fumarates and quinone

The Complex II family encompasses membrane bound succinate:quinones reductases and quinol:fumarate reductases that catalyze interconversion of succinate and fumarate coupled with reduction and oxidation of quinone. These enzymes are found in all biological genres and share a modular structure where a highly conserved soluble domain is bound to a membrane-spanning domain that is represented by distinct variations. The current classification of the complex II family members is based on the number of subunits and co-factors in the membrane anchor (types A-F). This classification also provides insights into possible evolutionary paths and suggests that some of the complex II enzymes (types A-C) co-evolved as the whole assembly. Origin of complex II types D and F may have arisen from independent events of de novo association of the conserved soluble domain with a new anchor. Here we analyze a recent structure of Mycobacterium smegmatis Sdh2, a complex II enzyme with two transmembrane subunits and two heme b molecules. This analysis supports an earlier hypothesis suggesting that mitochondrial complex II (type C) with a single heme b may have evolved as an assembled unit from an ancestor similar to M. smegmatis Sdh2.

Topics: Benzoquinones; Binding Sites; Fumarates; Heme; Hydroquinones; Quinones; Succinate Dehydrogenase; Succinic Acid

Over a decade has passed since the elucidation of the first X-ray crystal structure of any complex II homolog. In the intervening time, the structures of five additional integral-membrane complex II enzymes and three homologs of the soluble domain have been determined. These structures have provided a framework for the analysis of enzymological studies of complex II superfamily enzymes, and have contributed to detailed proposals for reaction mechanisms at each of the two enzyme active sites, which catalyze dicarboxylate and quinone oxidoreduction, respectively. This review focuses on how structural data have augmented our understanding of catalysis by the superfamily. This article is part of a Special Issue entitled: Respiratory complex II: Role in cellular physiology and disease.

Topics: Benzoquinones; Biocatalysis; Electron Transport Complex II; Fumarates; Humans; Kinetics; Models, Molecular; Molecular Structure; Protein Binding; Protein Structure, Tertiary; Protein Subunits; Succinates

Topics: Bacteria; Benzoquinones; Electron Transport Complex II; Fumarates; Hydroquinones; Intracellular Membranes; Models, Chemical; Models, Molecular; Multienzyme Complexes; Oxidoreductases; Succinate Dehydrogenase

Topics: Anaerobiosis; Bacteroides fragilis; Cytochromes; Electron Transport; Fumarates; Humans; NAD; Oxygen; Quinones; Respiration; Succinate Dehydrogenase; Vitamin K 2

Recent studies on the respiratory chain of Ascaris suum showed that the mitochondrial NADH-fumarate reductase system composed of complex I, rhodoquinone and complex II plays an important role in the anaerobic energy metabolism of adult A. suum. The system is the major pathway of energy metabolism for adaptation to a hypoxic environment not only in parasitic organisms, but also in some types of human cancer cells. Thus, enzymes of the pathway are potential targets for chemotherapy. We found that flutolanil is an excellent inhibitor for A. suum complex II (IC50 = 0.058 μM) but less effectively inhibits homologous porcine complex II (IC50 = 45.9 μM). In order to account for the specificity of flutolanil to A. suum complex II from the standpoint of structural biology, we determined the crystal structures of A. suum and porcine complex IIs binding flutolanil and its derivative compounds. The structures clearly demonstrated key interactions responsible for its high specificity to A. suum complex II and enabled us to find analogue compounds, which surpass flutolanil in both potency and specificity to A. suum complex II. Structures of complex IIs binding these compounds will be helpful to accelerate structure-based drug design targeted for complex IIs.

