Amide groups are common in biological molecules (e.g. peptide bonds), but thioamides are rare. Thioamide groups are found naturally in the copper-chelating compound methanobactin described in Methylosinus trichosporium OB3b (Kim et al., 2004). The antibiotic sulfinemycin, produced by Streptomyces albus NRRL 3384, has a primary thioamide S-oxide moiety (Lee et al., 1995). Thioacetamide is used as a sulfur source for organic syntheses and has applications in leather, textile, paper, rubber, and petroleum industries. 2,6-Dichlorothiobenzamide (chlorthiamid) is used as an herbicide. Thioamide compounds such as 2-ethyl-4-pyridinecarbothioamide (ethionamide) are important second-line drugs in the treatment of multi-drug resistant Mycobacterium tuberculosis and M. leprae (Schroeder et al., 2002; Shepard et al., 1985). Toxicity of thioamides in mammals and Mycobacterium spp. is dependent on metabolic activation of the compounds via sequential oxygenations of the thioamide sulfur atom by flavoprotein monooygenases or cytochromes P450 (Debarber et al., 2000; Wang et al., 2000; Porter and Neal, 1978). Thioamide S-oxides are not toxic without further oxygenation and investigators have proposed that thioamide S,S-dioxides (which have not been isolated) or further oxidized species exert the observed toxic effects (Vannelli et al., 2002; Hanzlik and Cashman, 1983; Porter and Neal, 1978). This activity results in elimination of the thioamide sulfur and formation of nitrile or amide derivatives (Vannelli et al., 2002; Porter and Neal, 1978).
Ralstonia pickettii TA can grow using thioacetamide as a sole source of nitrogen and carbon (Dodge et al., 2006), but the pathway of degradation has not been completely determined. Thioacetamide S-oxide was detected as a metabolic intermediate, supporting an oxygenase-mediated mechanism. During thioacetamide degradation, 3,5-dimethyl-1,2,4-thiadiazole accumulated in the medium and was not further metabolized. This species did not form when thioacetamide and thioacetamide S-oxide were combined. Therefore it was proposed that a further oxidized species, possibly thioacetamide S,S-dioxide, reacts with thioacetamide to form this dead-end metabolite. Sulfur eliminated from thioacetamide during metabolism was detected in the medium as sulfur dioxide/sulfite. Elimination of sulfur at this oxidation state from thioacetamide S,S-dioxide requires an additional two-electron oxidation, which occurs by an unknown mechanism. Nitrogen released during thioactamide degradation was detected as ammonium ion. Using thiobenzamide metabolism by this strain as a model (Dodge et al., 2006), it was predicted that elimination of the thioacetamide sulfur would generate acetonitrile and/or acetamide. R. pickettii TA grew using acetonitrile or acetamide as the sole source of carbon and nitrogen, but neither could be detected during thioacetamide degradation, possibly because hydrolysis of these substrates was rapid relative to sulfur elimination (Dodge et al., 2006).
The following is a text-format thioacetamide degradation pathway map. The organism which can initiate the pathway is given, but other organisms may also carry out later steps. Follow the links for more information on compounds or reactions. This map is also available in graphic (5k) format.
Thioacetamide Ralstonia pickettii TA | | | thioacetamide | S-oxygenase | | v Thioacetamide S-oxide | | | thioacetamide S-oxide | S-oxygenase | | v [Thioacetamide S,S-dioxide] | | | A | | v [Acetonitrile] | | | nitrile | hydratase | | v [Acetamide] <---- from the 2-Chloro-N-isopropylacetanilide Pathway | | | acetamidase | | v [Acetate] | | | | | v to Intermediary Metabolism (KEGG)
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