Inhibition of mitochondrial electron transport

Hydramethylnon [67485-29-4] is tetrabydro-5,5-dimetbyl-2-(1 H)-pyrimidinone [bis-l,5-(4-trifluoromethylphenyl)-3-penta-l,4-dienylidene] hydrazone (152) (mp 189°C). It is a slow-acting stomach poison used in baits and traps to control ants and cockroaches. Its mode of action is inhibition of mitochondrial electron transport. 

Radi, R., Rodriguez, M., Castro, L., and Telleri, R. (1994). Inhibition of mitochondrial electron transport by peroxynitrite. Arch. Biochem. Biophys. 308, 89-95. 

Granger, D. L., and Lehninger, A. L. (1982). Sites of inhibition of mitochondrial electron transport in macrophage-injured neoplastic cells. J. Cell Biol. 95, 521-535. 

Hollinshaus, J.G., Inhibition of mitochondrial electron transport by hydra methyl non A new amidi-nohydrazone insecticides, Pestic. Biochem. Physiol, 27, 61,1987... 

Kleiner D, von Jagow G (1972) On the inhibition of mitochondrial electron transport by Zn(2+) ions. FEBS Lett 20 229—232... 

V y of pyruvate, fatty acids, and other fuels. In many cases, the inhibition of mitochondrial electron transport results in higher than normal levels of lactate and pyruvate in the blood and an increased lactate/pyruvate ratio. NADH oxidation requires the completed transfer of electrons from NADH to O2, and a defect anywhere along the chain will result in the accumulation of NADH and decrease of NAD+. The increase in NADH/NAD inhibits pyruvate dehydrogenase and causes the accumulation of pyruvate. It also increases the conversion of pyruvate to lactate, and elevated levels of lactate appear in the blood. A large number of genetic defects of the proteins in respiratory chain complexes have, therefore, been classified together as "congenital lactic acidosis."... 

Pardini, R. S., j. C. Heidker, and D. C. Fletcher Inhibition of Mitochondrial Electron Transport by Nor-Dihydroguaiaretic Acid (NDGA). Biochem. Pharmac. 19, 2695 (1970). 

Atovaquone is a hydroxy-1,4-naphthoquinone, an analog of ubiquinone, with antipneumocystic activity. Since 2000 atovaquone is available as a fixed dose preparation (Malarone) with proguanil for the oral treatment of falciperum malaria. Its activity probably is based on a selective inhibiton of mitochondrial electron transport with consequent inhibition of pyrimidin synthesis. Malarone should not be used to treat severe malaria, when an injectable drug is needed. 

Mechanism of Action A systemic anti-infective that inhibits the mitochondrial electron-transport system at the cytochrome bcl complex (Complex 111), which interrupts nucleic acid and adenosine triphosphate synthesis. Therapeutic Effect Antiprotozoal and antipneumocystic activity. 

MPTP is a molecule, which is sufficiently lipophilic to cross the blood-brain barrier and enter the astrocyte cells. Once in these cells, it can be metabolized by monoamine oxidase B to MPDP and then MPP both of which are charged molecules. These metabolites are therefore not able to diffuse out of the astrocyte into the bloodstream and away from the brain. However, the structure of MPP allows it to be taken up by a carrier system and concentrated in dopaminergic neurones. In the neurone, it inhibits the mitochondrial electron transport chain leading to damage to the neurone. 

The level of another metabolite, formate, was also elevated in ALS and Hirayama patients. This metabolite is responsible for dismption of mitochondrial electron transport and energy production by inhibiting cytochrome oxidase activity. Cell death as a result of formate inhibition of cytochrome oxidase is believed to be the result of partial loss of ATP and, therefore, the loss of energy needed for basic cell functions. In addition, inhibition of cytochrome oxidase by formate can facilitate the production of cytotoxic reactive oxygen species, which also implies cell death. 

Inhibition of the electron transport chain in coupled mitochondria can occur at any of the three constituent functional processes electron transport per se, formation of ATP, or antiport translocation of ADP/ATP (Table 16-1). The best known inhibitor of the ADP/ATP translocase is atractyloside in the presence of which no ADP for phosphorylation is transported across the inner membrane to the ATP synthase and no ATP is transported out. In the absence of ADP phosphorylation the proton gradient is not reduced allowing other protons to be extruded into the intermembrane space because of the elevated [H+], and thus electron transfer is halted. Likewise the antibiotic oligomycin directly inhibits the ATP synthase, causing a cessation of ATP formation, buildup of protons in the intermembrane space, and a halt in electron transfer. Similarly, a blockade of complex I, III, or IV that inhibits electron flow down the chain to would also stop both ATP formation and ADP/ATP translocation across the inner mitochondrial membrane. 

Whereas inhibition of chloroplast electron transport has been correlated with binding to a protein(s), the sites and mechanisms through which herbicides interfere with mitochondrial and chloroplast mediated phosphorylations remain to be identified. When lipophilic herbicides partition into the lipid phases of membranes, they could perturb lipid-lipid, lipid-protein, and protein-protein interactions that are required for membrane functions such as electron transport, ATP formation, and active transport. Evidence for general membrane perturbations caused by chlorpropham, 2,6-dinitroanilines, perfluidone, and certain phenylureas have been reported previously (8-11). 

Table I. Inhibition (ISO s) of Mitochondrial Electron Transport in Pathogenic Fungi by A -formylsalicylamide (FSA) V...

When induced in macrophages, iNOS produces large amounts of NO which represents a major cytotoxic principle of those cells. Due to its affinity to protein-bound iron, NO can inhibit a number of key enzymes that contain iron in their catalytic centers. These include ribonucleotide reductase (rate-limiting in DNA replication), iron-sulfur cluster-dependent enzymes (complex I and II) involved in mitochondrial electron transport and cis-aconitase in the citric acid cycle. In addition, higher concentrations of NO,... 

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