Mitochondrial electron transport analogs

One of the earliest recognized Fe S proteins was that associated with mitochondrial electron transport (Rieske et al., 1964). Even in the first partial in vivo characterization it was apparent that the protein had spectral properties that set it apart from the bacterial and plant-type ferredoxins which had just been discovered. Namely, the EPR spectrum had a gave near 1.91 and the high-held g value was shifted upheld. Furthermore, the protein had an Eq of approximately -t-250 mV, 600 mV more positive than the ferredoxins. Due to the instability of the protein, a more detailed analysis was not possible until the 1980s, when an analogous protein was isolated from bacterial sources (Fee etal., 1984). The ensuing... 

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. 

Fluorescent analogs of DCC are N-cyclohexyl-N -[4-(dimethylamino)-Q -naphthyl]carbodiimide (NCD ) and N-cyclohexyl-N -(l-pyrenyl)carbodiimide (PCD) which form fluorescent conjugates with mitochondrial electron transport particles or purified ATPase vehicles.N-cyclohexyl-N -(4-dimethylamino)-a-naphthylcarbodiimide... 

Mechanisms Etoposide increases degradation of DNA, possibly via interaction with topoisomerase II, and also inhibits mitochondrial electron transport. TTie drug is most active in the late S and early G2 phases of the cell cycle. Teniposide is an analog with very similar pharmacologic characteristics. 

Inhibition of chitin synthase (CS, EC 2.4.1.16) is widely recognized as a largely untapped, intrinsically manunalian-safe, arthropodicidal mechanism of action. Certain classes of cyanine dyes were observed as hits in a high-throughput Lepidopteran (tobacco budworm, Heliothis virescem) chitin synthase assay. Optimization produced in v/vo-active analogs however, ultimately these were shown to be off-target, active instead as mitochondrial electron transport inhibitors (METl) at Complex 1. An overview of the chitin synthase project and chemistry is presented. 

Synthetic analogs were evaluated for potency as mitochondrial electron transport inhibitors in a 96-well plate assay, based on oxidation of NADH by mitochondrial fragments and the associated reduction in absorbance at 340 nm. Table I shows that, based on I50 values, V is a potent mitochondrial inhibitor across a broad spectrum of fungal pathogens, including the important cereal... 

Most of the components involved in electron transport in mitochondria are contained in four supramolecular protein complexes that traverse the inner mitochondrial membrane. Complex I, which contains FMN and various iron-sulfur clusters as active sites, transfers electrons from NADH to ubiquinone (Fig. 6-8). Complex II, which contains FAD, various iron-sulfur clusters, and a Cyt >, transfers electrons from succinate also to a ubiquinone. Ubiquinone functions as a pool of two-electron carriers, analogous to the function of plastoquinone A in the lamellar membranes of chloroplasts, which accepts electrons from Complexes I and II and delivers them to the... 

The hypothesis that a proton-motive force across the inner mitochondrial membrane is the immediate source of energy for ATP synthesis was proposed in 1961 by Peter Mitchell. Virtually all researchers working in oxidative phosphorylation and photosynthesis Initially opposed this chemlosmotic mechanism. They favored a mechanism similar to the well-elucidated substrate-level phosphorylation in glycolysis, in which oxidation of a substrate molecule is directly coupled to ATP synthesis. By analogy, electron transport through the... 

Electron transport in the respiratory chain of propionic acid bacteria shown above can be accompanied by ATP synthesis. The following sites of coupling between oxidation and phosphorylation may be tentatively identified by analogy with the mitochondrial ETC NAD—FP,... 

Fig. 3. These diagrams (A, B) are intended to illustrate the regulation and operation of these mitochondrial fatty acid synthetic systems using a hydrodynamic analogy. Electron pressure and flow are depicted as fluid pressure and flow under gravitational influence. Electron flow down the electron transport chain is ultimately controlled by (ADP Pi) ATP ratio. When the latter ratio is high (A, left) electron flow rate is maximal and the steady-state NADHiNAD" ratio is low (State 3 Chance and Williams, 1956), On the other hand, (B, right) when either the (ADP + P,) ATP ratio is low or oxygen is lacking, substrate reduces NAD+ faster than it can be oxidized. The elevated NADHiNAD ratio reverses the usual flow of electrons from fatty acid oxidation. Acetate now becomes incorporated into fatty acids with the consequent oxidation of NADH and, therefore, perhaps permits some ATP to be synthesized via other substrate-level energy conserving steps.

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