Biosynthesis of Erythromycin

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). 

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., Hutchinson, C.R., Cane, D.E. and Khosla, C. (1997) Precursor-directed biosynthesis of erythromycin analogs by an engineered polyketide synthase. Science, 277, 367-369. 

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

J Staunton. Combinatorial biosynthesis of erythromycin and complex polyketides. Curr Opin Chem Biol 2 339-345, 1998. 

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...

The biosynthesis of erythromycin can be divided into two phases (Scheme 1). In the first constructive phase of the pathway a set of key enzymes, collectively known as the polyketide synthase (PKS), assembles the typical polyketide chain by sequential condensation of one unit of propionyl-CoA and six units of methylmalonyl-CoA 6. The initially formed chain is cyclised to give the first macrocychc lactone (macrolide) intermediate 6-deoxyerythronolide B 7 [6,7]. In the second phase 6-deoxyerythronohde B is elaborated by a series of tailoring enzymes which carry out regiospecific hydroxylations, glycosylations and a methylation (of an added sugar residue) to give finally erythromycin A. The core polyketide structure is generated by the PKS in phase one, but the later steps of phase two are essential to produce active antibiotics. 

The first enzyme-free intermediate in the biosynthesis of erythromycin is the polyketide 6-deoxyerythronolide B. All of the carbons come from either acetate or propanoate. 

Beauveridn, hexadepsipeptide antibiotic produced by fungi 12MOL2367. Biosynthesis and combinatorial biosynthesis of erythromycin 12CJ01232. Biosynthesis and total synthesis studies on the jadomycin family ofpoly-ketide antibiotics 12EJO2095. 

Biosynthesis of erythromycin represents a typical polyketide pathway and structural organization of PKSs. Erythromycin PKS (6-deoxyerythronolide B synthase, DEBS) uses propionyl-CoA as a priming unit and six methylmalonyl-CoA molecules as extender units. Each module in a modular PKS contains domains for one round of chain elongation (KS, AT, ACP) and p-keto modification (ketoreductase, KR dehy-drase, DH enoylreductase, ER). DEBS consists of six modules (mod 1 -6) encoded on three separate polypeptide subunits. 

Diverse polyketide-type libraries were synthesized using a-chiral aldehydes attached by a silyl linker to a hydromethylpolysyrene resin (Figure 11.24). " Aldol chain extension with chiral ketone modules, and subsequent ketone reduction and manipulation on the solid support led to elaborated stereopentad sequences found in natural products such as 6-deoxyerythronolide B and discoder-molide. Based on the biosynthesis of erythromycin, the same methodology was used in the combinatorial synthesis of polyketide sequence mimetics with a great variety of chain-extending units. " ... 

Figure 4 The biosynthesis of erythromycin A in SocdwTOpolysporo erythraea. The names of the principal genes or classes of genes involved are indicated above the thin or thick arrows for single or multiple steps, respectively. The inset shows the hybrid antibiotic 2-norerythromycin A made by introducing DNA from the oleandomycin producer into a blocked mutant of the erythromycin producer.

As shown in Scheme 11.38, the biosynthesis of erythromycin uses PKS consisting of a complex of three units that are named after the 6-deoxyerythronolide B product eventually elaborated into the antibiotic erythromycin. The three units are deoxyerythronolide B synthase DEBSl, DEBS2, and DEBS3 and, as noted in Scheme 11.38, involve beginning with propanoyl CoA and adding methyhnalonyl... 

FIGURE 25.16 An outline of the pathway forthe biosynthesis of erythromycin A. One propionate and six methylmalonate units are first assembled into the macrocyclic lactone 6-deoxyerythronolide B, which is then hydroxylated, glycosylated by two different sugars, hydroxylated again, and finally methylated. 

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