Combinatorial biosynthesis libraries

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

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... 

Until the biosynthesis of aromatic polyketides can be controlled as precisely as modular PKSs, the most likely utility for this class of PKS is in the generation of libraries to screen for new activities. Due to the highly reactive nature of the aromatic polyketide backbones, a variety of cyclization patterns have been created through combinatorial biosynthesis with aromatic PKS gene clusters... 

Figure 10.42 Combinatorial biosynthesis structure of a hypothetical three-member discrete library of modified natural products.

Figure 10.48 Combinatorial biosynthesis of the PK library L29 from modified DEBS modules single-domain substitution products.

Manipulation of the DEBS system has led to the most impressive demonstration of combinatorial biosynthesis to date. McDaniel and coworkers have utilized specific module-swapping strategies to access a variety of 6-deoxyerythronolide B analogs with modifications at each carbon of the macrolide backbone [26]. Modules 1-6 of DEBS were systematically replaced with individual rapamycin synthase components to alter oxidation state and methylation in the final polyketide product. The study produced 60 unique structures at yields ranging from 1 to 70% of that of 6-deoxyerythronolide B (Fig. 9.2-5). However, each new compound required independent synthase engineering, which made library construction quite tedious. 

Like conventional combinatorial biosynthesis, glycorandomization requires flexible glycosyltransferases. As recently pointed out in the case of novobiocin [79], a highly specific glycosyltransferase limits the library size. Despite such issues that need to be addressed in future work, glycorandomization is a promising approach to make use of the metabolic potential of procaryotic cells and should promote drug development in the future. 

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]. 

Lee, RE, Smith, M D, Pickering, L, Fleet, G W J, An approach to combinatorial library generation of galactofuranose mimics as potential inhibitors of mycobacterial cell wall biosynthesis Synthesis of a peptidomimetic of uridine 5 -diposphogalactofuranose (UDP-galf), Tetrahedron Lett., 40, 8689 8692, 1999. 

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