3SQP

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

3SQP の概要

• エントリーDOI: 10.2210/pdb3sqp/pdb
• 分子名称: Glutathione reductase, mitochondrial, FLAVIN-ADENINE DINUCLEOTIDE, SULFATE ION, ... (6 entities in total)
• 機能のキーワード: cellular reductants, glutathione reductase, plasmodium falciparum, pyocyanin, alternative initiation, flavoprotein, mitochondrion, oxidoreductase, phosphoprotein, redox-active center, transit peptide, oxidoreductase-antibiotic complex, oxidoreductase/antibiotic
• 由来する生物種: Homo sapiens
• 細胞内の位置: Isoform Mitochondrial: Mitochondrion. Isoform Cytoplasmic: Cytoplasm: P00390
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 105832.49

構造登録者

Fritz-Wolf, K.,Schirmer, R.H.,Koenig, I.,Goebel, U. (登録日: 2011-07-06, 公開日: 2011-09-14, 最終更新日: 2024-11-27)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.21 Å)