The shikimic acid pathway, sometimes referred to as the aromatic biosynthetic pathway, is conserved in bacteria, plants and fungi, however it is absent in mammals. Overall, the pathway effects the conversion of two simple products of carbohydrate catabolism (phosphoenolpyruvate (1) and erythrose-4-phosphate (2)) into the unstable diene chorismate (9). Chorismate (9) represents a major bifurcation point of the pathway and is a common non-aromatic precursor for the biosynthesis of a range of important aromatic metabolites. These include para aminobenzoic acid (PABA, which is converted into the folates), ubiquinone and the aromatic amino acids (Phe, Tyr and Trp).

i) DAHP synthase ii) 3-dehydroquinate synthase iii) 3-dehydroquinate dehydratase iv) shikimate dehydrogenase v) shikimate kinase vi) 5-enolpyruvyl-shikimate -3-phosphate synthase vii) chorismate synthase.

It has recently been demonstrated that the shikimate pathway is vital for the survival of several parasites of the phylum Apicomplexa. This phylum includes species of Plasmodium, Toxoplasma and Cryptosporidium, which are responsible for a variety of devastating diseases in both humans and in livestock. The absence of the pathway in mammals makes it a particularly attractive target for the development of novel antibacterial, herbicidal and, antiparasitic agents. Indeed, agents that target the shikimate pathway may inhibit the growth of bacterial pathogens as well as apicomplexan parasites and the development of such compounds may prove to be particularly beneficial for the treatment of immunecompromised patients who are suffering multiple infections from bacterial and parasitic organisms. A number of recent discoveries have demonstrated that some inhibitors of enzymes of the shikimate pathway possess potent antiparasitic properties and the current aim of our research is to develop rapid synthetic approaches to small libraries of compounds, which have been selected as potential inhibitors of different enzymes on the pathway. In this regard, we have recently been successful in carrying out efficient syntheses of 3-deoxy-3a-fluoroshikimic acid, 3-deoxy-3,3-difluoroshikimic acid and a novel difluoromethylene homologue of shikimic acid.

 

Collaborations with colleagues both in the UK as well as in the USA will allow rapid assessment of the biological properties of these compounds.

 

 

Bacteria, plants and other lower organisms have the ability to synthesise almost everything that they require for survival whereas many of the enzymes necessary to accomplish this were lost at a relatively early stage of animal evolution. Over recent years, a huge amount of effort has been invested in the search for new inhibitors of amino acid biosynthesis with the aim of discovering highly potent herbicides and antibacterial agents with low mammalian toxicity. Relatively little effort has been expended on studying the enzymes of the histidine biosynthetic pathway as targets for the design of inhibitors and it is the aim of our proposed research to prepare novel analogues of intermediates on this pathway which, it is predicted, will possess desirable herbicidal and/or anti-bacterial properties. We are interested in preparing competitive inhibitors of imidazole glycerol phosphate dehydratase which catalyses the conversion of imidazole glycerol phosphate to imidazole acetol phosphate. Several inhibitors of this enzyme have previously been reported, a number of which show herbicidal activity.

 

 

THE TRYPTOPHAN BIOSYNTHETIC PATHWAY

 

The aim of our research has been to prepare a variety of novel fluorinated analogues of intermediates on the tryptophan biosynthetic pathway using both chemical and chemo-enzymatic approaches. We are particularly interested in the enzyme tryptophan synthase which catalyses the conversion of indole-3-glycerol phosphate to L-tryptophan. Our principle targets have been selected as rationally designed "prodrugs" for the intracellular liberation of highly toxic agents, and, as such, our targets are expected to possess antibacterial and/or antifungal activity.

 

tryptophan synthase a-subunit