Complex I inhibitor rotenone

Similarly, abnormalities in the mitochondrial machinery and resulting oxidative stress may also intervene in Parkinson s disease (PD) [31, 32]. The decreased activity of mitochondrial complex I in PD patients [33], and the preferential toxicity of the complex I inhibitor rotenone [34] and MPP+ (the active metabolite of MPTP)... 

ATP is instead released as heat. Plant mitochondria also have an alternative NADH dehydrogenase, insensitive to the Complex I inhibitor rotenone (see Table... 

The action of some inhibitors is indicated in Figure 17.4. It is sometimes difficult to pinpoint exactly where an inhibitor may act, however, because our knowledge of the composition and function of the four complexes is far from complete. Complex I inhibitors, such as rotenone, piericidin A, and the barbiturates, are believed to inhibit the transfer of elctrons from the Fe-S centers to UQ. In complex III, antimycin appears to inhibit the reduction of UQ by cytochrome b. Myxothiazol and 2,3-dimercaptopropanol (BAL) inhibit the transfer of electrons from UQH2 to Rieske s protein, because they destroy the Fe-S centers. The action of cyanide and azide on complex IV is also unclear, but it is believed that these substances combine with the Fe3+ moiety of the a3 heme prosthetic group. 

The activity of complex II (succinate dehydrogenase) is measured as the succinate-dependent reduction of decylubiquinone, which is in turn recorded spectro-photometrically through the reduction of dichlorophenol indophenol at 600 nm (e 19,100-M -cm Fig. 3.8.5). In order to ensure a linear rate for the activity, the medium is added with rotenone, ATP, and a high concentration of succinate. As noticed previously for complex I, decylubiquinone is not a perfect acceptor for electrons from the membrane-inserted complex II [70]. Malonate, a competitive inhibitor of the enzyme, is used to inhibit it. Rather than decylubiquinone, phenazine methosulfate can be utilized, which diverts the electrons from the complex before they are conveyed through subunits C and D, therefore allowing measurement of the activity of subunits A and B. 

In addition to their potential as antitumor agents, acetogenins have great potential as natural "organic" pesticides (Mikolajczak et al., 1988,1989 McLaughlin et al., 1997). Bullata-cin (1) and trilobacin (3) (see Figure 13.1) were more potent than rotenone, a classic complex I mitochondrial inhibitor, in a structure-activity relationship (SAR) study using yellow fever mosquito (YFM) larvae (He et al., 1997). 

Inhibitors of electron transport Rotenone Complex I Fish poison, insecticide... 

Two different sites of the mitochondrial respiratory chain were considered to contribute to the univalent reduction of dioxygen. An iron-sulfur protein of complex I was reported to undergo auto-oxidation independent of the height of the membrane potential [8,11,12]. The identity of the complex I constituent was concluded from the use of rotenone, which did not affect H2O2 generation from complex I substrates, in combination with selective inhibitors of iron centers. The second center suggested to be involved in mitochondrial ROS for-... 

Next to rotenone, the Streptomyces mobaraensis metabolite piericidin (also known as shaoguanmycin B), specifically piericidin Ai (44), is perhaps the most studied NADH—U(i oxidoreductase inhibitor and is commonly used as a pharmacological probe of the role of complex I in the mitochondrial ETC. For example, glucose deprivation causes upregulation of ER chaperone protein GRP78 and induces etoposide resistance in human cancer cells. GRP78 is also known to protect tumor cells from apoptosis induced by topoisomerase inhibitors. " Studies have shown that glucose-deprived etoposide-resistant HT-29 human colon carcinoma cells are uniquely sensitive to piericidin A. ... 

The fact that the reduced form of arylazido- -alanine NAD+ in the presence of complex I catalyzes the reduction of CoQi in a rotenone-sensitive reaction indicates clearly that the reduced analog is acting as a substrate for the NADH dehydrogenase of complex I. The p3rridine nucleotide analog is as well a potent photodependent inhibitor of the enzyme complex. In fact the reduced form of the arylazido-iS-alanine NAD is a more effective inhibitor with greater than 95% inhibition of... 

Rotenone, the active ingredient of derris powder, an insecticide prepared from the roots of the leguminous plant Lonchocarpus nicou. It is an inhibitor of complex I (NADH — ubiquinone reduction). The same effect is seen in the presence of amytal (amobarbital), a barbiturate sedative drug, which again inhibits complex I. These two compounds inhibit oxidation of malate, which requires complex I, but not succinate, which reduces ubiquinone directly. The addition of the uncoupler... 

The mitochondrial ETC consists of four huge, multieomponent complexes whose function is to transfer electrons from reducing equivalents such as NADH and FADH2, which are produced during glycolysis and the Krebs eyele (Fig. 1). Complex I of the ETC is an NADH dehydrogenase (Fig. 7). Here, NADH is redueed to NAD as it transfers its two electrons to ubiquinone, whieh is oxidized to ubiquinol. Rotenone is a specific inhibitor of complex I. Complex II is a flavoprotein... 

Oligomycin is an antibiotic that inhibits respiration in intact mitochondria. Respiration is not inhibited in uncoupled mitochondria, i.e., those mitochondria in which 02 consumption occurs but in which no ATP is synthesized. Thus, oligomycin does not block respiratory carriers, in contrast to inhibitors such as rotenone and cyanide. Instead, oligomycin blocks proton translocation through the F component to the F( component, through a specific interaction with a subunit of the membrane-associated F . The subscript o in the term F was originally used to indicate the oligomycin-sensitive" complex. 

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