Journal
JOURNAL OF BIOTECHNOLOGY
Volume 124, Issue 1, Pages 242-257Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.jbiotec.2005.12.001
Keywords
combinatorial biosynthesis; metabolic engineering; natural products; rifamycin; maytansinoids; polyketides
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Funding
- NCI NIH HHS [R01 CA076461-06] Funding Source: Medline
- NIAID NIH HHS [R01 AI020264-21] Funding Source: Medline
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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. (c) 2006 Elsevier B.V. All rights reserved.
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