Carbon monoxide, electron transport chain

The electron transport chain is vital to aerobic organisms. Interference with its action may be life threatening. Thus, cyanide and carbon monoxide bind to haem groups and inhibit the action of the enzyme cytochrome c oxidase, a protein complex that is effectively responsible for the terminal part of the electron transport sequence and the reduction of oxygen to water. 

Two examples of toxicity, where the target is known, are carbon monoxide, which interacts specifically with hemoglobin, and cyanide, which interacts specifically with the enzyme cytochrome a3 of the electron transport chain (see chap. 7). The toxic effects of these two compounds are a direct result of these interactions and, it is assumed, depend on the number of molecules of the toxic compound bound to the receptors. However, the final toxic effects involve cellular damage and death and also depend on other factors. Other examples where specific receptors are known to be involved in the mediation of toxic effects are microsomal enzyme inducers, organophosphorus compounds, and peroxisomal proliferators (see chaps. 5-7). 

The number of receptor sites and the position of the equilibrium (Eq. 1) as reflected in KT, will clearly influence the nature of the dose response, although the curve will always be of the familiar sigmoid type (Fig. 2.4). If the equilibrium lies far to the right (Eq. 1), the initial part of the curve may be short and steep. Thus, the shape of the dose-response curve depends on the type of toxic effect measured and the mechanism underlying it. For example, as already mentioned, cyanide binds very strongly to cytochrome a3 and curtails the function of the electron transport chain in the mitochondria and hence stops cellular respiration. As this is a function vital to the life of the cell, the dose-response curve for lethality is very steep for cyanide. The intensity of the response may also depend on the number of receptors available. In some cases, a proportion of receptors may have to be occupied before a response occurs. Thus, there is a threshold for toxicity. With carbon monoxide, for example, there are no toxic effects below a carboxyhemoglobin concentration of about 20%, although there may be... 

Fig. 5. Proposed mechanism of ATP synthesis coupled to methyl-coenzyme M (CH3-S-C0M) reduction to CH4 The reduction of the heterodisulfide (CoM-S-S-HTP) as a site for primary translocation. ATP is synthesized via membrane-bound -translocating ATP synthase. CoM-S-S-HTP, heterodisulfide of coenzyme M (H-S-CoM) and 7-mercaptoheptanoylthreonine phosphate (H-S-HTP) numbers in circles, membrane-associated enzymes (1) CH3-S-C0M reductase (2) dehydrogenase (3) heterodisulfide reductase 2[H] can be either H2, reduced coenzymeF420 F420H2) or carbon monoxide the hatched box indicates an electron transport chain catalyzing primary translocation the stoichiometry of translocation (2H /2e , determined in everted vesicles) was taken from ref. [117] z is the unknown If /ATP stoichiometry A/iH, transmembrane electrochemical...

Fig. 11. Proposed function of electrochemical and Na potentials in energy conservation coupled to acetate fermentation to CH4 and CO2. The Na /H antiporter is involved in the generation of A/iH from A/iNa. CH3CO-S-C0A, acetyl-coenzyme A [CO], CO bound to carbon monoxide dehydrogenase CH3-H4MPT, methyl-tetrahydromethanopterin CH3-S-C0M, methyl-coenzyme M. The hatched boxes indicate membrane-bound electron transport chains or membrane-bound methyl-transferase catalyzing either IT or Na translocation (see Figs. 5, 6 and 12). It is assumed that enzyme-bound [CO] is energetically equal to free CO. ATP is synthesized via membrane-bound H -translocating ATP synthase. The stoichiometries of translocation were taken from refs. [107,234] n, X, y and z are unknown stoichiometric factors.

