Cytochrome oxidase action

Nature has had a long time to perfect her inorganic chemistry, and understanding the mechanisms of enzymatic action can suggest ways for the inorganic chemist to develop corresponding in vitro catalysts. We shall show how knowledge of cytochrome oxidase and cytochrome P-450 has led to such possibilities. 

HCN is a systemic poison toxicity is due to inhibition of cytochrome oxidase, which prevents cellular utilization of oxygen. Inhibition of the terminal step of electron transport in cells of the brain results in loss of consciousness, respiratory arrest, and ultimately, death. Stimulation of the chemoreceptors of the carotid and aortic bodies produces a brief period of hyperpnea cardiac irregularities may also occur. The biochemical mechanisms of cyanide action are the same for all mammalian species. HCN is metabolized by the enzyme rhodanese which catalyzes the transfer of sulfur from thiosulfate to cyanide to yield the relatively nontoxic thiocyanate. 

Cyanide ion exerts an inhibitory action on certain metabolic enzyme systems, most notably cytochrome oxidase, the enzyme involved in the ultimate transfer of electrons to molecular oxygen. Because cytochrome oxidase is present in practically all cells that function under aerobic conditions, and because the cyanide ion diffuses easily to all parts of the body, cyanide quickly halts practically all cellular respiration. The venous blood of a patient dying of cyanide is bright red and resembles arterial blood because the tissues have not been able to utilize the oxygen brought to them. Cyanide intoxication produces lactic acidosis, the result of an increased rate of glycolysis and production of lactic acid. ... 

As early as the 1980s, it was indicated that some proteins such as cytochrome oxidase in the membranes and mitochondria were a target for the action of qin-ghaosu. Meshnick et al. have performed a series of experiments about the interaction between qinghaosu and proteins in the presence of heme and have concluded that the binding between qinghaosu and albumin probably involves thiol and amino groups via both iron-dependent and -independent reactions. However, they have not isolated and confirmed such covalent adducts and have presented the ques-... 

Its action has been postulated to be intraneuronal on the oxidation cycle at a phase above the cytochrome b level of the cytochrome oxidase system though its precise mechanism has not been elucidated. It is primarily a neurotoxin with a chemical structure that allows for easy penetration of the blood-brain barrier. 

The mechanism of action of the phenothiazines is still not definitely known. They tend to block important effector substances such as acetylcholine, epinephrine, and histamine. The phenothiazines produce uncoupling of phosphorylation from oxidation. They appear to act at all steps along the electron transport chain. Cytochrome oxidase, succinoxidase, and adenosine triphosphatase are inhibited. Some data indicate that the phenothiazines may decrease the permeability of storage granules for brain amines. 

In the cell, electron flow in the electron transport chain must be sequential from NADH or a flavoprotein all the way to O2 to generate ATP (see Fig. 21.5). In the absence of O2, there is no ATP generated from oxidative phosphorylation because electrons back up in the chain. Even complex I cannot pump protons to generate the electrochemical gradient, because every molecule of CoQ already has electrons that it cannot pass down the chain without an O2 to accept them at the end. The action of the respiratory chain inhibitor cyanide, which binds to cytochrome oxidase, is similar to that of anoxia it prevents proton pumping by all three complexes. Complete inhibition of the b-c complex prevents pumping at cytochrome... 

Cell-free Nitrobacter extracts were shown by Aleem and Alexander (1958) to be able to oxidize nitrite to nitrate. Subsequently, Aleem and Nason (1959) reported that the nitrite-oxidizing activity resided in a cytochrome-containing particle designated as nitrite oxidase. Nason (1962) states that their data implicated the action of the nitrite oxidase system to involve the enzymatic transfer of electrons from nitrite to molecular oxygen via cytochrome c- and cytochrome oxidase-like components. Iron is specifically required in the oxidation process. 

The toxicity of cyanide is attributed to its ability to inhibit enzyme reactions. The action of one such enzyme, cytochrome oxidase, essential for the respiration of cells is inhibited by cyanide ions. Cytochrome oxidase is a component of the mitochondrial electron transport system. It transfers electrons from cytochrome c to oxygen, forming water, while releasing sufficient free energy to permit the formation of adenosine 5 -triphosphate (ATP). The latter is essential for normal metabolic processes. Cyanide ion forms complexes with heavy metal ions such as iron and copper to stop electron transport and thus prevent ATP formation. Several enzyme reactions have been listed that cyanide can inhibit several enzyme reactions by forming complexes. 

I. Mechanism of toxicity. Hydrogen sulfide causes cellular asphyxia by inhibition of the cytochrome oxidase system, similar to the action of cyanide. Because it is rapidly absorbed by inhalation, symptoms occur nearly immediately after exposure, leading to rapid unconsciousness or knockdown. Hydrogen sulfide is also a mucous membrane irritant. 

---