Phosphorylation uncoupling

Figure 12-8. Principles of the chemiosmotic theory of oxidative phosphorylation. The main proton circuit is created by the coupling of oxidation in the respiratory chain to proton translocation from the inside to the outside of the membrane, driven by the respiratory chain complexes I, III, and IV, each of which acts as a protonpump. Q, ubiquinone C, cytochrome c F Fq, protein subunits which utilize energy from the proton gradient to promote phosphorylation. Uncoupling agents such as dinitrophenol allow leakage of H" across the membrane, thus collapsing the electrochemical proton gradient. Oligomycin specifically blocks conduction of H" through Fq.

In addition to the above-mentioned properties, the piperidine alkaloids exhibit a wide range of physiological activities. Thus, neuromuscular transmission is shown to be blocked by Ic and Id (72). Mitochondrial respiration is decreased and oxidative phosphorylation uncoupled at low concentrations of Ig (75), which, in addition to cw-6-methyl-2-(cw-6 - -pentadecenyl)piperidine (2c), inhibits the reactions of the Na+, K + -ATPase (14). 

A series of 36 plants showed only two that form no glucosides when sucrose is injected into the leaves. In the two exceptions, the sucrose was converted into nonsugars. Phosphorylation uncouplers (2,4-dinitrophenol, iodoacetate, and the like) did not affect o-glucoside formation.226... 

DNP is an oxidative phosphorylation uncoupler. It makes the process only about 40% efficient by uncoupling a high energy phosphate molecule from ATP and therefore turning ATP into ADP. To maintain an adequate supply of ATP, the body must step-up production. For this reason metabolism is significantly increased and an incredible amount of calories are burned. During this accelerated metabolic state, and due to the need for ATP production, most of the calories come from fatty acids (adipose/fat tissue). So little or no muscle is lost (With adequate protein intake). 

TABLE 23.3 Examples of Baseline Toxicity (BT), Polar Narcosis (PN), and Oxidative Phosphorylation Uncoupling (OPU) QSARs... 

The rate of 0 incorporation showed that ATP and ADP are in equilihrium at the catalytic site, implying that ATP formation from enzyme-hound ADP can proceed at the catalytic site without an external energy input hy an imposed proton gradient. This reaction is also insensitive to phosphorylation uncouplers such as dinitrophenol and can he catalyzed even hy water-soluhle MF, and CF, complexes. However, ATP is not released from the catalytic site without an external energy input, i.e., a proton flux through the enzyme. These observations led Boyer and coworkers to formulate the so-called binding change theory to explain the mechanism for ATP synthesis. 

DE Fleischman and RK Clayton (1968) The effect of phosphorylation uncouplers and electron transport inhibitors upon spectral shifts and delayed light emission of photosynthetic bacteria. Photochem Photobiol 8 287-298... 

See also Chemiosmotic Coupling, Oxidative Phosphorylation, Uncoupling ETS and Oxidative Phosphorylation, Respiratory Control... 

Diuron (10 mol/L), as a photosynthetic inhibitor, as well as dinitrophenol (DNP 10 mol/L), as an oxidative phosphorylation uncoupler, facilitated the adverse effect of high temperature. This can testify to the influence of CMS on stabilization of electron transport chain carriers in the lipid membrane. 

That the active concentration of iodide in the thyroid is energy dependent is suggested by several observations. The active concentration of iodide requires oxygen. It is blocked by metabolic poisons, such as cyanide and azides. There is a correlation between concentration ability and rate of oxidative phosphorylation. Uncouplers such as 2,4-dinitrophenol block iodine uptake in the thyroid. 

A. Salicylates - Evidence has been given that aspirin increases bleeding time and decreases blood platelet aggregation, probably by virtue of the acetoxy group. On the other hand, in oxidative phosphorylative uncoupling in mitochondria, the action is due to the salicylic acid moiety. ... 

Azido 4-nitrophenol Oxidative phosphorylation uncoupling site in mitochondria More effective uncoupler than dinitio-phenol, attachment sites on inner mitochondrial membrane subunit 1 of Fi-ATPase (MW 56,000) and a protein of MW 31,000 58-61... 

Also Bradbury and co-workers review the oxidative phosphorylation uncoupling QSARs, which embody these chemicals that are typically weak acids and are represent by phenols, anilines, and pyridines but, different from polar narcotics, include multiple electronegative groups... 

On the contrary, chemical classes not usually identified as acting by a baseline narcosis mode of action, such as the phenols, include chemicals that act through baseline narcosis, polar narcosis, oxidative phosphorylation uncoupling, or electrophilic-based modes of action (Bradbury et al., 2003). 

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