Erythromycins polyketide synthases

Petkovic, H., Lill, R.E., Sheridan, R.M. et al. (2003) A novel erythromycin, 6-desmethyl erythromycin D, made by substituting an acyltransferase domain of the erythromycin polyketide synthase. The Journal of Antibiotics, 56, 543. 

Ruan, X., Pereda, A., Stassi, D.L. et al. (1997) Acyltransferase domain substitutions in erythromycin polyketide synthase yield novel erythromycin derivatives. Journal of Bacteriology, 179, 6416. 

McDaniel, R., Thamchaipenet, A., Gustafsson, C. et al. (1999) Multiple genetic modifications of the erythromycin polyketide synthase to produce a library of novel unnatural natural products. Proceedings of the National Academy of Sciences of the United States of America, 96, 1846. 

Gokhale, R.S., Hunziker, D., Cane, D.E. and Khosla, C. (1999) Mechanism and specificity of the terminal thioesterase domain from the erythromycin polyketide synthase. Chemistry Biology, 6, 117. 

R Pieper, G Luo, DE Cane, C Khosla. Cell-free biosynthesis of polyketides by recombinant erythromycin polyketide synthases. Nature 378 263-266, 1995. 

RS Gokhale, J Lau, DE Cane, C Khosla. Functional orientation of the acyltransferase domain in a module of the erythromycin polyketide synthase. Biochemistry 37 2524-2528, 1998. 

Figure 5 Domain organization of the erythromycin polyketide synthase. Putative domains are represented as circles and the structural residues are ignored. Each module incorporates the essential KS, AT, and ACP domains, while all but one include optional reductive activities. AT, acyltransferase ACP, acyl carrier protein KS, (3-ketoacyl synthase KR, P-ketoacyl reductase DH, dehydratase ER, enoyl reductase TE, thioesterase.

KJ Weissman, M Timoney, M Bycroft, P Grice, U Hanefeld, J Staunton, PF Leadlay. The molecular basis of Celmer s rules the stereochemistry of the condensation step in chain extension on the erythromycin polyketide synthase. Biochemistry 36 13849-13855, 1997. 

Ruan, X., Pereda, A., Stassi, D. L., Zeidner, D., Summers, R. G., Jackson, M., Shivakumar, A., Kakavas, S., Staver, M.J., Donadio, S., and Katz, L. (1997). Acyl transferase domain substitutions in erythromycin polyketide synthase yield novel erythromycin derivatives./. Bacteriol., 179, 6416-6425. 

Well-known examples are novel glycosylated elloramycins (11), staurosporines (12), mithramycins (13), and steffimycins (14) generated by the group of/. Salas, in Oviedo, Spain (73, 99). One additional example concerns the formation of a macrolide in a mutant strain of Saccharopolyspora erythraea. This mutant strain lacks the erythromycin polyketide synthase gene as well as both GT genes required for the transfer of L-mycarose (eryBV) and D-desosamine (eryCII) moieties during the erythromycin biosynthesis, but still it provides the TDP-activated forms of the... 

Baerga-Ortiz A, Popovic B, Siskos AP, O Hare HM, Spiteller D, Williams MG, Campillo N, Spencer JB, Leadlay PF (2006) Directed Mutagenesis Alters the Stereochemistry of Catalysis by Isolated Ketoreductase Domains from the Erythromycin Polyketide Synthase. Chem Biol 13 277... 

McDaniel R, Thamchaipenet A, Gustafsson C, Fu H, Betlach M, Ashley G (1999) Multiple Genetic Modifications of the Erythromycin Polyketide Synthase to Produce a Library of Novel Unnatural Natural Products. Proc Natl Acad Sci USA 96 1846... 

Ostergaard, L. H., Kellenberger, L., Cortes, J., Roddis, M. P., Deacon, M., Staunton, J., Leadlay, P. F., Stereochemistry of catalysis by the ketoreductase activity in the first extension module of the erythromycin polyketide synthase. Biochemistry 2001, 41, 2719-2726. 

Pereda, A., R. G. Summers, D. L. Stassi, X. Ruan, and L. Katz (1998). The loading domain of the erythromycin polyketide synthase is not essential for erythromycin biosynthesis in Succharopoly-spora erythraea. Microbiol. 144 543-553. 

Wu, N., Kudo, F., Cane, D.E. Khosla, C. Analysis of the molecular recognition features of individual modules derived from the erythromycin polyketide synthase. J. Am. Chem. Soc. 122, 4847 852 (2000). 

D.E., Khosla, C. Stroud, R.M. Grystal structure of the macrocycle-forming thioesterase domain of the erythromycin polyketide synthase versatility from a unique substrate channel. Proc. Natl. Acad. Sci. USA 98, 14808-14813 (2001). 

Gane, D. E., Kudo, F., Kinoshita, K. Khosla, C. Precursor-directed biosynthesis biochemical basis of the remarkable selectivity of the erythromycin polyketide synthase toward unsaturated triketides. Chem. Biol. 9, 131—142 (2002). 

J. Lau, D. Cane, C. Khosla, Substrate specificity of the loading didomain of the erythromycin polyketide synthase, Biochemistry 2001, 29, 10514-10520. 

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