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J Biol Chem, Vol. 274, Issue 21, 14551-14559, May 21, 1999
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From On the basis of the experimentally determined
kinetic properties of the trypanosomal enzymes, the question is
addressed of which step limits the glycolytic flux in bloodstream form
Trypanosoma brucei. There appeared to be no single answer;
in the physiological range, control shifted between the glucose
transporter on the one hand and aldolase (ALD),
glyceraldehyde-3-phosphate dehydrogenase (GAPDH), phosphoglycerate
kinase (PGK), and glycerol-3-phosphate dehydrogenase (GDH) on the other
hand. The other kinases, which are often thought to control glycolysis,
exerted little control; so did the utilization of ATP.
We identified potential targets for anti-trypanosomal drugs by
calculating which steps need the least inhibition to achieve a certain
inhibition of the glycolytic flux in these parasites. The glucose
transporter appeared to be the most promising target, followed by ALD,
GDH, GAPDH, and PGK. By contrast, in erythrocytes more than 95%
deficiencies of PGK, GAPDH, or ALD did not cause any clinical symptoms
(Schuster, R. and Holzhütter, H.-G. (1995) Eur. J. Biochem. 229, 403-418). Therefore, the selectivity of drugs
inhibiting these enzymes may be much higher than expected from their
molecular effects alone. Quite unexpectedly, trypanosomes seem to
possess a substantial overcapacity of hexokinase, phosphofructokinase, and pyruvate kinase, making these "irreversible" enzymes mediocre drug targets.
Molecular Cell Physiology, BioCentrum Amsterdam,
Vrije Universiteit De Boelelaan 1087, NL-1081 HV Amsterdam, The
Netherlands, § E. C. Slater Institute, BioCentrum
Amsterdam, University of Amsterdam Plantage Muidergracht 12, NL-1018 TV
Amsterdam, The Netherlands, and Research Unit for Tropical
Diseases, Christian de Duve Institute of Cellular Pathology and
Laboratory of Biochemistry, Catholic University of Louvain, Avenue
Hippocrate 74, B-1200 Brussels, Belgium
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