6-phosphogluconate dehydrogenase (6PGDH)
6PGDH has been suggested as a potential target for chemotherapy (Barrett et al., 1993). In other eukaryotic organisms, deletion of the gene encoding 6PGDH is a lethal event (Lobo and Maitra, 1982; Rosemeyer, 1987). Since this is not the case for the first enzyme of the pathway (G6PD), this indicates that the PPP itself is dispensable, but that it is accumulation of 6-phosphogluconate that is toxic to cells. This is corroborated by the observation that the lethal effect of 6PGDH deficiency can be relieved by loss of G6PD in Drosophila melanogaster (Gvodzdev, 1976). Since 6-phosphogluconate (6PG) is a potent inhibitor of phosphoglucose isomerase (PGI), including the T. brucei enzyme (Marchand et al., 1989), inhibition of 6PGD is thought to lead to accumulation of 6PG and hence the inhibition of both pathways of glucose metabolism (Rosemeyer, 1987).
The gene that codes the T. brucei 6PGDH has been cloned, and the enzyme purified and crystallized (Barrett et al., 1993;1994; Phillips et al., 1993). It is remarkably different from other 6PGDHs in that it shares less than 40% amino-acid sequence identity with all other available bacterial and eukaryotic 6PGDH sequences, while these others share at least 50% sequence identity (Opperdoes, unpublished). This makes it more likely to find exploitable differences between the T. brucei and the host 6PGDH . The trypanocidal drug suramin inhibits 6PGD. Also the trivalent aromatic arsenoxides inactivate the enzyme with extreme potency, although it has been ruled out that this enzyme represents a primary target for trypanocidal arsenicals (Hanau et al., 1996).