8S65

1-deoxy-D-xylulose 5-phosphate reductoisomerase (DXR) as target for anti Toxoplasma gondii compounds: crystal structure, biochemical characterization and biological evaluation of inhibitors

Summary for 8S65

• Entry DOI: 10.2210/pdb8s65/pdb
• Descriptor: 1-deoxy-D-xylulose-5-phosphate reductoisomerase, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, 3-[FORMYL(HYDROXY)AMINO]PROPYLPHOSPHONIC ACID, ... (6 entities in total)
• Functional Keywords: 1-deoxy-d-xylulose-5-phosphate reductoisomerase, structural protein
• Biological source: Toxoplasma gondii
• Total number of polymer chains: 2
• Total formula weight: 105796.46

Authors

Mazzone, F.,Hoeppner, A.,Reiners, J.,Applegate, V.,Abdullaziz, M.,Gottstein, J.,Wesemann, M.,Kurz, T.,Smits, S.H.,Pfeffer, K. (deposition date: 2024-02-26, release date: 2024-08-21, Last modification date: 2024-09-04)

Primary citation

Mazzone, F.,Hoeppner, A.,Reiners, J.,Gertzen, C.G.W.,Applegate, V.,Abdullaziz, M.A.,Gottstein, J.,Degrandi, D.,Wesemann, M.,Kurz, T.,Smits, S.H.J.,Pfeffer, K.
1-Deoxy-d-xylulose 5-phosphate reductoisomerase as target for anti Toxoplasma gondii agents: crystal structure, biochemical characterization and biological evaluation of inhibitors.
Biochem.J., 481:1075-1096, 2024

PubMed Abstract: Toxoplasma gondii is a widely distributed apicomplexan parasite causing toxoplasmosis, a critical health issue for immunocompromised individuals and for congenitally infected foetuses. Current treatment options are limited in number and associated with severe side effects. Thus, novel anti-toxoplasma agents need to be identified and developed. 1-Deoxy-d-xylulose 5-phosphate reductoisomerase (DXR) is considered the rate-limiting enzyme in the non-mevalonate pathway for the biosynthesis of the isoprenoid precursors isopentenyl pyrophosphate and dimethylallyl pyrophosphate in the parasite, and has been previously investigated for its key role as a novel drug target in some species, encompassing Plasmodia, Mycobacteria and Escherichia coli. In this study, we present the first crystal structure of T. gondii DXR (TgDXR) in a tertiary complex with the inhibitor fosmidomycin and the cofactor NADPH in dimeric conformation at 2.5 Å resolution revealing the inhibitor binding mode. In addition, we biologically characterize reverse α-phenyl-β-thia and β-oxa fosmidomycin analogues and show that some derivatives are strong inhibitors of TgDXR which also, in contrast with fosmidomycin, inhibit the growth of T. gondii in vitro. Here, ((3,4-dichlorophenyl)((2-(hydroxy(methyl)amino)-2-oxoethyl)thio)methyl)phosphonic acid was identified as the most potent anti T. gondii compound. These findings will enable the future design and development of more potent anti-toxoplasma DXR inhibitors.

PubMed: 39105673
DOI: 10.1042/BCJ20240110

Experimental method

SOLUTION SCATTERING
X-RAY DIFFRACTION (2.56 Å)