Inhibition of ATP synthesis

Administration of KA also produces profound alterations in energy metabolites in the striatum within 2 h of injection (Retz and Coyle, 1982). The depletion in ATP levels may result from either an inhibition of ATP synthesis or an increase in ATP consumption in toxicity induced by KA. Collective evidence suggests that the reduction in glucose levels and concomitant increase in lactate after intrastriatal injections of KA result from an increase in energy consumption during toxicity. It has been proposed that in toxicity induced by KA, ATP depletion to a critical level invariably precedes the onset of cell death (Coyle, 1983). 

Phosphorylation of ADP to ATP by mitochondria is driven by an electrochemical proton gradient established across the inner mitochondrial membrane as a consequence of vectoral transport of protons from NADH and succinate during oxidation by the respiratory chain (see Chapter 17). Hence, lipophilic weak acids or bases (such as 2,4-dinitrophenol) that can shuttle protons across membranes will dissipate the proton gradient and uncouple oxidation from ADP phosphorylation. Intrami-tochondrial ADP can be rate-limiting as demonstrated by inhibition of the mitochondrial adenosine nucleotide carrier by atractyloside. Inhibition of ATP synthesis... 

The anaerobic phosphorylation of ADP to ATP in mitochondria offers an excellent site for chemotherapeutic attack. The uncoupling of oxidative phosphorylation would lead to inhibition of ATP synthesis and subsequent starvation of the worms. A number of uncouplers of oxidative phosphorylation are now known, the first being 2,4-dinitrophenol (9) described by Loomis and Lipmann in 1948 [44]. Niclosamide (10) and other salicylanilide anthelmintics have been found to inhibit an-... 

Fig. 2. Inhibition of ATP synthesis and ATP hydrolysis by oligomycin at different concentrations of chromatophores. Chromatophores containing 0.05 mM (o, ) 0.10 mM (v) 0.19 mM (X) 0.40 mM ( , i) and 0.5 mM (A) BChl were incubated with the indicated concentrations of oligomycin for 30 min at 22 0. Samples were withdrawn and the ATP synthesis rate ( , ) and the ATPase activity in the presence of 1 pM FCCP (o,v,x,d,A) were determined.

Lipophilic tertiary amines (t-amines) are effective inhibitors of photophosphorylation (1-3) Bound up with the inhibition, light-induced uptake of (l C)-methylamine and quenching of 9 afflinoacridine (9 AA) fluorescence disappear. This indicates that inhibition of ATP synthesis may be related to a decline of the transthylakoid proton gradient, ApH (4). IntriguingTy, a strong pH-dependent control of electron flow was maintained in the presence of t-amines (3 5) despite of the low ApH Therefore, t-amines were termed selective uncouplers (1). 

ATP synthesis. In those instances where ATP production is known to be inhibited by other means (e.g. nitrogen, Fig. 5.5), no germination occurs. Prevention by inhibitors of terminal oxidation may make more oxygen available within a seed and somehow promote its germination, but inhibition of ATP synthesis probably always inhibits germination. A fuller account of oxidative processes and the control of dormancy and germination will appear in the second volume. 

FIGURE 2. Concentration dependence of triphenyltin inhibition of ATP synthesis in continuous light. Reactions were carried out at 20° in a medium containing 100 mM sorbitol, 25 mM Tricine-KOH (pH 7.8), 3 mM Mg Acetate, 0.5 mM 1... 

TABLE Comparison of DCCD inhibition of ATP synthesis in flashing vs continuous light. The series of 30 single turnover flashes was preceded by a 1 s illumination followed by a 30 s dark period prior to the addition of The... 

The effects of the electron inhibitor DCMU, the uncoupler S-13 and the energ transfer inhibitor DCCD on electron transfer and photophosphorylation in membrane vesicles of Syneohocoocus 6716 are shown in Fig. 1. DCMU behaves as expected, fully blocking electron transfer and the resulting phosphorylation at 1 to 10 yM. S-13 is a potent uncoupler full inhibition of ATP synthesis occurs at 1 yM however, electron transfer is not enhanced. In linear electron transfer DCCD seems to act as an electron transfer inhibitor at lower concentrations as was found before in chloroplasts, where DCCD bloc) the reduction site of plastoquinone (Sane et al. 1979). Only at higher concentrations (10 M) DCCD also inhibits energy transfer as can be seen in th< PMS-mediated cyclic photophosphorylation. 

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