Control of glycolysis and drug development
Recent studies have addressed the question which steps in the EMP control the glycolytic flux in the bloodstream form of T.brucei. Such information is relevant for the development of new anti-trypanosomal drugs because the selectivity of a drug may be enhanced by choosing an enzyme which has a high control in the parasite, but a low control in the host. Since for T. brucei sufficient kinetic data about the individual enzymes of the glycolytic pathway are now available, the answer to this question can be calculated. Interestingly, and contrary to what had been claimed before, control is not limited to the glucose transporter alone (Eisenthal, 1989; Gruenberg et al., 1978; Seyfang and Duszenko, 1991; Ter Kuile and Opperdoes, 1991), but is spread over the transporter and several of the glycolytic enzymes (Bakker et al., 1998). Even conditions can be found where the transporter does not, or only partially, control the glycolytic flux. Control depends considerably on the external glucose concentration and on the individual enzyme activities. Under the conditions studied control shifts from the transport of glucose on the one hand and aldolase, GAPDH, PGK and G3PDH on the other hand, with the increase in the glucose concentration. Under physiological conditions most of the control seems associated with the transporter. The other kinases, HK, PFK and PYK, which are thought to control glycolysis in other organisms, have no significant control under any of the investigated conditions (Bakker et al., 1998).
Most studies aiming at the design of new anti-glycolytic trypanocides have focused on the individual enzymes without taking into consideration whether the inhibition of such an enzyme would lead to the inhibition of the glycolytic flux. Until now efforts have focused on the enzymes aldolase (Perié et al., 1993; Samson et al., 1997) GAPDH (Kim et al., 1995; Perié et al., 1993; Van Calenbergh et al., 1995; Vellieux et al., 1993; Verlinde et al., 1994, Willson et al., 1994) and PGK (Bernstein et al., 1997). Although the studies by Bakker et al. (1998) have shown that the individual enzymes of glycolysis exert less control than the transporter step this does not imply that all efforts should now be shifted to the synthesis of inhibitors of glucose transport. In the case of the enzymes GAPDH and PGK it could be calculated that a difference in effectiveness for inhibition of the glycolytic flux could be overcome by the design of inhibitors that had a two-fold higher affinity for their respective enzymes.