UBC Theses and Dissertations

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UBC Theses and Dissertations

Progress towards the synthesis of the bacterial menaquinone biosynthetic enzyme, 1,4-dihydroxy-6-naphthoate synthase Hrysio, Ursula Winter


1,4-dihydroxy-6-naphthoate (DHN) synthase is one of several enzymes of the menaquinone biosynthetic pathway found in pathogenic bacteria including Campylobacter jejuni and Helicobacter pylori. It is responsible for catalyzing the formation of the 1,4-dihydroxy-6-naphthoate core of the electron transport system cofactor, menaquinone. Since humans lack the ability to synthesize menaquinone, enzymes of bacterial menaquinone biosynthesis have been targeted for inhibitor design. In order to aid the design of potential inhibitors of DHN synthase, its mechanism of catalysis has to be conclusively proven. We have proposed two possible reaction mechanisms that can be distinguished from one another, as they release different 3-carbon byproducts in addition to DHN. In order to establish the identity of these byproducts, and thus establish DHN synthase’s mechanism of action, hundred milligram quantities of substrate, much higher than the natural quantity of enzymatically-produced substrate, have to be synthesized. Accesss to synthetic substrate will allow for kinetic testing of potential inhibitors. In this thesis, progress towards the synthesis of two compounds will be presented. One is the natural substrate, CDHF, cyclic de-hypoxanthine futalosine and the other, de-carboxy CDHF, is a substrate analog devoid of a carboxylic acid functionality. We have demonstrated that an oxidative aromatic cyclization of a naphthol core successfully produces a key intermediate in the overall synthesis. This should ultimately allow for the completion of the synthesis of the substrate and the elucidation of the mechanism.

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