Topics: Anilides; Animals; Ascaris suum; Benzoquinones; Binding Sites; Cell Respiration; Electron Transport Complex II; Enzyme Inhibitors; Fumarates; Mitochondria; Models, Molecular; Oxidoreductases; Parasites; Phosphoenolpyruvate Carboxykinase (ATP); Substrate Specificity; Succinic Acid; Sus scrofa

The cationic oxazaborolidine-catalyzed Diels-Alder reactions of butadiene and a series of five dienophiles have been studied using density functional theory (B3LYP/6-31G(d)). In each case, the computational results successfully reproduce the experimentally observed sense of stereoinduction and enantiomeric ratio. The computed structures of the lowest energy Lewis acid-carbonyl complexes and Lewis acid-transition state complexes are closely related to the models for stereoselection proposed by Corey and co-workers.

Topics: Acrolein; Acrylates; Benzoquinones; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Butadienes; Computer Simulation; Dimethyl Fumarate; Fumarates; Models, Molecular; Molecular Conformation; Stereoisomerism; Substrate Specificity

Parkinson's disease is a neurodegenerative disorder associated with progressive loss of dopaminergic cells in the substantia nigra. Oxidative stress has been implicated in the pathogenesis of the disease, and dopamine has been suggested as a contributing factor that generates reactive oxygen species due to its unstable catechol moiety. We have previously shown that tetrahydrobiopterin (BH4), an obligatory cofactor for dopamine synthesis, also contributes to the vulnerability of dopamine-producing cells by generating oxidative stress. This study shows that the presence of dopamine in the cytosol enhances the cell's vulnerability to BH4. Upon exposure to ketanserin, a vesicular monoamine transporter inhibitor, BH4-induced dopaminergic cell death is exacerbated, accompanied by increased lipid peroxidation and protein bound quinone. While intracellular amount of DOPAC is elevated by ketanserin, the monoamine oxidase inhibitor pargyline showed no significant protection. Instead, the thiol agent N-acetylcysteine and quinone reductase inducer dimethyl fumarate abolish BH4/ketanserin-induced cell death, suggesting that quinone production plays an important role. Therefore, it can be concluded that the presence of dopamine in the cytosol seems to contribute to the cells' vulnerability to BH4 and that vesicular monoamine transporter plays a protective role in dopaminergic cells by sequestering dopamine not only from monoamine oxidase but also from BH4-induced oxidative stress.

Topics: 3,4-Dihydroxyphenylacetic Acid; Acetylcysteine; Animals; Benzoquinones; Biopterins; Cell Death; Cell Line; Cytosol; Dimethyl Fumarate; Dopamine; Drug Resistance; Enzyme Inhibitors; Fumarates; Ketanserin; Lipid Peroxidation; Membrane Glycoproteins; Membrane Transport Modulators; Membrane Transport Proteins; Mice; Monoamine Oxidase Inhibitors; Neurons; Oxidative Stress; Parkinson Disease; Substantia Nigra; Vesicular Biogenic Amine Transport Proteins; Vesicular Monoamine Transport Proteins

The antimicrobial activity of tobramycin against anaerobic cultures of Escherichia coli was tested in the presence of various electron carriers. The presence of 2,6-dichlorophenol 4-indophenol (DCIP) significantly enhanced the killing efficacy of tobramycin. Only 0.003% of the initial cell population (i.e. 10(6) cfu/mL) remained viable after exposure for 10 h to the mixture of antibiotic (20 x MIC, i.e. 40 mg/L) and electron acceptor (10(-3) M), as compared with 9% of surviving organisms in the presence of tobramycin alone. Less synergy was obtained with p-benzoquinone and 1,2-naphthoquinone. Fumarate did not affect the efficiency of the antibiotic. The mixture of tobramycin and DCIP was ineffective against agar-entrapped bacteria which, like biofilm organisms, are subject to oxygen limitation.

Topics: 2,6-Dichloroindophenol; Anaerobiosis; Anti-Bacterial Agents; Benzoquinones; Biofilms; Electrons; Escherichia coli; Fumarates; Indicators and Reagents; Microbial Sensitivity Tests; Naphthoquinones; Tobramycin