The answer is c. (Murray, pp 123-148. Scriver, pp 2367-2424. Sack, pp 159-175. Wilson, pp 287-317.) The electron transport chain shown contains three proton pumps linked by two mobile electron carriers. At each of these three sites (NADH-Q reductase, cytochrome reductase, and cytochrome oxidase) the transfer of electrons down the chain powers the pumping of protons across the inner mitochondrial membrane. The blockage of electron transfers by specific point inhibitors leads to a buildup of highly reduced carriers behind the block because of the inability to transfer electrons across the block. In the scheme shown, rotenone blocks step A, antimycin A blocks step B, and carbon monoxide (as well as cyanide and azide) blocks step E. Therefore a carbon monoxide inhibition leads to a highly reduced state of all of the carriers of the chain. Puromycin and chloramphenicol are inhibitors of protein synthesis and have no direct effect upon the electron transport chain. 

The second type of asphyxiants is that which works at the cellular level. Here, they interfere with the mitochondrial cytochrome oxidase s function in the electron transport chain. Because this is the fuel cell for the body, energy production ceases within the cell, with cell death following close behind. The key substance implicated here is cyanide, which is usually found only in a chemical laboratory setting, but can also be a side effect of smoke inhalation. As previously mentioned, hydrogen sulfide and carbon monoxide also have some effect at this site. In addition, azides are cellular asphyxiants. The azides, along with the nitro-ate-ites, are also vasodilators and can cause headaches and hypotension. 

Carbon monoxide poisoning interferes with transport to tissues and the interaction of with cytochromes, especially the cytochromes in the electron transport chain (ETC). 

As early as in 1925, Keilin s work indicated that the individual compounds involved in the electron transport chain act in sequence. He observed that urethane blocks electron transport from cytochrome b to cytochrome c. Thus, cytochrome b precedes cytochrome c in the sequence of electron transfer. It was also known that carbon monoxide competes with oxygen for cytochrome a3, and it was therefore concluded that cytochrome a 3 and cytochrome oxidase are identical compounds. From this early knowledge, the following sequence emerged cytochrome b, cytochrome c, cytochrome a. 

When they further observed that the normal nucleus contains a high proportion of mono-, di-, and trinucleotides of adenine, they claimed to have provided direct proof of their theory by demonstrating that the mono-or dinucleotides in the nucleus may be converted to ATP when oxygen is present. (The nucleotides can be extracted from the nucleus with acetate buffer at pH 5.1.) This conversion certainly suggested the existence of an intranuclear process of oxidative phosphorylation. As in mitochondria, oxidative phosphorylation in the nucleus is inhibited by uncouplers or agents blocking the electron transport chain. Nuclear oxidative phosphorylation is blocked by cyanide, azide, and antimycin A, or by dinitrophenol but, in contrast to mitochondria, it is resistant to Janus green, methylene blue, carbon monoxide, Dicumarol, and calcium. 

Figure 1. Electron transport chains of the endoplasmic reticulum. (A) Microsomal acyl-Co A desaturation system composed of NADH-cytochrome reductase, cytochrome fos (a flavoprotein), and fatty acyl-CoA desaturase. (B) Microsomal hydroxylase system depicting participation of the NADPH-cytochrome P-450 reductase (a flavoprotein), cytochrome P-450, and phosphatidylcholine. The role of the phospholipid appears to be in enhancing interaction of the proteins. The reduced form of the hemoprotein cytochrome P-450, on addition of carbon monoxide, envinces a Soret maximum at 450 nm, accounting for its designation. There is evidence that these two systems (A and B) interact in the membrane.

Certain compounds inhibit the activity of the respiratory chain by blocking the transfer of electrons at certain points. Rotenone and amytal inhibit electron transfer through Complex I. Antimycin A inhibits at the level of Complex III. Cytochrome oxidase activity is inhibited by carbon monoxide, cyanide and hydrogen sulphide. The prevention of electron transport by cyanide which is very rapidly absorbed is responsible for the high toxicity of this compound. 

Cyanide inhibits the action of one of the electron transfer chain proteins, but proton transport remains coupled to ATP production. Other inhibitors of oxidative phosphorylation are rotenone, amytal and carbon monoxide. 

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