Erythromycin, biosynthesis

FIGURE 4.1 Representative examples of the diverse structure and functionality achievable from PKS- and NRPS-mediated biosynthesis erythromycin A (1), actinorhodin (2), epothilone D (3), and vancomycin (4). 

Chemical degradation of erythromycin A yielded its aglycone, erythronoHde A (16, R = R = OH), whereas erythronoHde B (16, R = H, R = OH) was obtained from fermentation (63,64). Biosynthesis of erythromycin proceeds via 6-deoxyerythronoHde B (16, R = R = H) and then erythronoHde B (64,65). The first total synthesis of erythromycin-related compounds was erythronoHde B (66) syntheses of erythronoHde A and 6-deoxyerythronoHde B soon foUowed (67,68). 

NMR, 4, 575 Erythritol, 1,4-anhydro-structure, 4, 546 Erythromycin antibacterial veterinary use, 1, 206 as pharmaceutical, 1, 153 synthesis, 1, 480 Erythropterin biosynthesis, 3, 321 occurence, 3, 323 structure, 3, 276 synthesis, 3, 289 Erythropterin, 3,5-dimethyl-methyl ester synthesis, 3, 303 Erythrosine application, 3, 879 Esculetin... 

Aminoglycosides Tetracyclines Chloramphenicol Erythromycin Clindamycin Spectinomycin Mupirodn Fusldfc add Inhibition of protein biosynthesis... 

Figure 11.4 6-DEBS 1, 2 and 3 that are modularly organized PKSs direct the biosynthesis of erythromycin A (a), and genetic engineering on genes encoding DEBSs gave rise to various 6-DEB analogs (b)...

Jacobsen, J.R., Keatinge-Clay, A.T., Cane, D.E. and Khosla, C. (1998) Precursor-directed biosynthesis of 12-ethyl erythromycin. Bioorganic and Medicinal Chemistry, 6, 1171. 

There are at least three types of PKS. Type I PKSs catalyze the biosynthesis of macrolides such as erythromycin and rapamycin. As modular enzymes, they contain separate catalytic modules for each reaction catalyzed sequentially in the polyketide biosynthetic pathway. Type II PKSs have only a few active sites on separate polypeptides, and the active sites are used iteratively, catalyzing the biosynthesis of bacterial aromatic polyketides. Type III are fungal PKSs they are hybrids of type I and type II PKSs [49,50]. 

Zou X, Hang H-F, Chu J, Zhuang Y-P, Zhang S-L. (2009) Enhancement of erythromycin A production with feeding available nitrogen sources in erythromycin biosynthesis phase. Biores Technol 100 3358-3365. 

The PKS TE from erythromycin biosynthesis and the NRPS TE from surfactin biosynthesis are remarkably similar in three-dimensional topology (Figure 7.3) [42, 43]. It is expected that the application of enzyme-directed evolution will be able to further broaden the synthehc applications of TEs by increasing their activity and stability [44]. 

Recently, a novel fluorinated erythromycin (16-fluoroerythromycin A) has been produced by Saccharopolyspora erythraea, using an m-fluorobutyrate as precursor for the biosynthesis (Fig. 46) [124]. 

Deoxyerythronolide B synthase (DEBS) is a modular Type I PKS involved in erythromycin biosynthesis (see page 96) and its structure and function are illustrated in Figure 3.85. The enzyme contains three subunits (DEBS-1, 2, and 3), each encoded by a gene (eryA-l, II, and III). It has a linear organization of six modules, each of which... 

Staunton J and Wilkinson B (1997) Biosynthesis of erythromycin and rapamycin. Chem Rev 97, 2611-2629. 

S. Donadio, M. J. Staver, J. B. McAlpine, S. J. Swanson, and L. Katz, Biosynthesis of the erythromycin macrolactone and a rational approach for producing hybrid macrolides, Gene, 115 (1992) 97-103. 

Seno ET, Hutchinson CR (1986) The biosynthesis of tylosin and erythromycin Model systems for the studies of the genetics and biochemistry of antibiotic formation. In Queener SW, Day LE (eds) The Bacteria Volume IX Antibiotic-Producing Streptomyces. Academic Press, Orlando, p 231... 

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