Biosynthesis combinatorial

The utilization of whole cells as bioreactors for the synthesis of oligosaccharides and engineering cell lines for the production of glycoproteins with a human-Hke glycosylation pattern are highlights in the field of glycobiotechnology. 

Synthesis of Oligosaccharides with Metaboiicaiiy Engineered Ceiis 

The database DoBISCUIT (Database of BloSynthesis clusters CUrated and InTegrated) integrates the literature information and provides standardized gene/module/domain descriptions related to the gene clusters [13]. 

Combinatorial biosynthesis, which is also known as genetic engineering of natural product biosynthetic pathways, involves a series of methods that establish novel enzyme combinations that are used for the generation of encoded libraries of bioactive small molecules [14-21]. The feasibility of this approach was first demonstrated by Hop wood et al. [22]. 

Two types of enzyme systems operate like an assembly line, produce a diverse group of natural products, and have proven to be useful for generation of compound libraries. These systems are composed of multiple modules, in which an individual module consists of either a PKS or an NRPS. Each module has a specific set of catalytic domains that determines the structure of the metabolic product. 

A limitation of biotransformation is its inability to generate target modifications. The knowledge of the metabolic pathway allows the introduction of desired 

An interesting example is the hybrid tri-modular PKS which produces a 8-lactone equivalent to the 8-lactone moiety of lovastatin. This functional combination of modules, which are derived from the erythromycin and rapamycin PKSs, was achievable because of an understanding of the modular PKS structure and function. 

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Rohlin, L., Oh, M.K., and Liao, J.C., Microbial pathway engineering for industrial processes evolution, combinatorial biosynthesis and rational design, Curr. Opin. Microbiol. 4, 330, 2001. 

Mijts, B.N., Lee, PC., and Schmidt-Dannert, C., Identification of a carotenoid oxygenase synthesizing acyclic xanthophylls combinatorial biosynthesis and directed evolution, Chem. Biol., 12, 453, 2005. 

JulsingMK et al. (2006) Combinatorial biosynthesis of medicinal plant secondary metabolites. Biomol Eng 23(6) 265-279... 

Chapters 11-13 are devoted to combinatorial biosynthesis, metabolic engineering, and autonomous enzymes for the synthesis and development of complex medicinal molecules. 

Figure 11.3 Principle of combinatorial biosynthesis. Genetic engineering and recombination of the biosynthetic pathways are two major strategies in combinatorial biosynthesis to expand structural diversity...

Examples of Combinatorial Biosynthesis of Pharmaceutical Natural Products... 

Since the first description was only two decades ago, combinatorial biosynthesis has advanced from a limited set of proof-of-principle experiments into a more mature scientific discipline. To reach the maximal potential of natural product structural diversity, the combination of this approach with other established and emerging technologies will ultimately provide access to a rich variety of unnatural natural products with improved properties or new biological activities for future drug discovery and development. 

Galm, U. and Shen, B. (2006) Expression of biosynthetic gene clusters in heterologous hosts for natural product production and combinatorial biosynthesis. Expert Opinion on Drug Discovery, 1, 409. 

Menzella, H.G. and Reeves, C.D. (2007) Combinatorial biosynthesis for drug development. Current Opinion in Microbiology, 10, 238. 

Staunton, J. and Wilkinson, B. (2001) Combinatorial biosynthesis of polyketides and nonribosomal peptides. Current Opinion in Chemical Biology, 5, 159. 

Thomas, M.G., Bixby, K.A. and Shen, B. (2005) Combinatorial biosynthesis of anticancer natural products, in Anticancer Agents from Natural Products (eds G.M. Cragg, D.G.I. Kingston and D.J. Newman), CRC Press, Boca Raton, FL, pp. 519-551. 

Walsh, C.T. (2002) Combinatorial biosynthesis of antibiotics challenges and opportunities. Chembiochem A European Journal of Chemical Biology, 3, 125. 

Weissman, K.J. and Leadlay, P.F. (2005) Combinatorial biosynthesis of reduced polyketides. Nature Reviews Microbiology, 3, 925. 

Hutchinson, C.R. and McDaniel, R. (2001) Combinatorial biosynthesis in microorganisms as a route to new antimicrobial, antitumor and neuroregenerative drugs. Current Opinion in Investigational Drugs, 2, 1681. 

Nguyen, K.T., Ritz, D., Gu, J.-Q. et al. (2006) Combinatorial biosynthesis of novel antibiotics related to daptomycin. Proceedings of the National Academy of Sciences of the United States of America, 103, 17462. 

Piel, J. (2006) Combinatorial biosynthesis in symbiotic bacteria. Nature Chemical Biology, 2, 661. 

Khosla, C.Z.R. (1996) Generation of polyketide libraries via combinatorial biosynthesis. Trends in Biotechnology, 14, 335-341. 

Hutchinson, C.R. (1998) Combinatorial biosynthesis for new drug discovery. Current Opinion in Microbiology, 1, 319-329. 

In this chapter, we will introduce an exciting class of natural product biosynthetic enzymes, the modular synthases, as well as their associated enzyme partners. We will discuss the use of metabolic engineering as a tool for small-molecule discovery and development, both through directed fermentation and combinatorial biosynthesis. In addition, we will review six classes of partner enzymes involved in the modification of polyketide (PK) and nonribosomal peptide (NRP) natural products. We believe that these enzymatic transformations hold great opportunities for synthetic chemists and will serve as the foundation for a new trend in both discovery and process chemistry. 

Comb copolymers, 7 610t Combed yarn, 11 178 Combes synthesis, of quinolines, 21 189 Combicat, 7 387, 392 Combinational libraries, 7 382 characterization, 7 404-405 composition gradient libraries, 7 407 design, 7 399-400 fabrication, 7 414-419 temperature gradient libraries, 7 407—408 thickness gradient libraries, 7 406 Combination electrodes, 14 30 Combination vaccines, 25 504-505 Combinatorial biology, 16 414 Combinatorial biosynthesis, 15 301-302, 305... 

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