Metabolic control analysis of glycolysis in trypanosomes as an approach toimprove selectivity and effectiveness of drugs

Glycolysis is the only ATP-generating process in bloodstream form trypanoso mes and is therefore a promising drug target. Inhibitors which decrease sig nificantly the glycolytic flux will kill the parasites. Both computer simul ation and experimental studies of glycolysis in bloodstream form Trypanosom a brucei indicated that the control of the glycolytic flux is shared by sev eral steps in the pathway. The results of these analyses provide quantitati ve information about the prospects of decreasing the flux by inhibition of any individual enzyme. The plasma membrane glucose transporter appears the most promising target from this perspective, followed by aldolase, glyceral dehyde-3-phosphate dehydrogenase, phosphoglycerate kinase and glycerol-3-ph osphate dehydrogenase. Non-competitive or irreversible inhibitors would be most effective. but it is argued that potent competitive inhibitors can be suitable, provided that the concentration of the competing substrate cannot increase unrestrictedly. Such is the case for inhibitors that compete with coenzymes or with blood glucose. (C) 2000 Elsevier Science B.V. All rights reserved.