Synthases, polyketide

Polyketide synthases (PKSs) are large protein complexes responsible for the biosynthesis of an array of complex, biologically active compounds, many of which are employed in medicine. Several classes of PKSs exist, each with an architectural variation on a common mechanistic thane. 

8-DMAC, Aloesaponarin II (41, 42) RM20, RM20b, RM20c (43, 44, 45) Tetracenomycin F2 (46) 

New compounds generated by recombinant assembly of enzymatic subunits. 

These and other experiments proposed the designation of the KS as chain length factor (CLF) determinant [38]. It must be mentioned that genes coding for CLFs can not be interchanged in all cases as some of the KS-CLF combinations are not functional. 

Variation of the Folding Pattern - Influence of Aromatases and Cyclases 

The influence of the Actlll KR on the final product has been studied in some detail. Actlll interacts with the bacterial PKSs and reduces the carbonyl that is nine carbons from the carboxyl end of the poly-[i-ketonc intermediates this results in the absence of a hydroxyl at the corresponding position of the polyketide. The reduction influences the cy-clization pattern. When actlll was expressed together with tcmK, tcmL and tcmM, RM20b (44) was produced. In the absence of actlll, SEK15 (39) was the main accumulated product (see above). 

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Role of polyketide synthases in biosynthesis of some heterocycles, in particular macrolides 97CRV2465. 

It is very likely that a similar Type I polyketide synthase constructs the naphthoate fragment of azinomycin B. This will be a very interesting enzyme to study, since it will need to perform an unprecedented three regioselective reduction reactions, as well as controlling the polyketide chain length and directing its cycliza-tion. 

The biosynthesis of maduropeptin has not been studied in detail, but an iterative type I polyketide synthase gene predicted to be responsible for forming the enediyne core structure has been identified [188]. 

Hutchinson, R.C., Microbial polyketide synthases more and more prolific, Proc. Natl. Acad. Sci. USA, 96, 3336, 1999. 

Kim, J.E. et ah. Putative polyketide synthase and laccase for biosynthesis of auro-fusarin in Gibberella zea, Appl. Environ. Microbiol., 71, 1701, 2005. 

Will it be possible to use individual dehydrogenase modules from large assemblies such as polyketide synthases ... 

B. Nowak-Thompson, S. J. Gould, and J. E. Loper, Identification and sequence analysis of the genes encoding a polyketide synthase required for pyoluteorin biosynthesis in Pseudomonas fluorescens Pf-5. Gene (1997). 

It was proposed that a Diels-Alder cyclization occurred during a polyketide synthase assembly of the bicyclic core of Lovastatin by Aspergillus terreus MF 4845." In vitro Diels-Alder cyclization of the corresponding model compounds generated two analogous diastere-omers in each case, under either thermal or Lewis-acid-catalyzed conditions (Eq. 12.37). As expected, the Diels-Alder reaction occurred faster in aqueous media. The cyclization half-life in chloroform at room temperature is 10 days while in aqueous media at either pH 5 or 7, the half-life drops to two days. 

Hutchinson, C.R. and Fujii, I. (1995) Polyketide synthase gene manipulation a structure-function approach in engineering novel antibiotics. Annual Review of Microbiology, 49, 201. 

Khosla, C. (1997) Harnessing the biosynthetic potential of modular polyketide synthases. Chemical Reviews, 97, 2577. 

Shen, B. (2003) Polyketide biosynthesis beyond the type I, II and III polyketide synthase paradigms. Current Opinion in Chemical Biology, 7, 285. 

Jenke-Kodama, H., Sandmann, A., Muller, R. and Dittmann, E. (2005) Evolutionary implications of bacterial polyketide synthases. Molecular Biology and Evolution, 22, 2027. 

Liu, W., Nonaka, K., Nie, L. et al. (2005) The neocarzinostatin biosynthetic gene cluster from Streptomyces carzinostaticus ATCC 15944 involving two iterative type I polyketide synthases. Chemistry Biology, 12, 293. 

Liu, W., Ahlert, J., Gao, Q. et al. (2003) Rapid PCR amplification of minimal enediyne polyketide synthase cassettes leads to a predictive familial classification model. Proceedings of the National Academy of Sciences of the United States of America, 100, 11959. 

