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Characterization of plasmodium falciparum 6-phosphogluconate dehydrogenase as an antimalarial drug target

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Fritz-Wolf,  Karin
Department of Biomolecular Mechanisms, Max Planck Institute for Medical Research, Max Planck Society;

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引用

Haeussler, K., Fritz-Wolf, K., Reichmann, M., Rahlfs, S., & Becker, K. (2018). Characterization of plasmodium falciparum 6-phosphogluconate dehydrogenase as an antimalarial drug target. Journal of Molecular Biology (London), 430(21), 4049-4067. doi:10.1016/j.jmb.2018.07.030.


引用: https://hdl.handle.net/21.11116/0000-0001-ECF4-2
要旨
The enzyme 6-phosphogluconate dehydrogenase (6PGD) of the malaria parasite Plasmodium falciparum catalyzes the third step of the pentose phosphate pathway (PPP) converting 6-phosphogluconate (6PG) to ribulose 5-phosphate. The NADPH produced by 6PGD is crucial for antioxidant defense and redox regulation and ribose 5-phosphate is essential for DNA and RNA synthesis in the rapidly growing parasite. Thus, 6PGD represents an attractive antimalarial drug target. In this study, we present the X-ray structures of Pf6PGD in native form as well as in complex with 6PG or NADP+ at resolutions of 2.8 Å, 1.9 Å, and 2.9 Å, respectively. The overall structure of the protein is similar to structures of 6PGDs from other species; however, a flexible loop close to the active site rearranges upon binding of 6PG and likely regulates the conformation of the cofactor NADP+. Upon binding of 6PG, the active site loop adopts a closed conformation. In the absence of 6PG the loop opens and NADP+ is bound in a waiting position indicating that the cofactor and 6PG bind independently from each other. This sequential binding mechanism was supported by kinetic studies on the homodimeric wildtype Pf6PGD. Furthermore, the function of the Plasmodium-specific residue W104 L mutant was characterized by site-directed mutagenesis. Notably, the activity of Pf6PGD was found to be post-translationally redox regulated via S-nitrosylation and screening the MMV Malaria Box identified several compounds with IC50s in the low micromolar range. Together with the three-dimensional structure of the protein, this is a promising starting point for further drug discovery approaches.