R., Ballabio, D., Bell, S., Benfenati, E., Bhattacharya, S., Bastos, J.V., Boyd, S., Brown, J.B., Capuzzi, S.J., Chushak, Y., Ciallella, H., Clark, A.M., Consonni, V., Daga, P.R., Ekins, S., Farag, S., Fedorov, M., Fourches, D., Gadaleta, D., Gao, F., Gearhart, J.M., Goh, G., Goodman, J.M., Grisoni, F., Grulke, C.M., Hartung, T., Hirn, M., Karpov, P., Korotcov, A., Lavado, G.J., Lawless, M., Li, X., Luechtefeld, T., Lunghini, F., Mangiatordi, G.F., Marcou, G., Marsh, D., Martin, T., Mauri, A., Muratov, E.N., Myatt, G.J., Nguyen, D.-T., Nicolotti, O., Note, R., Pande, P., Parks, A.K., Peryea, T., Polash, A.H., Rallo, R., Roncaglioni, A., Rowlands, C., Ruiz, P., Russo, D.P., Sayed, A., Sayre, R., Sheils, T., Siegel, C., Silva, A.C., Simeonov, A., Sosnin, S., Southall, N., Strickland, J., Tang, Y., Teppen, B., Tetko, I.V., Thomas, D., Tkachenko, V., Todeschini, R., Toma, C., Tripodi, I., Trisciuzzi, D., Tropsha, A., Varnek, A., Vukovic, K., Wang, Z., Wang, L., Waters, K.M., Wedlake, A.J., Wijeyesakere, S.J., Wilson, D., Xiao, Z., Yang, H., Zahoranszky-Kohalmi, G., Zakharov, A.V., Zhang, F.F., Zhang, Z., Zhao, T., Zhu, H., Zorn, K.M., Casey, W., Kleinstreuer, N.C. (2021). CATMoS: Collaborative Acute Toxicity Modeling Suite. Published in Environmental Health Prespectives.
  8. Wijeyesakere, S.J., Wilson, D.M., and Marty M.S. (2020). Prediction of cholinergic compounds by machine-learning. Published in Computational Toxicology.
  9. Richardson, R.J., Fink, J.K., Glynn, P., Hufnagel, R.B., Makhaeva, G.F., and Wijeyesakere, S. J. (2020). Chapter 1: Neuropathy target esterase (NTE/PNPLA6) and organophosphorus compound-induced delayed neurotoxicity (OPIDN). In Advanced in Neurotoxicology (1st ed., Vol. 4).
  10. Richardson, R.J., Fink, J.K., Worden, R.M., Hufnagel, R.B., Wijeyesakere, S.J., Makhaeva, G.F.(2020). Chapter 58 - Neuropathy target esterase as a biomarker and biosensor of delayed neuropathic agents. In Handbook of Toxicology of Chemical Warfare Agents (3rd ed.).
  11. 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.
  12. 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.
  13. 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.
  14. 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.
  15. 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.
  16. 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).
  17. 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.
  18. 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.
  19. 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.
  20. 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.
  21. 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.
  22. 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.
  23. 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.
  24. Wijeyesakere, S.J., and Richardson, R.J. (2010). Neuropathy target esterase. In The Hayes Handbook of Pesticide Toxicity (3rd ed). pp 1435-1455.
  25. Wijeyesakere, S.J. (2009). Enzyme aging: structural insights from NTE and patatin. PhD Dissertation. The University of Michigan, Ann Arbor. (Link in Mirlyn).
  26. 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.
  27. 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).
  28. Wijeyesakere, S.J., Richardson, R,J,, and Stuckey J.A. (2007). Modeling the Patatin Domain of Neuropathy Target Esterase.  Published in the Protein Journal.
  29. Upton, L.G., and Wijeyesakere, S.J. (2004). Occurrence of Tinnitus in the TMD Population. Published in the International Tinnitus Journal.

Selected Platform and Poster Presentations

  1. Wijeyesakere, S.J., Wilson, D.M., Auernhammer, T., Parks, A., and Marty M.S. (2022). Profiling mechanisms that drive acute oral toxicity in mammals and its prediction via machine learning. Platform presentation given at the 11th Annual Meeting of the American Society for Cellular and Computational Toxicology. Chapel Hill, NC.
  2. Wijeyesakere, S.J., Wilson, D., Auernhammer, T., Parks, A., and Marty, M.S. (2019). Using machine learning to predict interactions with the nervous system. Poster presented at Society of Toxicology Annual Meeting, Baltimore, MD.
  3. Wilson, D., Wijeyesakere, S.J., Auernhammer, T., Parks, A., and Marty, M.S. (2019). Machine-learning model predicts mitochondrial inhibition. Presented at Society of Toxicology Annual Meeting, Baltimore, MD.
  4. Wijeyesakere, S.J., Wilson, D., Auernhammer, T., Parks, A., and Marty, S. (2018). Developing highly accurate computational models for neuronal targets. Presented at QSAR 2018 meeting, Bled, Slovenia.
  5. Wijeyesakere, S.J., Parks, A., Auernhammer, T., Zhang, F., and Wilson, D., (2018). Computational approaches for acute toxicity. Poster presented at the Predictive Models for Acute Oral Systemic Toxicity workshop, National Institutes of Health in Bethesda, MD.
  6. Wijeyesakere, S.J., Wilson, D., Parks, A., Auernhammer, T., and Marty, S. (2018). Using public data to develop an open-access computational KNIME workflow to identify any cholinergic compound. Poster presented at Society of Toxicology Annual Meeting, San Antonio, TX.
  7. Andrus, A.K., Wijeyesakere, S.J., Wilson, D.M., Auernhammer, R.T., Parks, A., and Marty, S. (2018). Development of a computerized workflow to predict nicotinic acetylcholine receptor-mediated acute mammalian toxicity. Poster presented at Society of Toxicology Annual Meeting, San Antonio, TX.
  8. Settivari, R., Wijeyesakere, S.J., Wilson, D.M., Auernhammer, R.T., Parks, A., and Marty, S. (2018). Assessment of the accuracy of OECD ToolBox profilers to identify reactive chemicals associated with skin sensitization. Presented at Society of Toxicology Annual Meeting, San Antonio, TX.
  9. Wijeyesakere, S.J., Wilson, D., Parks, A., Auernhammer, T., and Marty, S. (2017). Using public data to develop open-access computational KNIME workflows that identify neurologic compounds. Poster presented at the University of Michigan MIDAS meeting, Ann Arbor, MI.
  10. Wijeyesakere, S.J., Gagnon, J., Arora, K., Brooks, C.L III., and Raghavan, M. (2015). ATP regulates interactions between calreticulin and monoglucosylated substrates. Poster presented at the 20th Annual Midwest Stress Response and Molecular Chaperone Meeting. Northwestern University, Evanston, IL.
  11. Wijeyesakere, S.J., Rizvi, S., and Raghavan M. (2014). Modes of interaction between the chaperone calreticulin (CRT) and protein substrates. Poster presented at the Society of Toxicology's annual meeting in Phoenix, AZ.
  12. Wijeyesakere, S.J., Rizvi, S., and Raghavan M. (2012). Glycan dependent and independent modes of calreticulin-substrate binding. Poster presented at the Molecular Chaperones and the Heat Response meeting in Cold Spring Harbor, NY.
  13. 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.
  14. 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.
  15. 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.
  16. 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.
  17. 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.

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