Combinatorial Biosynthesis--potential and Problems

Overview

Journal J Biotechnol

Specialties Biomedical Engineering
Biotechnology

Date 2006 Jan 18

PMID 16414140

Citations 37

Authors

Heinz G Floss

Affiliations

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Abstract

Because of their ecological functions, natural products have been optimized in evolution for interaction with biological systems and receptors. However, they have not necessarily been optimized for other desirable drug properties and thus can often be improved by structural modification. Using examples from the literature, this paper reviews the opportunities for increasing structural diversity among natural products by combinatorial biosynthesis, i.e., the genetic manipulation of biosynthetic pathways. It distinguishes between combinatorial biosynthesis in a narrower sense to generate libraries of modified structures, and metabolic engineering for the targeted formation of specific structural analogs. Some of the problems and limitations encountered with these approaches are also discussed. Work from the author's laboratory on ansamycin antibiotics is presented which illustrates some of the opportunities and limitations.

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References

Floss H, Yu T . Rifamycin-mode of action, resistance, and biosynthesis. Chem Rev. 2005; 105(2):621-32. DOI: 10.1021/cr030112j. View

Eustaquio A, Gust B, Li S, Pelzer S, Wohlleben W, Chater K . Production of 8'-halogenated and 8'-unsubstituted novobiocin derivatives in genetically engineered streptomyces coelicolor strains. Chem Biol. 2004; 11(11):1561-72. DOI: 10.1016/j.chembiol.2004.09.009. View

Xu J, Wan E, Kim C, Floss H, Mahmud T . Identification of tailoring genes involved in the modification of the polyketide backbone of rifamycin B by Amycolatopsis mediterranei S699. Microbiology (Reading). 2005; 151(Pt 8):2515-2528. DOI: 10.1099/mic.0.28138-0. View

Luzhetskyy A, Bechthold A . It works: combinatorial biosynthesis for generating novel glycosylated compounds. Mol Microbiol. 2005; 58(1):3-5. DOI: 10.1111/j.1365-2958.2005.04815.x. View

Stratmann A, Toupet C, Schilling W, Traber R, Oberer L, Schupp T . Intermediates of rifamycin polyketide synthase produced by an Amycolatopsis mediterranei mutant with inactivated rifF gene. Microbiology (Reading). 2000; 145 ( Pt 12):3365-3375. DOI: 10.1099/00221287-145-12-3365. View

Wu K, Chung L, Revill W, Katz L, Reeves C . The FK520 gene cluster of Streptomyces hygroscopicus var. ascomyceticus (ATCC 14891) contains genes for biosynthesis of unusual polyketide extender units. Gene. 2000; 251(1):81-90. DOI: 10.1016/s0378-1119(00)00171-2. View

Staunton J, Wilkinson B . Combinatorial biosynthesis of polyketides and nonribosomal peptides. Curr Opin Chem Biol. 2001; 5(2):159-64. DOI: 10.1016/s1367-5931(00)00185-x. View

Rawlings B . Type I polyketide biosynthesis in bacteria (Part A--erythromycin biosynthesis). Nat Prod Rep. 2001; 18(2):190-227. DOI: 10.1039/b009329g. View

Admiraal S, WALSH C, Khosla C . The loading module of rifamycin synthetase is an adenylation-thiolation didomain with substrate tolerance for substituted benzoates. Biochemistry. 2001; 40(20):6116-23. DOI: 10.1021/bi010080z. View

10.

Egorin M, Lagattuta T, Hamburger D, Covey J, White K, Musser S . Pharmacokinetics, tissue distribution, and metabolism of 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (NSC 707545) in CD2F1 mice and Fischer 344 rats. Cancer Chemother Pharmacol. 2002; 49(1):7-19. DOI: 10.1007/s00280-001-0380-8. View

11.

Reeves C, Chung L, Liu Y, Xue Q, Carney J, Revill W . A new substrate specificity for acyl transferase domains of the ascomycin polyketide synthase in Streptomyces hygroscopicus. J Biol Chem. 2002; 277(11):9155-9. DOI: 10.1074/jbc.M111915200. View

12.

Walsh C . Combinatorial biosynthesis of antibiotics: challenges and opportunities. Chembiochem. 2002; 3(2-3):125-34. DOI: 10.1002/1439-7633(20020301)3:2/3<124::AID-CBIC124>3.0.CO;2-J. View

13.

Carroll B, Moss S, Bai L, Kato Y, Toelzer S, Yu T . Identification of a set of genes involved in the formation of the substrate for the incorporation of the unusual "glycolate" chain extension unit in ansamitocin biosynthesis. J Am Chem Soc. 2002; 124(16):4176-7. DOI: 10.1021/ja0124764. View

14.

Kato Y, Bai L, Xue Q, Revill W, Yu T, Floss H . 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. J Am Chem Soc. 2002; 124(19):5268-9. DOI: 10.1021/ja0127483. View

15.

Moss S, Bai L, Toelzer S, Carroll B, Mahmud T, Yu T . Identification of asm19 as an acyltransferase attaching the biologically essential ester side chain of ansamitocins using N-desmethyl-4,5-desepoxymaytansinol, not maytansinol, as its substrate. J Am Chem Soc. 2002; 124(23):6544-5. DOI: 10.1021/ja020214b. View

16.

Yu T, Bai L, Clade D, Hoffmann D, Toelzer S, Trinh K . The biosynthetic gene cluster of the maytansinoid antitumor agent ansamitocin from Actinosynnema pretiosum. Proc Natl Acad Sci U S A. 2002; 99(12):7968-73. PMC: 123004. DOI: 10.1073/pnas.092697199. View

17.

Rix U, Fischer C, Remsing L, Rohr J . Modification of post-PKS tailoring steps through combinatorial biosynthesis. Nat Prod Rep. 2002; 19(5):542-80. DOI: 10.1039/b103920m. View

18.

Reeves C . The enzymology of combinatorial biosynthesis. Crit Rev Biotechnol. 2003; 23(2):95-147. DOI: 10.1080/713609311. View

19.

Spiteller P, Bai L, Shang G, Carroll B, Yu T, Floss H . The post-polyketide synthase modification steps in the biosynthesis of the antitumor agent ansamitocin by Actinosynnema pretiosum. J Am Chem Soc. 2003; 125(47):14236-7. DOI: 10.1021/ja038166y. View

20.

Cassady J, Chan K, Floss H, Leistner E . Recent developments in the maytansinoid antitumor agents. Chem Pharm Bull (Tokyo). 2004; 52(1):1-26. DOI: 10.1248/cpb.52.1. View