Engineered biosynthesis polyketides

Kato, Y., Bai, L., Xue, Q. et al. (2002) Functional expression of genes involved in the biosynthesis of the novel polyketide chain extension unit, methoxymalonyl-acyl carrier protein, and engineered biosynthesis of 2-desmethyl-2-methoxy-6-deoxyerythronolide B. Journal of the American Chemical Society, 124, 5268. 

Kao, C.M., Luo, G.L., Katz, L. et al. (1995) Engineered biosynthesis of a triketide lactone from an incomplete modular polyketide synthase. Journal of the American Chemical Society, 117, 9105. 

Engineered Biosynthesis of Plant Polyketides Structure-Based and Precursor-Directed Approach... 

Keywords Chalcone synthase superfamily enzyme, Engineered biosynthesis, Precursor-directed biosynthesis, Structure-based engineering, Type III polyketide synthase... 

Abe I, Oguro S, Utsumi Y, Sano Y, Noguchi H (2005) Engineered biosynthesis of plant polyketides chain length control in an octaketide-producing plant Type III polyketide synthase. J Am Chem Soc 127 12709-12716... 

Fu H, Ebert-Khosla S, Hopwood DA, Khosla C (1994) Engineered biosynthesis of novel polyketides dissection of the catalytic specificity of the act ketoreductase. J Am Chem Soc 116 4166-4170... 

Abe I, Watanabe T, Morita H, Kohno T, Noguchi H (2006) Engineered biosynthesis of plant polyketides manipulation of chalcone synthase. Org Lett 8 499-502... 

Yu T-W, Shen Y, McDaniel R, Floss HG, Khosla C, Hopwood DA, Moore BS (1998) Engineered biosynthesis of novel polyketides from Streptomyces spore pigment polyketide synthases. J Am Chem Soc 120 7749-7759... 

Schell U, Haydock SF, Kaja AL et al (2008) Engineered biosynthesis of hybrid macrolide polyketides containing D-angolosamine and D-mycaminose moieties. Org Biomol Chem 6 3315-3327... 

R McDaniel, S Ebert-Khosla, DA Hopwood, C Khosla. Engineered biosynthesis of novel polyketides. Science 262 1546-1550, 1993. 

CM Kao, M McPherson, RN McDaniel, HFu, DE Cane, C Khosla. Gain of function mutagenesis of a modular polyketide synthase II. Engineered biosynthesis of an eight-membered ring tetraketide lactone. J Am Chem Soc 119 11339-11340,... 

PJ Kramer, RJX Zawada, R McDaniel, CR Hutchinson, DA Hopwood, C Khosla. Rational design and engineered biosynthesis of a novel 18-carbon aromatic polyketide. J Am Chem Soc 119 635-639, 1997. 

A final example of metabolic pathway engineering is based on polyketide and nonribosomal peptide biosynthesis. Polyketides and nonribosomal peptides are complex natural products with numerous chiral centers, which are of substantial economic benefit as pharmaceuticals. These natural products function as antibiotics [erythromycin A (65), vancomycin (66)], antifungals (rapamycin, amphotericin B), antiparasitics [avermectin Ala (67)], antitumor agents [epothiolone A (68), calicheamicin yj, and immunosuppressants [FK506 (69), cyclosporin A], Because this exponentially growing and intensely researched field has developed, the reader is directed to review articles for additional details.347-359 Also with the potential economic benefit to develop the next blockbuster pharmaceutical, a number of patents and patent applications have been published.360-366... 

Schell U, Haydock SF, Kaja AL, Carletti I, Lill RE, Read E, Sheehan LS, Low L, Fernandez MJ, Grolle F, McArthur HA, Sheridan RM, Leadlay PF, Wilkinson B, Gaisser S (2008) Engineered Biosynthesis of Hybrid Macrolide Polyketides Containing D-Angolosamine and D-Mycaminose Moieties. Org Biomol Chem 6 3315... 

The power of combinatorial biosynthesis has been best demonstrated through the engineered biosynthesis of polyketides." Polyketides consist of a structurally diverse family of natural products and are mostly biosynthesized by soil-bome actinomyces as secondary metabolites. Fungi and plants have also been sources of polyketides. 

Type III PKSs are found widely among plants and bacteria. They consist of a homodimer ketosynthase that iteratively condenses malonyl-CoA to give relatively smaller aromatic polyketides than those discussed in the last section (Figure 10). Type III PKS differs from Type II PKS in two important aspects (1) the KS directly recraits mal-onyl-CoA in the absence of an acyltransferase or an AGP and (2) the KS active site catalyzes decarboxylative condensation and chain elongation, and also defines the regioselectivity of intramolecular cyclization. The relatively simple mode of chain assembly has made Type III PKSs attractive targets for engineered biosynthesis. 

Yu,T.-W. Shen,Y. McDonald, R. Floss, H. G. Khosla, C. Hopwood, D.A. Moore, B. S., Engineered Biosynthesis of Novel Polyketides from Streptomyces Spore Pigment Polyketide Synthases. J.Amer. Chem. Soc. 1998, 120, 7749. 

Keywords Aliphatic polyketides Biosynthesis Polyketide Synthase Genetic Engineering Erythromycin A Rapamycin. 

---