Long, P.F., Wilkinson, C.J., Bisang, C.P. et al. (2002) Engineering specificity of starter unit selection by the erythromycin-producing polyketide synthase. Molecular Microbiology, 43, 1215. 

Marsden, A.F., Wilkinson, B., Cortes, J. et al. (1998) Engineering broader specificity into an antibiotic-producing polyketide synthase. Science, 279, 199. 

Petkovic, H., Lill, R.E., Sheridan, R.M. et al. (2003) A novel erythromycin, 6-desmethyl erythromycin D, made by substituting an acyltransferase domain of the erythromycin polyketide synthase. The Journal of Antibiotics, 56, 543. 

Ruan, X., Pereda, A., Stassi, D.L. et al. (1997) Acyltransferase domain substitutions in erythromycin polyketide synthase yield novel erythromycin derivatives. Journal of Bacteriology, 179, 6416. 

Del Vecchio, F., Petkovic, H., Kendrew, S.G. et al. (2003) Active-site residue, domain and module swaps in modular polyketide synthases. Journal of Industrial Microbiology Biotechnology, 30, 489. 

Reeves, C.D., Murli, S., Ashley, G.W. et al. (2001) Alteration of the substrate specificity of a modular polyketide synthase acyltransferase domain through site-specific mutations. Biochemistry, 40, 15464. 

Kumar, P., Koppisch, A.T., Cane, D.E. and Khosla, C. (2003) Enhancing the modularity ofthe modular polyketide synthases transacylation in modular polyketide synthases catalyzed by malonyl-CoA ACPtransacylase. Journal of the American Chemical Society, 125, 14307. 

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. 

Roberts, G.A., Staunton, J. and Leadlay, P.F. (1993) Heterologous expression in Escherichia coli of an intact multienzyme component of the erythromycin-producing polyketide synthase. European Journal of Biochemistry, 214, 305. 

The biosynthesis of polyketides (including chain initiation, elongation, and termination processes) is catalyzed by large multi-enzyme complexes called polyketide synthases (PKSs). The polyketides are synthesized from starter units such as acetyl-CoA, propionyl-CoA, and other acyl-CoA units. Extender units such as malonyl-CoA and methylmalonyl-CoA are repetitively added via a decarboxylative process to a growing carbon chain. Ultimately, the polyketide chain is released from the PKS by cleavage of the thioester, usually accompanied by chain cyclization [49]. 

Pohl, N.L. (2002) Nonnatural substrates for polyketide synthases and their associated modifying enzymes. Current Opinion in Chemical Biology, 6, 773-778. 

Yoon, Y.J., Beck, B.J., Kim, B.S. et al. (2002) Generation of multiple bioactive macrolides by hybrid modular polyketide synthases in Streptomyces venezuelae. Chemistry Biology, 9, 203-214. 

Menzella, H.G., Reid, R., Carney, J.R. et al. (2005) Combinatorial polyketide biosynthesis by de novo design and rearrangement of modular polyketide synthase genes. Nature Biotechnology, 23, 1171-1176. 

Ward, S.L., Desai, R.P., Hu, Z. et al. (2007) Precursor-directed biosynthesis of 6-deoxyerythronolide B analogues is improved by removal of the initial catalytic sites of the polyketide synthase. Journal of Industrial Microbiology and Biotechnology, 34, 9-15. 

Cane, D.E. and Walsh, C.T. (1999) The parallel and convergent universes of polyketide synthases and nonribosomal peptide synthetases. Chemistry Biology, 6 (12), R319—R325. 

Moore, B.S. and Hertweck, C. (2002) Biosynthesis and attachment of novel bacterial polyketide synthase starter units. Natural Product Reports, 19 (1), 70-99. 

MacNeil, D.J., Occi, J.L., Gewain, K.M. et al. (1992) Complex organization of the Streptomyces avermetilis genes encoding the avermectin polyketide synthase. Gene, 115, 119-125. 

Lu, H., Tsai, S.-C., Khosla, C. and Cane, D.E. (2002) Expression, site-directed mutagenesis, and steady state kinetic analysis of the terminal thioesterase domain of the methymycin/picromycin polyketide synthase. Biochemistry, 41, 12590-12597. 

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