On the basis of the experimentally determined kinetic properties of the try
panosomal enzymes, the question is addressed of which step limits the glyco
lytic flux in bloodstream form Trypanosoma brucei. There appeared to be no
single answer; in the physiological range, control shifted between the gluc
ose transporter on the one hand and aldolase (ALD), glyceraldehyde-3-phosph
ate dehydrogenase (GAPBH), phosphoglycerate kinase (PGK), and glycerol-3-ph
osphate dehydrogenase (GDH) on the other hand. The other kinases, which are
often thought to control glycolysis, exerted little control; so did the ut
ilization of ATP.
We identified potential targets for anti-trypanosomal drugs by calculating
which steps need the least inhibition to achieve a certain inhibition of th
e glycolytic flux in these parasites. The glucose transporter appeared to b
e the most promising target, followed by ALD, GDH, GAPDH, and PGK, By contr
ast, in erythrocytes more than 95% deficiencies of PGK, GAPDH, or ALD did n
ot cause any clinical symptoms (Schuster, R. and Holzhutter, H.-G. (1995) f
ur. J. Biochem. 229, 403-418), Therefore, the selectivity of drugs inhibiti
ng these enzymes may be much higher than expected from their molecular effe
cts alone, Quite unexpectedly trypanosomes seem to possess a substantial ov
ercapacity of hexokinase, phosphofructokinase, and pyruvate kinase, making
these "irreversible" enzymes mediocre drug targets.