Rifamycin, polyketide assembly

Rifamycin B, produced by Amycolatopsis mediterranei, is one of the most notable members of the ansamycin family [36, 37, 64, 65] (Fig. 14). It has been used clinically in a synthetically modified form called rifampicin and it is still one of the first-line therapies effective in the treatment of tuberculosis and other mycobacterial infections. The starter unit for rifamycin polyketide assembly is part of the chromophore and is derived from 3-amino-5-hydroxybenzoic acid. Five polyketide synthases are involved in the formation of rifamycin chromophore and the first polyketide synthase contains at the N terminus the loading domain for 3-amino-5-hydroxybenzoic acid, which consists of an acyl-CoA ligase linked to ACP, and module 1-3. The rifamycin polyketide synthase lacks a TE domain at the C terminus. The release of polyketide chain from polyketide synthase and the formation of amide to generate the macrocyclic lactam will be catalyzed by RifF, which is very similar to arylamine A-acetyltransferase. 

Yu, T. W., Shen, Y, Doi-Katayama, Y, Tang, L., Park, C., and Hutchinson, C. R. (1999). Direct evidence that the rifamycin polyketide synthase assembles polyketide chains processively. Proc. Natl. Acad, Sci. USA 96, 9051-9056. 

S.J. Admiraal, C. Khosla, C.T. Walsh, A switch for the transfer of substrate between nonri-bosomal peptide and polyketide modules of the rifamycin synthetase assembly line. J. Am. Chem. Soc. 125, 13664-13665 (2003)... 

Polyketide and non-ribosomal peptides produced by bacteria and fungi often attain the conformations that establish biological activity by cychzation constraints introduced by tailoring enzymes. This includes heterocychzation of cysteines, serines and threonines in non-ribosomal peptides. The second cychzation constraint is macrocychzation in polyketides, such as the above-mentioned antibiotic erythromycin and the antitumor epothilones. Regio- and stereospecific macrocychzation usuaUy occurs at the end of the polyketide and non-ribosomal peptide assembly hnes during chain release by thioesterase domains [49]. However, in the case of antibiotics of the ansamycin class, like the antitubercular drug rifamycin, the final... 

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