Macrocyclic polyketide macrocyclization

Kopp, F. and Marahiel, M.A. (2007) Macrocyclization strategies in polyketide and nonribosomal peptide biosynthesis. Natural Product Reports, 24, 735. 

Kohli, R.M., Burke, M.D., Tao, J. and Walsh, C.T. (2003) Chemoenzymatic route to macrocyclic hybrid peptide/ polyketide-like molecules. Journal of the American Chemical Society, 125, 7160-7161. 

Boddy, C.N., Schneider, T.L., Hotta, K. et al. (2003) Epothilone C macrocyclization and hydrolysis are catalyzed by the isolated thioesterase domain of epothilone polyketide synthase. Journal of the American Chemical Society, 125, 3428-3429. 

Macrocyclic polyketides have so far been the primary focus of combinatorial biosynthesis technologies. The mutagenesis techniques outlined in Sec. VI sug-... 

A multifunctional biosynthetic machinery mediates the synthesis of these complex natural products from acetyl- and propionyl-coenzyme A [3). In the case of type I polyketide-synthases, the )8-oxo-esters made by polycondcnsa-tion steps are modified for example by reduction or dehydration after the chain elongation. Additional specific enzymatic transformations, e.g. oxidations and glycosylations, usually take place after the decoupling at the completed macrocyclic ring framework [1,3],... 

Gene clusters (or parts thereof) controlling the biosynthesis of several other complex polyketides, including avermectin [25],rapamycin [26], oleandomycin [164], and soraphen [165], have been isolated and sequenced. In aU cases, the PKSs have been found to be organized into individual modules with each module containing the appropriate sets of active sites. Thus, the modular hypothesis appears to be well-substantiated now in several model systems. Intriguingly, in the case of rapamycin, biosynthesis of the entire macrocycle involves activity of a 12-module PKS as well as a peptide synthetase module (see below). 

Termination of polyketide biosynthesis typically involves the TF mediated cleavage of the ACP-bound thioester, followed by cyclization to generate a macrolactone. Alternatively, the TF catalyzes the simple hydrolysis of the thioester to generate a linear free acid product. Here, we consider two of the relatively few known examples of polyketide natural products that are neither a macrocycle nor a free acid, but instead terminate with a double bond. 

Tsai SC, Lu H, Cane DE, Khosla C, Stroud RM. Insights into channel architecture and substrate specificity from crystal structures of two macrocycle-forming thioesterases of modular polyketide synthases. Biochemistry 2002 41 12598-12606. 

Epothilones A (56) and B (57), 16-membered macrocyclic polyketide lactones, were first isolated from the cellulose-degrading myxobac-terium Sorangium cellulosum by Hoefle, Reichenbach, and coworkers (86) as narrow-... 

There is no major distinction between the avermectins and milbemycins, which are based on the same complex polyketide macrocycle (168) the avermectins are oxygenated at C-13 and bear a disaccharide on this oxygen. They have been isolated from cultures of a... 

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. 

The ansamycin polyketide ansatrienin A 57 also contains a fully reduced cyclohexane carboxylic (CHC) unit attached to the macrocyclic structure via a... 

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 macrocyclic lactone (macrolide) intermediate 6-deoxyerythronolide B 7 [6,7]. In the second phase 6-deoxyerythronolide 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. 

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