Biosynthesis pathway engineering

In summary, a novel cyclohexyl avermectin analog B1 with enhanced antiparasitic activity was discovered and produced with high selectivity and excellent fermentation titer through deciphering biosynthesis, pathway engineering, and directed evolution. The new product, doramectin, is sold commercially as Dectomax. 

In avermectin Bl, there is a double bond between C-22 and C-23, whereas in avermectin B2 R OH. The product ratio of B2 to Bl is 1.6 1. Since the Bl analog is much more effective as an antiparasite, there is a desire to improve the B1 B2 ratio, which can be achieved by a dehydratase domain [88, 89]. Its directed evolution and mutant screening led to a mutant giving an excellent fermentation titer of Bl B2 = 1 0.07 [90, 91]. As a result of understanding the biosynthesis, pathway engineering, and directed evolution, a biologically superior new product, doramectin (Dectomax ), was evolved from a mixture of eight natural products. 

Synthesis of Glycoconjugates through Biosynthesis Pathway Engineering... 

YE X, AL-BABILI s, KLOTZ A, ZHANG J, LUCCA p, BEYER p and POTRYKUS I (2000) Engineering provitamin A ( 3-carotene) biosynthesis pathway into (carotenoid-free) rice endosperm . Science, 287, 303-5. 

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. 

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...

Strohl, W.R. (2001) Biochemical engineering of natural product biosynthesis pathways. Metabolic Engineering, 3, 4. 

Mutka, S.C., Bondi, S.M., Carney, J.R. et al. (2006) Metabolic pathway engineering for complex polyketide biosynthesis in Saccharomyces cerevisiae. FEMS Yeast Research, 6, 4047. 

Liu Y, Wang H, Ye H-C, Li G-F. (2005) Advances in the plant isoprenoid biosynthesis pathway and its metabolic engineering. J Integr Plant Biol 47 769-782. 

Amino Acid Biosynthesis - Pathways, Regulation and Metabolic Engineering... 

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... 

Wittmann C, Becker J (2007) The L-lysine story from metabolic pathways to industrial production. In Wendisch VF (ed) Amino acid biosynthesis - pathways, regulation and metabolic engineering. Springer, Berlin... 

Steinbtichel, A. (2001) Perspedives for biotechnological production and utilization of biopolymers metabolic engineering of polyhydroxyalkanoate biosynthesis pathways as a successful example. Macromol. Biosci., 1,1-24. 

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