Saccharopolyspora erythraea erythromycin

Pacey, M.S., Dirlam, J.P., Geldart, R.W. et al. (1998) Novel erythromycins from a recombinant Saccharopolyspora erythraea strain NRRL 2338 pIGl. I. Fermentation, isolation and biological activity. The Journal of Antibiotics, 51, 1029. 

Oliynyk, M., Samborskyy, M., Lester, J.B. et al. (2007) Complete genome sequence of the erythromycin-producing bacterium Saccharopolyspora erythraea NRRL23338. Nature Biotechnology, 25, 447-453. 

Reeves AR, Brikun lA, Cemota WH, Leach BI, Gonzalez MC, Weber JM. (2007) Engineering of the methylmalonyl-CoA metabolite node of Saccharopolyspora erythraea for increased erythromycin production. Metab Eng 9 293-303. 

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]. 

A 26-kb gene cluster encoding enzymes for synthesis of the blue antibiotic actinorhodin by Streptomyces coelicolor has been cloned and sequenced.332337 The three large 10-kb genes required for formation of the broad-spectrum antibiotic erythromycin by Saccharopolyspora erythraea have also been cloned and sequenced.337 339 In both cases, the genes... 

The erythromycins (Figure 3.65) are macrolide antibiotics produced by cultures of Saccharopolyspora erythraea (formerly Streptomyces erythreus). The commercial product... 

Erythromycin A 64 and spinosyns A and D 65a/65b are important macrolides produced by Saccharopolyspora erythraea and Sacch. spinosa, respectively. Compound 65a contains per-O-methylated L-rhamnose and D-forosamine attached O-glycosidically to the aglycone. Gene knockouts in respective strains as well as expression of various sugar cassettes (along with appropriate GT gene(s)) in Sacch. erythraea mutants led to production of many derivatives of 64 and 65a and tylosin [111-114],... 

J Cortes, SH Haydock, GA Roberts, DJ Bevitt, PF Leadlay. An unusually large multifunctional polypeptide in the erythromycin-producing polyketide synthase of Saccharopolyspora erythraea. Nature 348 176-178, 1990. 

P Caffrey, DJ Bevitt, J Staunton, PF Leadlay. Identification of DEBS 1, DEBS 2 and DEBS 3, the multienzyme polypeptides of the erythromycin-producing polyketide synthase from Saccharopolyspora erythraea. FEBS Lett 304 225-228, 1992. 

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.

Figure 20 Altering the starter unit specificity of DEBS. A hybrid PKS was constructed by introducing the avermectin loading domains in place of those of DEBS. Expression of the mutant strain in Saccharopolyspora erythraea resulted in erythromycin analogs incorporating both the expected isobutyrate and 2-methylbutyrate starter units characteristic of avermectin.

S Donadio, MJ Staver, L Katz. Erythromycin production in Saccharopolyspora erythraea does not require a functional propionyl-CoA carboxylase. Mol Microbiol 19 977-984, 1996. 

A similar technique has been used to investigate the elasticity and mechanical strength of the commercially important erythromycin-producing filamentous bacterium Saccharopolyspora erythraea where the mean Young s modulus was estimated to be 100 + 20 MPa (Stocks and Thomas, 2001). 

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... 

Fig. 4. X-ray determined protein crystal structures of multienzyme ensembly lines, (a) Mammalian fatty acid synthase at 4.5 A resolution (PDB 2cf2). Domain organization A starter substrate, acetyl-CoA or malonyl-CoA, gets loaded onto the acyl-carrler protein (ACP/absent in the structure) via the malonyl-CoA-/acetyl-CoA-ACP transacylase (MAT). Then, the ketoacyl synthase (KS) catalyzes a decarboxylative condensation reaction and forms the B-ketoacyl-ACP. This is followed from a reduction reaction catalyzed by the B-ketoacyl reductase (KR). Subsequently, the Intermediate gets dehydrated by a dehydratase (DH) and additionally reduced by a B-enoyl reductase (ER). The product gets released from the ACP by a thloesterase (absent in the structure), (b) Module 3 of 6-deoxyerthronolide B synthase at 2.6 A resolution (PDB 2qo3) bound to the inhibitor cerulin. The ketosynthase (KS) - acyltransferase (AT) di-domain is part of the large homodimeric polypeptide involved in biosynthesis of erythromycin from Saccharopolyspora erythraea...

Oliynyk M, Samborskyy M, Lester JB, Mironenko T, Scott N, Dickens S, Haydock SF, Leadlay PF (2007) Complete Genome Sequence of the Erythromycin-Producing Bacterium Saccharopolyspora erythraea NRRL23338. Nat Biotechnol 25 447... 

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,... 

Erythromycin (109) was isolated, in 1952, from a strain of Saccharopolyspora erythraea... 

Macrolide antibiotics are glycosides with a macrocyclic lactone aglycon, which is formed in the polyketide biosynthetic pathway [38,39]. The lactone ring is 12-, 14-, 16-, or 18-mem-bered. The polyoxo-macrolides such as the classical antibiotic erythromycin are produced by streptomyces microorganisms and form a clinically important group of polyketide antibiotics. Erythromycin (O Fig. 5) is the major component out of a mixture of macrolide antibiotics which is formed by Saccharopolyspora erythraea. It contains two deoxysugars attached to the aglycon, L-cladinose and D-desosamine. 

Hessler, P.E., Larsen, P.E., Constantinou, A.I., Schram, K.H., and Weber, J.M. 1997. Isolation of isoflavones from soy-based fermentations of the erythromycin-producing bacterium Saccharopolyspora erythraea. Applied Microbiol. Biotech, 47 398 404. 

Erythromycin, naturally produced by Saccharopolyspora erythraea, is among the most widely used antibiotics. It acts through the inhibition of protein synthesis by binding to the 508 ribosomal subunit [2]. The tetracycline antibiotics are produced by a number of Streptomyces organisms, and inhibit bacterial protein synthesis by preventing aminoacyl-tRNA association with the bacterial ribosome [3]. The epothilones, isolated from Sorangium cellu-losum, are potential anti-cancer agents with the same mechanism of action as taxol, the stabilization of microtubules that leads to the arrest of cell division and ultimately cell death [4, 5]. Doxorubicin, isolated from Streptomyces peucetius, is a cytotoxic molecule that has been used for the treatment... 

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). 

Paulus, T.)., Tuan, ).S., Luebke, V. E., Maine, G.T., DeWitt, ).P. Katz, L. Mutation and cloning of eryG, the structural gene for erythromycin O-methyltransferase from Saccharopolyspora erythraea, and expression of eryC in Escherichia coli. J. Bacteriol. 172, 2541—2546 (1990). 

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