Browsing by Author "Frantz, Tagwin Claire"
Now showing 1 - 1 of 1
Results Per Page
Sort Options
- ItemThe control of GAPDH on glycolytic flux in Lactococcus lactis and Plasmodium falciparum.(Stellenbosch : Stellenbosch University, 2022-03) Frantz, Tagwin Claire; Van Niekerk, David Douglas; Snoep, Jacob Leendert; Stellenbosch University. Faculty of Science. Dept. of Biochemistry.ENGLISH ABSTRACT: The parasitic disease, malaria, has the highest prevalence in Africa, and Plasmodium fal- ciparum, the parasite responsible for severe malaria, has rapidly become resistant to cur- rent treatment options. There is a need for new drug targets, and the glycolytic pathway presents several possibilities since it is a source of energy and carbon for the parasite in certain stages of its life cycle. The malaria parasite utilizes host erythrocyte-derived glu- cose via glycolysis. The enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) has emerged as a potential drug target in glycolysis, and several studies have associated glycolytic inhibition with organismal death. However, the overall glycolytic inhibition by an irreversible inhibitor, iodoacetic acid (IAA), acting on GAPDH activity has not been investigated in Plasmodium falciparum. The lactic acid bacterium, Lactococcus lactis, has a glycolytic pathway that is similar in structure to that of P. falciparum, and can serve as a model organism in the laboratory environment. It is also of significant industrial impor- tance. Previous studies have, however, found conflicting results for the glycolytic flux control of GAPDH in L. lactis. In this study we investigated GAPDH flux control by using experimental enzyme kinet- ics, mathematical modeling, and metabolic control analysis to analyze detailed models of glycolysis within L. lactis and P. falciparum, respectively, and to elucidate the flux control of GAPDH under titrations of IAA. We show that low flux control is exerted by GAPDH in both species, with the control in P. falciparum being marginally larger than in L. lactis, but when strongly inhibited, GAPDH obtained full control and was a good target to decrease the glycolytic flux. These results are in excellent agreement with independent simulations of detailed mathematical models that were previously constructed in our group.