Introduction to Antimycin
Antimycin is a mitochondrial inhibitor which is involved in the energy-coupling site of the respiratory system . Antimycin works by inhibiting the flow of electrons from cytochrome b to cytochrome c1. It was first discovered as a potent fungicide which was produced by a species of Streptomyces. Researchers found that the toxic effects of antimycin were a result of their inhibitory effects on mitochondrial respiration.
Chemical Properties of Antimycin
There are four co-crystallizable compounds designated as A1 to A4 . Through various degradation studies two of the most predominant forms of antimycin, A1 and A3, were detected. The basic structure of antimycin consists of an acyl and alkyl-substituted, nine-member dilactone ring which is linked by an amide bond to 3-formamidosalicyclic acid. Upon closer examination three additional components Ao, A5, and A6, were discovered. . These components only make up about 1% of the antimycin complex. Out of all the components which compose the antimycin complex it is antimycin A which appears most frequently and is considered to be the principal component of antimycin.
Antimycin is only slightly soluble in water and petroleum ether however, it is soluble in chloroform and water-miscible solvents such as acetone, alcohol, etc. When antimycin is placed in an alcohol solution it fluoresces. This characteristic has been utilized and used to create antimycin assays.
Toxicity of Antimycin
There is a wide range of effects which may occur depending on the individual species which comes into contact with antimycin. In keeping with its specific binding to Complex III of the respiratory chain, antimycin has been found to be toxic to all organisms which are dependent on mitochondrial respiration for their energy source.
Structure-acitivity studies have implicated the formamido and phenolic hydroxyl groups of the salicyclic acid portion of the antimycin molecule as the principal site of interaction for which antimycin to exert its inhibitory and toxic effects. Apparently the formamido group contributes to the inhibitory activity by way of its electron withdrawing function since it can be replaced with a nitro group which functions as either the ortho or para positions with respect to the phenolic hydroxyl group.
Antimycin Analogs
There have been a number of synthetic homologs and analogs of antimycin which exhibit anti-inhibitory effects. These analogs have their dilactone ring group replaced with either a straight-chain alkyl group or a 15-member dilactone ring which exists in two steroisomeric forms. Antimycin homologs in which the alkl and acyl groups attached to the dilactone ring were replaced with hydrogens.
Mechanism of Mitochondrial Inhibition
It is clear that all of the toxic effects of antimycin can be directly or indirectly traced to an inhibition of energy-yielding electron-transport . Early studies done with rats determined that the amount of antimycin which is required to inhibit succinate oxidation is directly proportional to the activity of the respiratory enzyme in tissue. In vivo inhibition of succinate oxidation in a given tissue by antimycin is much greater in tissues of low respiratory activity( i.e. spleen, lung, and thymus) then tissues of high respiratory activity ( i.e. heart, brain, and muscle.) There have been some discrepancies in the effects of antimycin on various tissues depending on whether the experiment was conducted in vivo or in vitro. These discrepancies are attributed to variations in rate of blood flow or capillary permeability in different organs. The fact that physiological signs of intoxication are abated in parallel with recovery of respiratory activity confirms the fact that antimycin is due primarily to its inhibition of cellular respiration
It is not clear what species are or are not sensitive to antimycin. The fact that antimycin binds specifically to and inhibits stoichiometrically Complex III of the mitochondrial respiratory chain of eukaryotic organisms is a possible criterion of antimycin sensitivity. The presence of cytochromes of b and c types is generally considered characteristic of Complex III. There have however, been examples of organisms which contain respiratory chains which are similar to those found in mitochondria and are yet insensitive to antimycin.
It was discovered that serum albumin was capable of restoring succinate oxidation in vitro in tissues which had been inhibited by antimycin. This suggests that serum albumin may be able to transfer antimycin from its inhibitory site in various tissues to the liver for inactivation or to the kidneys for excretion.
Effects of Antimycin on Biological Organisms
It was discovered that lethal doses of antimycin which were administered to mice intraperitoneally and intravenously caused respiratory distress prior to death. However those mice which received antimycin intraperitoneally also experienced neurotoxic signs such as incoordination of hind limbs and impaired pinnal, corneal placing, positioning, and grasping reflexes which precede the respiratory symptoms. Although these additional effects suggest neurotoxicity as well as respiratory toxicity it more likely that these effects are a secondary result of inhibition of cellular respiration in nerve tissue rather than a direct effect on nerve tissue.
There are some other effects which may occur when high doses of antimycin are administered. Some of these include uncoupling of oxidative phosphorylation, photophosphorylation, and effects which are connected with modification of protein synthesis.
Scientific Uses of Antimycin
The primary use of Antimycin is as a tool to study the mechanism of respiratory electron-transport. There are three sets of phenomena which occur when complex is treated with antimycin. First, electron transport between ubiquinol and ferricytochrome c is inhibited by stoichiometric concentrations of antimcyin. Second, the b cytochromes are altered with respect to their reducibility by substrates and in their spectral properties. Third, antimycin strongly inhibits the dissociation of cytochromes b from cytochrome c1 as promoted by dissociating reagents such as detergents and guanidinium salts. This has been designated as the cleavage reaction.
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