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UBC Theses and Dissertations

In search of an effective inhibitor of glutamate racemase Yu, Warrick Sze Chung


Glutamate racemase is an enzyme involved in the biosynthesis of peptidoglycan in bacteria. Designing an effective inhibitor of this enzyme can lead to a better understanding of the mechanism employed by this enzyme as well as the development of new antibiotics. A potential inhibitor, 3-(l-hydroxy-2-imidazolyl)propanoic acid, 1, was designed. This compound was synthesized via the construction of an Nhydroxyimidazole ring and the attachment of the glutamate side chain to Position 2 of the ring. A well-established procedure was used in the construction of the imidazole ring involving condensation of hydroxylamine, glyoxal and formaldehyde. However, the attachment of the glutamate side chain involved the introduction of an aldehyde group at Position 2 of the ring and then the attachment of the rest of the side chain via Wittig reaction. Finally, hydrogenation removed the benzyl protecting groups and yielded the desired compound. The potential inhibitor, 1, was then tested with glutamate racemase in a coupled spectrophotometric assay, which involved the use of L-glutamate dehydrogenase and diaphorase as the coupling enzymes. It was found that Compound 1 was a good competitive inhibitor of the coupling enzyme, L-glutamate dehydrogenase, but not of glutamate racemase. The K₁ value of 1 towards L-glutamate dehydrogenase was found to be 1.66 ± 0.52 mM. However, the precise K₁ value towards glutamate racemase was not pursued due to ineffective inhibition. It was suggested that the poor inhibition of 1 towards glutamate racemase was caused by two possible factors. First, the absence of essential charged groups required for substrate binding to the glutamate racemase active site might lead to poor binding of Compound 1. Second, the bulkiness of the imidazole ring might cause steric problems such that the inhibitor could not fit into the glutamate racemase active site.

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