The emergence of antibiotic resistance to current treatments of bacterial
infection represents a major challenge that needs to be addressed with the
development of new generations of inhibitors. The enzyme 5-enolpyruvylshikimate 3-
phosphate synthase (EPSPS) catalyses the sixth step in the shikimate biosynthetic
pathway, which is essential for the synthesis of aromatic compounds such as the
aromatic amino acids phenylalanine, tryptophan and tyrosine. It occurs in plants,
bacteria and some parasites. Since the pathway is absent in mammals but essential for
the pathogenicity of a number of organisms, EPSPS is considered a prospective target
for new inhibiter design. A number of EPSPS inhibitors have been reported in the
literature. What we are lacking is an understanding of the features that are important
for binding EPSPS. We have synthesized compounds to probe the active site of the
enzyme based on the knowledge of an enzyme-catalyzed intermediate with a high
cationic character. This will include assembling bipartite/tripartite inhibitors to
discover what interactions or structural motifs are important for binding. Once the
features important for binding to EPSPS are understood, the possibility of elaborating
them to create potent inhibitors of EPSPS will be investigated. In addition, the
synthesis of two shikimate analogs [5-^(18)O] shikimic acid and 4-deoxyshikimic acid
were completed for further experiments to probe the enzyme mechanism in detail, and for transition state structure by transition state analysis. Transition state analysis using
kinetic isotopic effects (KIE) will elucidate the transition state structure of the
enzyme-catalyzed EPSP reaction, and provide a detailed starting point for designing
EPSPS inhibitors. / Thesis / Master of Science (MSc)
| Identifer | oai:union.ndltd.org:mcmaster.ca/oai:macsphere.mcmaster.ca:11375/21598 |
| Date | 10 1900 |
| Creators | Gawuga, Vivian |
| Contributors | Berti, Paul, Capretta, Fred, Chemistry |
| Source Sets | McMaster University |
| Language | English |
| Detected Language | English |
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