Erythromycins biosynthetic genes

Brikun, I.A., Reeves, A.R., Cernota, W.H. et al. (2004) The erythromycin biosynthetic gene cluster of Aeromicrobium erythreum. Journal of Industrial Microbiology Biotechnology, 31, 335. 

Summers, R.G., Donadio, S., Staver, M.J., Wendt-Pienkowski, E., Hutchinson, C. R. Katz, L. Sequencing and mutagenesis of genes from the erythromycin biosynthetic gene cluster of Saccharopolyspora erythraea that are involved in L-mycarose and D-desosamine production. Microbiology 143, 3251-3262 (1997). 

Reeves AR, English SR, Lampel JS, Post DA, Vanden Boom TJ (1999) Transcriptional organization of the erythromycin biosynthetic gene cluster of Saccharopolyspora erythraea. J Bacteriol 181 7098-7106... 

Gaisser S, Lill R, Wirtz G et al (2001) New erythromycin derivatives from Saccharopoly-spora erythraea using sugar O-methyltransferase from the spinosyn biosynthetic gene cluster. Mol Microbiol 41 1223-1231... 

Fig. 1. Map of the S. erythraea genome containing genes associated with the late stages of the erythromycin biosynthetic pathway...

D-desosamine and L-oleandrose genes. A similar situation occurs in the erythromycin and tylosine pathways. This contrasts with the behavior of most antibiotic biosynthetic genes which tend to be clustered in the chromosomes of the producer strains, as has been shown in the various pathways that have been characterized. 

It may be argued that this unusual biosynthetic sequence is due to the unique composition and organization of the dps (dauno- or doxorubicin polyketide synthase) genes of Streptomyces peucetius [88]. But, also in more typical biosyntheses of polyketide oligodeoxysaccharides, for example, the macrolides erythromycin A (14) [24, 58, 89] in Saccharopolyspora erythraea and tylosin in Streptomyces fradiae [90], or urdamycin biosynthesis in Streptomyces fradiae TU2717 [77,91,... 

Figure 2.7 Domain organisation of erythromycin polyketide synthase. Gene sequence putative domains are represented as circles and the structural residues are ignored. Each module incorporates the essential KS, AT andACP domains, while all but one include optional reductive activities (KR, DH, ER). The one-to-one correspondence between domains and biosynthetic transformations explains how programming is achieved in this modular PKS. DEBS—deoxyerythronolide B synthase (reproduced with permission of Prof. James Staunton)...

Tylosin [46-49] (Fig. 6), produced by Streptomyces fradiae, was one of the first antibiotics for which a comprehensive set of blocked mutants was isolated. They were used to help define the biosynthetic pathway. Whereas erythromycin is a 14-membered macrolide, tylosin has a 16-membered lactone structure. The gene for the final step of biosynthesis was cloned by reverse genetics from the protein sequence of the enzyme [46], and specific segments of surrounding DNA were found to complement other classes of blocked mutants. The formation of tylosin aglycon, protylonolide, is involved in five polyketide synthases. 

Since the PKS (polyketide synthase) gene cluster for actinorhodin (act), an antibiotic produced by Streptomyces coelicolor[ 109], was cloned, more than 20 different gene clusters encoding polyketide biosynthetic enzymes have been isolated from various organisms, mostly actinomycetes, and characterized [98, 100]. Bacterial PKSs are classified into two broad types based on gene organization and biosynthetic mechanisms [98, 100, 102]. In modular PKSs (or type I), discrete multifunctional enzymes control the sequential addition of thioester units and their subsequent modification to produce macrocyclic compounds (or complex polyketides). Type I PKSs are exemplified by 6-deoxyerythronolide B synthase (DEBS), which catalyzes the formation of the macrolactone portion of erythromycin A, an antibiotic produced by Saccharopolyspora erythraea. There are 7 different active-site domains in DEBS, but a given module contains only 3 to 6 active sites. Three domains, acyl carrier protein (ACP), acyltransferase (AT), and P-ketoacyl-ACP synthase (KS), constitute a minimum module. Some modules contain additional domains for reduction of p-carbons, e.g., P-ketoacyl-ACP reductase (KR), dehydratase (DH), and enoyl reductase (ER). The thioesterase-cyclase (TE) protein is present only at the end of module 6. 

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