Academic Title: Associate Professor
Office: DB 462
Research Homepage: http://www.chem.utoronto.ca/staff/mnitz/homepage.html
Our research focuses on using organic synthesis coupled with the power of biocatalysis and state of the art biophysical techniques such as fluorescence, NMR, mass spectrometry, and microcalorimetry, to creatively assemble new tools for studying biology.
The initial thrust of the proposed research is in the area of glycosaminoglycan (GAG) chemistry and biology. Glycosaminoglycans (below) were once thought to only serve structural roles, but are now beginning to be understood in terms of their crucial functions in mediating communication between a cell and its environment. Recently, glycosaminoglycans have been shown to be essential to the function of the immune system, to be involved in the metastasis of many cancers, to be necessary for invasion of many viruses, and to be important in neuronal regeneration. It is surprising given the successful clinical application of Heparin, a short chain glycosaminoglycan, and the large number of potential biological targets, that glycosaminoglycans drugs have not been widely pursued. By understanding the underlying biology and learning new techniques to synthesize and manipulate this interesting class of natural products, we hope to learn new ways of intervening in a wide variety of human diseases.
The commonly encountered glycosaminoglycans
Our projects focus on four areas:
Chemoenzymatic Synthesis of Glycosaminoglycan Substrates. Using commercially available enzymes, defined Glycosaminoglycan fragments will be generated and used as synthetic starting materials. We will focus on making substrates to define the activities of the important class of cancer related mammalian glycosaminoglycan degrading enzymes, the Hyaluronidases.
Synthesis of Glycosaminoglycan Sensors. It is an extremely challenging task to define the sulfation patterns of glycosaminoglycans. We seek to synthesize fluorescent sensors of specific glycosaminoglycan sulfation patterns based on naturally occurring glycosaminoglycan-binding elements to facilitate this process. Using Fluorescent Resonance Energy Transfer (FRET), environmentally sensitive fluorophores, and peptide design, new GAG sensors will be developed.
The Synthesis of Simple Mimics of Glycosaminoglycans. By oligomerizing monosaccharides that display the sulfate esters crucial to GAG binding events, glycosaminoglycan mimics will be developed. The chemokines are small GAG binding proteins crucial to immune response. Due to their role in many autoimmune diseases, they are ideal targets for the first generation of GAG mimics.
The Directed Evolution of Bacterial Enzymes for Synthesis. The development of new enzymes for chemoenzymatic synthesis with directed evolution is a challenging task requiring grounding in physical chemistry, the tools of organic synthesis, and a lot of creativity. We would like to design enzymes to enable the rapid assembly of large glycosaminoglycans with defined sulfation patterns for studying their biology and potential therapeutic value.
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