Malarial parasite hexokinase and hexokinase-dependent glutathione reduction in the Plasmodium falciparum-infected human erythrocyte.
The metabolism of glucose in Plasmodium falciparum-infected human erythrocytes is increased 50- to 100-fold. This is accomplished in part by parasite-directed synthesis of a protozoan hexokinase with unique kinetic, electrophoretic, and heat stability properties. The total hexokinase activity is increased approximately 25-fold over that of control uninfected erythrocytes of the same age from the same donor. The parasite hexokinase has a lower affinity for glucose than the mammalian enzyme (Km = 431 microM +/- 21 S.D. for the parasite enzyme versus 98 microM +/- 10 for the erythrocyte enzyme), but the Km for ATP and the Vmax for both glucose and ATP are similar. The NADPH-dependent reduction of oxidized glutathione (GSSG) requires the formation of glucose 6-phosphate which in turn is metabolized by the pentose shunt pathway in which NADPH is generated. Using glucose as the substrate, lysates of P. falciparum-infected normal erythrocytes demonstrated enhanced ability to reduce GSSG. The rate of GSSG reduction was proportional both to the parasitemia and the hexokinase activity of the lysates. However, infected glucose-6-phosphate dehydrogenase-deficient red cell lysates displayed a severely restricted ability to reduce GSSG under the same conditions. In conclusion, P. falciparum-infected red cells contain a parasite-encoded hexokinase with unique properties which initiates the large increase in glucose consumption. In normal infected red cells, reduction of GSSG is also dependent upon hexokinase activity, but in infected glucose-6-phosphate dehydrogenase-deficient red cells, the absence of this pentose shunt enzyme remains the rate-limiting step in GSSG reduction.
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Department of Medicine, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, New York 10467.
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D004912:Erythrocytes / Q000201:enzymology / Q000469:parasitology*; D005947:Glucose / Q000378:metabolism; D005954:Glucosephosphate Dehydrogenase / Q000097:blood; D005978:Glutathione / Q000378:metabolism*; D006593:Hexokinase / Q000378:metabolism*; D006358:Hot Temperature; D006801:Humans; D008288:Malaria / Q000201:enzymology*; D009249:NADP / Q000378:metabolism; D010084:Oxidation-Reduction; D010963:Plasmodium falciparum / Q000201:enzymology
D009249:NADP; D000255:Adenosine Triphosphate; D005954:Glucosephosphate Dehydrogenase; D006593:Hexokinase; D005978:Glutathione; D005947:Glucose