Erythromycin polyketide derivatives

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. 

R Pieper, RS Gokhale, G Luo, DE Cane, C Khosla. Purification and characterization of bimodular and trimodular derivatives of the erythromycin polyketide synthase. Biochemistry 36 1846-1851, 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. 

Oikawa, Y, Nishi, T, Yonemitsu, O, Chiral synthesis of polyketide-derived natural product. Chemical correlation of chiral synthons, derived from D-glucose for the synthesis of erythromycin A, with chemical cleavage products of the natural antibiotic, J. Chem. Soc., Perkin. Trans. 1, 27-33, 1985. 

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). 

Like tetracyclines, macrolides are also polyketides that are isolated from bacteria and inhibit protein synthesis in certain bacteria. Erythromycin (A.32) is the original macrolide (Figure A.9). Clarithromycin (Biaxin, A.33) and azithromycin (Zithromax, A.34) are semisynthetic derivatives of erythromycin. 

Figure 9 Construction of bimodular polyketide synthases, (a) Chromosomal repositioning of the thioesterase domain from the C-terminus of module 6 to the end of module 2 in the erythromycin PKS leads to production of triketide lactones and the disruption of erythromycin biosynthesis, (b) DEBS 1-TE contains a fusion within the ACP domains of modules 2 and 6. In Saccharopolyspora erythraea and Streptomyces coelicolor the construct produced both propionate and acetate-derived lactones, (c) DEBS 1+TE contains a fusion between ACP2 and the thioesterase domain. In S. coelicolor, the protein biosynthesized the same lactones.

Modern spectroscopic techniques have revolutionized compound identification and quantification. Only a few decades ago, identification of a structurally complex natural product would require multigram quantities of isolated material, which would then be subjected to series of derivatization and degradation experiments, aiming to deduce the unknown s structure from that of resulting derivatives or fragments that may represent known compounds. As a result of the tremendous advances in sensitivity and resolution of NMR spectroscopy over the past 30 years, identification of microgram quantities of new compounds has now become routine. For example, the structure of the polyketide antibiotic, erythromycin (1), was identified in 1957 only after extensive chemical and spectroscopic studies based on multigram amounts of isolated compound.1-3 By the time its... 

Many important therapeutics, in use in clinics today, are biosynthesized by the nonribosomal peptide synthetase (NRPS) and polyketide synthase (PKS) paradigm. For example, many of the antibiotics (penicillin, cephalosporin, vancomycin, erythromycin, etc.), immunosuppressors (cyclosporine, rapamycin), antiviral agents (luzopeptin A), antitumor agents (bleomycin), and toxins (thaxtomin) are NRPS and PKS derived.20-22 Figure 1 displays a small selection of natural products that are NRPS and PKS derived and illustrates the diversity of molecular structures generated by these biosynthetic paradigms. 

Owing to the fact that the primary source of antibacterial agents for biomedical applications are secondary metabolites and chemical derivates of actinomycetes, fungi, and certain soil bacteria such as myxobacteria, most of the recent advances in molecular engineering have been made in relation to polyketide and peptide antibiotics (e.g., erythromycin and vancomycin)24 Recent literature on this topic suggests a greater mechanistic diversity in biosynthetic potential of bacterial natural products that was believed previously. 

Natural products represent a diversity of chemical compounds with varied biological activities. Natural products are an important source of novel pharmaceuticals as well as agricultural pesticides (1,2). Natural products are derived from a number of pathways that create basic scaffolds that are further modified by various tailoring enzymes to create the wide diversity of structures that exist in nature. Polyketide synthases are responsible for the synthesis of an array of natural products including antibiotics such as erythromycin in bacteria (3) and mycotoxins such as aflatoxin in fungi (4). Furthermore, in plants they are part of the biosynthetic machinery of flavonoids, phytoalexins, and phenolic lipi (5,6). 

The most well-established system for heterologous expression involves the hosts S. coelicolor or its close relative S. lividans, and a bifimctional actino-myces- . coli vector with control elements for PKS gene expression that have been derived from the actinorhodin gene cluster [59]. This host-vector system has successfuUy been used to reconstitute functionally the polyketide pathways associated with biosynthesis of frenolicin [60], tetracenomycin [59], oxytetra-cycline [61], erythromycin [62], picromycin/methymycin [63], oleandomycin... 

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