8C79

Crystal structure of Leishmania donovani 6-Phosphogluconate Dehydrogenase complexed with NADPH

Summary for 8C79

• Entry DOI: 10.2210/pdb8c79/pdb
• Descriptor: 6-phosphogluconate dehydrogenase, decarboxylating, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, PHOSPHATE ION, ... (4 entities in total)
• Functional Keywords: leishmania donovani, trypanosoma, pentose phosphate pathway, 6-phosphogluconate dehydrogenase, oxidoreductase, antioxidant defense, drug target
• Biological source: Leishmania donovani
• Total number of polymer chains: 2
• Total formula weight: 105416.71

Authors

Fritz-Wolf, K.,Berneburg, I.,Rahlfs, S.,Becker, K. (deposition date: 2023-01-13, release date: 2023-05-24, Last modification date: 2024-02-07)

Primary citation

Berneburg, I.,Stumpf, M.,Velten, A.S.,Rahlfs, S.,Przyborski, J.,Becker, K.,Fritz-Wolf, K.
Structure of Leishmania donovani 6-Phosphogluconate Dehydrogenase and Inhibition by Phosphine Gold(I) Complexes: A Potential Approach to Leishmaniasis Treatment.
Int J Mol Sci, 24:-, 2023

PubMed Abstract: As unicellular parasites are highly dependent on NADPH as a source for reducing equivalents, the main NADPH-producing enzymes glucose 6-phosphate dehydrogenase (G6PD) and 6-phosphogluconate dehydrogenase (6PGD) of the pentose phosphate pathway are considered promising antitrypanosomatid drug targets. Here we present the biochemical characterization and crystal structure of 6PGD (6PGD) in complex with NADP(H). Most interestingly, a previously unknown conformation of NADPH is visible in this structure. In addition, we identified auranofin and other gold(I)-containing compounds as efficient 6PGD inhibitors, although it has so far been assumed that trypanothione reductase is the sole target of auranofin in . Interestingly, 6PGD from is also inhibited at lower micromolar concentrations, whereas human 6PGD is not. Mode-of-inhibition studies indicate that auranofin competes with 6PG for its binding site followed by a rapid irreversible inhibition. By analogy with other enzymes, this suggests that the gold moiety is responsible for the observed inhibition. Taken together, we identified gold(I)-containing compounds as an interesting class of inhibitors against 6PGDs from and possibly from other protozoan parasites. Together with the three-dimensional crystal structure, this provides a valid basis for further drug discovery approaches.

PubMed: 37239962
DOI: 10.3390/ijms24108615

Experimental method

X-RAY DIFFRACTION (3.1 Å)