scholarly journals Reversible Heme-Dependent Regulation of Human Cystathionine β-Synthase by a Flavoprotein Oxidoreductase

Biochemistry ◽  
2011 ◽  
Vol 50 (39) ◽  
pp. 8261-8263 ◽  
Author(s):  
Omer Kabil ◽  
Colin L. Weeks ◽  
Sebastián Carballal ◽  
Carmen Gherasim ◽  
Beatriz Alvarez ◽  
...  
Keyword(s):  
Flavoprotein Oxidoreductase

scholarly journals Transformation of 2,4,6-Trinitrotoluene by Purified Xenobiotic Reductase B from Pseudomonas fluorescensI-C

2000 ◽  
Vol 66 (11) ◽  
pp. 4742-4750 ◽  
Author(s):  
Jeong W. Pak ◽  
Kyle L. Knoke ◽  
Daniel R. Noguera ◽  
Brian G. Fox ◽  
Glenn H. Chambliss
Keyword(s):  
Functional Group ◽  
Ionization Mass ◽  
Enzymatic Reactions ◽  
Environmental Significance ◽  
Chemical Structures ◽  
Enzymatic Transformation ◽  
Group Reduction ◽  
Flavoprotein Oxidoreductase ◽  
Dimerization Reaction ◽  
Nitro Group Reduction

ABSTRACT The enzymatic transformation of 2,4,6-trinitrotoluene (TNT) by purified XenB, an NADPH-dependent flavoprotein oxidoreductase fromPseudomonas fluorescens I-C, was evaluated by using natural abundance and [U-14C]TNT preparations. XenB catalyzed the reduction of TNT either by hydride addition to the aromatic ring or by nitro group reduction, with the accumulation of various tautomers of the protonated dihydride-Meisenheimer complex of TNT, 2-hydroxylamino-4,6-dinitrotoluene, and 4-hydroxylamino-2,6-dinitrotoluene. Subsequent reactions of these metabolites were nonenzymatic and resulted in predominant formation of at least three dimers with an anionic m/z of 376 as determined by negative-mode electrospray ionization mass spectrometry and the release of ∼0.5 mol of nitrite per mol of TNT consumed. The extents of the initial enzymatic reactions were similar in the presence and in the absence of O2, but the dimerization reaction and the release of nitrite were favored under aerobic conditions or under anaerobic conditions in the presence of NADP+. Reactions of chemically and enzymatically synthesized and high-pressure liquid chromatography-purified TNT metabolites showed that both a hydroxylamino-dinitrotoluene isomer and a tautomer of the protonated dihydride-Meisenheimer complex of TNT were required precursors for the dimerization and nitrite release reactions. The m/z 376 dimers also reacted with either dansyl chloride or N-1-naphthylethylenediamine HCl, providing evidence for an aryl amine functional group. In combination, the experimental results are consistent with assigning the chemical structures of them/z 376 species to various isomers of amino-dimethyl-tetranitrobiphenyl. A mechanism for the formation of these proposed TNT metabolites is presented, and the potential enzymatic and environmental significance of their formation is discussed.

scholarly journals Leishmania mexicana Trypanothione Reductase Inhibitors: Computational and Biological Studies

Molecules ◽  
2019 ◽  
Vol 24 (18) ◽  
pp. 3216 ◽  
Author(s):  
Félix Matadamas-Martínez ◽  
Alicia Hernández-Campos ◽  
Alfredo Téllez-Valencia ◽  
Alejandra Vázquez-Raygoza ◽  
Sandra Comparán-Alarcón ◽  
...  
Keyword(s):  
New Drugs ◽  
Dynamics Simulation ◽  
Mammalian Host ◽  
Trypanothione Reductase ◽  
Leishmania Mexicana ◽  
Reductase Inhibitors ◽  
Zinc Database ◽  
Biological Studies ◽  
Starting Point ◽  
Flavoprotein Oxidoreductase

Leishmanicidal drugs have many side effects, and drug resistance to all of them has been documented. Therefore, the development of new drugs and the identification of novel therapeutic targets are urgently needed. Leishmania mexicana trypanothione reductase (LmTR), a NADPH-dependent flavoprotein oxidoreductase important to thiol metabolism, is essential for parasite viability. Its absence in the mammalian host makes this enzyme an attractive target for the development of new anti-Leishmania drugs. Herein, a tridimensional model of LmTR was constructed and the molecular docking of 20 molecules from a ZINC database was performed. Five compounds (ZINC04684558, ZINC09642432, ZINC12151998, ZINC14970552, and ZINC11841871) were selected (docking scores −10.27 kcal/mol to −5.29 kcal/mol and structurally different) and evaluated against recombinant LmTR (rLmTR) and L. mexicana promastigote. Additionally, molecular dynamics simulation of LmTR-selected compound complexes was achieved. The five selected compounds inhibited rLmTR activity in the range of 32.9% to 40.1%. The binding of selected compounds to LmTR involving different hydrogen bonds with distinct residues of the molecule monomers A and B is described. Compound ZINC12151998 (docking score −10.27 kcal/mol) inhibited 32.9% the enzyme activity (100 µM) and showed the highest leishmanicidal activity (IC50 = 58 µM) of all the selected compounds. It was more active than glucantime, and although its half-maximal cytotoxicity concentration (CC50 = 53 µM) was higher than that of the other four compounds, it was less cytotoxic than amphotericin B. Therefore, compound ZINC12151998 provides a promising starting point for a hit-to-lead process in our search for new anti-Leishmania drugs that are more potent and less cytotoxic.

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