Cyanide, oxidative phosphorylation

Inhibitors may act reversibly or irreversibly to limit the activity of the enzyme. Irreversible inhibitors are enzyme poisons and indeed many of them are poisonous in the common sense of the word cyanide for example, is an irreversible inhibitor of one of the cytochromes in oxidative phosphorylation. 

Oxidative phosphorylation DNP, potassium cyanide Antimycin A Sodium azide Formaldehyde Uncouples the oxidative phosphorylation from electron transport Acts at cytochrome oxidase B 7 Decreases the mitochondrial membrane potential 105 101,102 93,101,102... 

Dinitrophenol (1 mM) and potassium cyanide (KCN) (5 mM) are used as uncouplers of oxidative phosphorylation from electron transport (105). 

The function of the target molecule may be critical or mncritical. Thus, if the target molecule is an enzyme, this could be involved in a crucial metabolic pathway, such as mitochondrial oxidative phosphorylation. In this case, an adverse interaction with the ultimate toxicant is likely to lead to cell dysfunction and possibly death (e.g., as with cyanide or salicylate). Chemicals such as methimazole and resorcinol, which are activated to free radical intermediates by thyroperoxidase, cause destruction of the enzyme. This then disturbs thyroid hormone synthesis and thyroid function with pathological consequences such as thyroid tumors. 

Correct answer = D. Thirteen of the approximately 100 polypeptides required for oxidative phosphorylation are coded for by mitochondrial DNA, including the electron transport components cytochrome c and coenzyme Q. Oxygen directly oxidizes cytochrome oxidase. Succinate dehydrogenase directly reduces FAD. Cyanide inhibits electron flow, proton pumping, and ATP synthesis. 

Many inhibitors of catabolic pathways cause a decrease in cellular heat dissipation. They are therefore valuable tools to indicate the sources of the dissipation and give clues to the relative importance of each pathway in overall metabolic activity (see reviews by Kemp, 1987, 1993 Monti, 1987, 1991). To give a few examples from these reviews, sodium fluoride is a classical inhibitor of glycolysis and it has been shown to substantially reduce heat dissipation by human erythrocytes, lymphocytes, neutrophils, and murine macrophages, indicating the contribution of this pathway to metabolic activity. Cyanide inhibits oxidative phosphorylation by mitochondria at the cytochrome c oxidase complex (site 3) and studies revealed that it decreased heat production in a mouse LS-L929 fibroblast cell line but had no effect on human erythrocytes and neutrophils and murine macrophages, all of which lack mitochondria. Sodium azide inhibits at the same site and so it should come as no surprise that it had no effect on human neutrophils and lymphocytes, but it did reduce heat production by lymphocyte hybridoma cells, which contain... 

The role of L-lactate dehydrogenase in the physiology of aerobic yeast is not clear. It has been shown that its presence in yeast depends on the availability of oxygen (306), and that in the presence of antimycin A, which inhibits electron transfer to cytochrome c from NADH-linked substrates, L-or D-lactate can partially support the growth of Saccharo-myces cerevisiae (307). Under these conditions, cyanide inhibited the growth. Therefore, it has been concluded that l- and D-lactate-cyto-chrome c reductases can feed electrons to the respiratory chain at the level of cytochrome c and provide energy through the third site of oxidative phosphorylation (307). 

Cyanide primarily blocks oxidative phosphorylation and ATP production. Every heart beat uses up to 2% of the energy available to the cell. Arsenic primarily causes long QT (LQT) interval on the ECG, by blocking the fast potassium current, an action that is a precursor to ventricular fibrillation. 

Cyanide poisoning is marked by metabolic acidosis and a large anion gap. The latter is a consequence of the blocked oxidative phosphorylation and the increased rate of glycolysis. Maduh et al (1990) showed that cyanide also affects and thus the pH of the tissues. In turn, the Ca transport process is disrupted, leading to a rise in cystolic [Ca ]. Acidification depolarizes the cell membrane and changes the potassium conductance. 

The cyanide ion kills aerobic organisms by shutting down oxidative phosphorylation in the mitrochondria and therefore the utilization of oxygen in cells (Baskin and Brewer, 1997 Riordan et al, 2002). Cyanide has a propensity to affect certain organs (e.g. brain, heart, and lungs) more than... 

Cyanide is described as a cellular toxin because it inhibits aerobic metabolism. It reversibly binds with ferric (Fe " ") iron-containing cytochrome oxidase and inhibits the last step of mitochondrial oxidative phosphorylation. This inhibition halts carbohydrate metabolism from citric acid cycle, and intracellular concentrations of adenosine triphosphate are rapidly depleted. When absorbed in high enough doses, respiratory arrest quickly ensues, which is probably caused by respiratory muscle failure. Cardiac arrest and death inevitably follow. 

Once inhaled, absorbed through the skin, or ingested, cyanide acts at the cellular level by binding to the ferric ion in mitochondrial cytochrome oxidase, effectively blocking the enzyme responsible for oxidative phosphorylation. As a result, cells lose the ability to synthesize ATP, causing impairment of ATP-dependent processes and a shift to anaerobic metabolism, leading to cellular anoxia and lactic acidosis (7,8,31). 

Toxic effects caused by cyanide binding of ferric iron in mitochondrial cytochrome oxidase, affecting cellular ability to utilize 02 in oxidative phosphorylation, causing tissue hypoxia, anaerobic metabolism and lactic acidosis... 

Cyanide is the CN ion. At physiological pH, it exists as HCN in the body. The mechanism of cyanide toxicity is believed to be the inactivation of iron IB (ferric) enzymes in the body. The inhibition of cytochrome oxidase, which disrupts mitochondrial oxidative phosphorylation, is thought to be the most important mechanism for cyanide toxicity (Warburg, 1911 Keilin, 1929 DiPahna, 1971 Agency for Toxic Substances and Disease Registry, 1997). Cyanide also binds to the hemoglobin in erythrocytes (Farooqui and Ahmed, 1982). The binding of cyanide to Fe(III) enzymes and proteins is reversible (DiPahna, 1971 Way, 1984). 

Inhibition of oxidative phosphorylation by cyanide ion leads to increases in which of the following ... 

E. Gluconeogenesis requires ATP, which is in short supply, turning up the catabolism of glucose to lactate in the absence of an intact electron transport chain. ADP cannot be transported into the mitochondrion because ATP, its antiporter partner, isn t made by oxidative phosphorylation as a result of cyanide inhibition of cytochrome oxidase. Metabolism of fatty acids and ketone bodies requires a functional electron transport chain for their metabolism, and these possibilities are also ruled out. 

Highly lipophilic weak acids and bases that have the capacity to remain lipophilic in both their protonated and deprotonated forms can act as protonophores. Such compounds belong to another class of ionophores that are often referred to as mitochondrial uncouplers because of their unique ability to translocate protons across mitochondrial membranes, resulting in the subsequent loss of the mitochondrial proton gradient that is required to drive oxidative phosphorylation. While certain natural products act as mitochondrial uncouplers, most of the protonophores used as pharmacological probes are not natural products but are low-molecular-weight synthetic compounds (e.g., carbonyl cyanide -trifluoromethoxyphenylhydrazone (FCCP)). 

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