Complex I inhibitor

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)... 

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. 

Gutierrez-Ramos JC, Bluethmann H (1997) Molecules and mechanisms operating in septic shock lessons from knockout mice. Immunol Today 18 323-333 Hansen J, Cherwitz DL, Allen JI (1994) The role of tumor necrosis factor alpha in acute endotoxin-induced hepatotoxicity in ethanol-fed rats. Hepatology 20 461-474 Hartley A, Stone JM, Heron C, Cooper JM, Schapira AHV (1994) Complex I Inhibitors induce dose-dependent apoptosis in PC12 cells relevance to Parkinson s disease. J Neurochem 63 1987-1990... 

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

Since a detailed study of these unique inhibitors might provide new insight into the terminal electron transfer step of the enzyme, we further characterized their inhibitory action using the most potent Alac-acetogenin derivative (compound 1). Unlike ordinary Complex I inhibitors, 1 has a dose-response curve for inhibition of the reduction of exogenous short-chain ubiquinones that was difficult to... 

Essential structural factors of mitochondrial complex I inhibitor acetogenins (M. Abe, Kyoto Univ., Japan)... 

FIGURE 5.2 Representative plot of how AUC changes in regard to/m x/m p45o and K, dissociation constant of inhibitor-enzyme complex [I], inhibitor concentration at the enzyme /m, fraction of dose metabolized via all CYPs /m,P4505 fraction of total CYP-mediated metabolism catalyzed by inhibited CYP form the product of/m x/m,p45o represents the contribution of a specific CYP enzyme to overall clearance. 

Analysis by electron microscopy shows that Complex I from bovine heart, N. crassa, Y. lipolytica, and E. coli, can adopt a similar L shape structure, which spans the inner mitochondrial membrane with an arm extending into the matrix compartment [31, 32] (Fig. 13.1.2). A sub-domain representing part of this arm can be isolated that contains the FMN and retains NADH dehydrogenase activity coupled to reduction of ferricyanide (which is also an enzymic activity of intact Complex I). This activity is sensitive to the now superseded fungicide fenamino-sulf [33, 34]. Fenaminosulf is not a highly selective Complex I inhibitor, but its ability to inhibit ferricyanide reduction is unusual and defines its site of action... 

Fungicidal, acaricidal and insecticidal Complex I inhibitors are discussed in detail in Chapters 13.5 and 28.3 of this volume. 

Whereas fenazaquin (1) is a well-known complex I inhibitor, the primary mode of action of quinoxyfen (21) is, as yet, unknown. Although the lepidine compound 22 (Fig. 13.5.8) shows sub-micromolar activity level Ustilago maydis -IC50 0.73 pmol) in the biochemical complex I assay, the activity level in glasshouse tests is not satisfying at all. 

Evidently, therefore, mitochondria of different organs are not equally sensitive to 2. A supportive indication that mitochondria from different tissues can be affected differently by pesticide action was observed with fenpyroximate, a complex I inhibitor of the respiration chain (see Chapter 28.3). It causes morphological changes of mitochondria in peripheral nerve cells but not in muscular cells [39]. 

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