Macrocyclic polyketide

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

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-... 

Avermectins are a mixture of 16-membered macrocyclic polyketide aglycones with a dimeric o-methyl-a-L-oleandrose attached to C-13, and are widely used for broad spectrum parasite control (Figure 8.2). They vary in three substituents Ri, R2 and R3, where R3 can be either a hydroxyl or hydrogen, in which case there is a double bond... 

The potential for producing novel macrocyclic polyketides is even more promising, since, in this case, the physical and temporal functioning of biosynthetic enzymes has been implicated as being a sequential process (86). If substrate specificities can be overcome, then an enormous number of compounds could be produced representing all of the possible combinations of oxidation... 

Kahn, K., and Bruice, T. C. [2002], Parameterization of OPLS-AA force field for the conformational analysis of macrocyclic polyketides, J. Comput. Chem. 23, pp. 977-996, doi 10.1002/jcc.l0051. 

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. 

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). 

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