3SQP

Structure of human glutathione reductase complexed with pyocyanin, an agent with antimalarial activity

Summary for 3SQP

• Entry DOI: 10.2210/pdb3sqp/pdb
• Descriptor: Glutathione reductase, mitochondrial, FLAVIN-ADENINE DINUCLEOTIDE, SULFATE ION, ... (6 entities in total)
• Functional Keywords: cellular reductants, glutathione reductase, plasmodium falciparum, pyocyanin, alternative initiation, flavoprotein, mitochondrion, oxidoreductase, phosphoprotein, redox-active center, transit peptide, oxidoreductase-antibiotic complex, oxidoreductase/antibiotic
• Biological source: Homo sapiens
• Cellular location: Isoform Mitochondrial: Mitochondrion. Isoform Cytoplasmic: Cytoplasm: P00390
• Total number of polymer chains: 2
• Total formula weight: 105832.49

Authors

Fritz-Wolf, K.,Schirmer, R.H.,Koenig, I.,Goebel, U. (deposition date: 2011-07-06, release date: 2011-09-14, Last modification date: 2024-11-27)

Primary citation

Kasozi, D.M.,Gromer, S.,Adler, H.,Zocher, K.,Rahlfs, S.,Wittlin, S.,Fritz-Wolf, K.,Schirmer, R.H.,Becker, K.
The bacterial redox signaller pyocyanin as an antiplasmodial agent: comparisons with its thioanalog methylene blue.
Redox Rep., 16:154-165, 2011

PubMed Abstract: The quorum sensor and signalling molecule pyocyanin (PYO) contributes significantly to the pathophysiology of Pseudomonas aeruginosa infections. Comparison to phenothiazine drugs suggests that the antimalarial compound methylene blue (MB) can be regarded as a sulfur analog of PYO. This working hypothesis would explain why the synthetic drug MB behaves as a compound shaped in biological evolution. Here we report on redox-associated biological and biochemical properties of PYO in direct comparison to its synthetic analog MB. We quantitatively describe the reactivity of both compounds toward cellular reductants, the reactivity of their reduced leuco-forms towards O2, and their interactions with FAD-containing disulfide reductases. Furthermore, the interaction of PYO with human glutathione reductase was studied in structural detail by x-ray crystallography, showing that a single PYO molecule binds to the intersubunit cavity of the enzyme. Like MB, also PYO was also found to be active against blood schizonts of the malaria parasite P. falciparum in vitro. Furthermore, both compounds were active against the disease transmitting gametocyte forms of the parasites, which was systematically studied in vitro. As shown for mice, PYO is too toxic to be used as a drug. It may, however, have antimalarial activity in numerous human patients with concomitant Pseudomonas infections. MB, in contrast to PYO, is well tolerated and represents a promising agent for MB-based combination therapies against malaria. Current and future clinical studies can be guided by the comparisons between MB and PYO reported here. Additionally, it is of interest to study if and to what extent the protection from malaria in patients with cystic fibrosis or with severe wound infections is based on PYO produced by Pseudomonas species.

PubMed: 21888766
DOI: 10.1179/174329211X13049558293678

Experimental method

X-RAY DIFFRACTION (2.21 Å)