Ribose metabolism and nucleic acid synthesis in normal and glucose-6-phosphate dehydrogenase-deficient human erythrocytes infected with Plasmodium falciparum.

Abstract

The metabolism of pentose-phosphate was investigated in Plasmodium fakiparum-infected normal and glucose-6-phosphate dehydrogenase (G6PD)-deficient human red blood cells in vitro.5'-Phosphoribosyl-l-pyrophosphate (PRPP) content of infected normal red blood cells was increased 50-60-fold at the parasite trophozoite growth stage over that of uninfected cells. The PRPP increment in infected G6PD-deficient cells at comparable stage and parasitemia was only 40% of the value in normal infected cells. Red blood cell PRPP synthetase activity did not change during the growth cycle of the parasite and was similar in both normal and G6PD-deficient cells. Reduced glutathione (GSH) content of G6PD-deficient cells under conditions of culture fell to low or undetectable levels. These low levels of GSH were shown to inhibit the function of red blood cell PRPP synthetase, which requires GSH for full activity. Measurements of the incorporation of 1-14C or 6-04C selectively labeled glucose into parasite nucleic acids revealed that in normal infected red cells, -20% of the pentose was produced via the oxidation of glucose-6-phosphate, whereas in infected G6PD-deficient cells (Mediterranean type), none of the pentose was produced via the oxidative pathway. It is concluded that the low level of reduced GSH found in G6PD deficiency and the resultant partial inhibition of PRPP synthetase together with the missing oxidative pathway for ribose phosphate production can account fully for the reduced parasite growth rate in G6PD-deficient red blood cells described previously. Of these two mechanisms, the predominant one is the impaired PRPP synthetase activity due to low GSH levels in enzyme-deficient red blood cells. The contribution to the ribose-phosphate pool by the hexose monophosphate shunt is relatively minor. A co-existing oxidative stress (which is often hypothesized to mediate the destruction of parasitized red blood cells) is not required to explain growth inhibition in this scheme and does not represent the most straightforward explgnation of the data described in this report.

Plasmodium falciparum glutathione metabolism and growth are independent of glutathione system of host erythrocyte

“…Parasite growth has been reported in some studies to be inhibited in RBC mutants with low GSH levels, such as in glucose‐6‐phosphate dehydrogenase (G6PD)‐deficient RBC [5–8], while in other studies parasite growth appeared to be normal in G6PD‐deficient RBC [5, 9]. Growth inhibition data [5, 9], and results by Roth et al [10]showing that GSH was extremely low in parasitized G6PD‐deficient RBC, seemed to imply that parasite GSH was dependent on the host's glutathione system.…”

Data mining of the transcriptome of Plasmodium falciparum: the pentose phosphate pathway and ancillary processes

“…The reverse activity of the non-oxidative arm of PPP has also been demonstrated by measuring the incorporation of radiolabel from [1- 14 C]glucose into nucleotides [6,8]. The former investigators have shown that 4/5 of the glucose incorporated into parasite nucleic acids comes from the condensation of F6P and GAP in the reverse action of this arm.…”

“…Activity of 6-phosphogluconate dehydrogenase in Plasmodium- infected erythrocytes has been detected indirectly and alluded to a parasite enzyme, but not characterized [15-17]. Ribose-phosphate diphosphokinase of P. falciparum activity has been characterized and levels of its product 5'-phosphoribosyl-pyrophospate (PRPP) were measured in P. falciparum- infectederythrocytes [8,18]. The levels of PRPP were found to be increased 56-fold in infected cells at the trohozoite stage compared to uninfected erythrocytes.…”

Oxidative Stress: Cause and Consequence of Diseases

“…On the other hand, PRPP synthetase was shown to be strongly dependent on the level of reduced glutathione (GSH). Since G6PDH-deficient erythrocytes possess low GSH level, the activity of PRPP synthetase is low in these cells and restricts parasite growth rate (Roth et al, 1986).…”