Combinatorial biosynthesis--potential and problems.
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.
Floss
Heinz G
HG
Department of Chemistry, University of Washington, Seattle, 98195-1700, USA. floss@chem.washington.edu
D000900:Anti-Bacterial Agents / Q000096:biosynthesis / Q000737:chemistry / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D020650:Combinatorial Chemistry Techniques; D015195:Drug Design; D005818:Genetic Engineering / Q000379:methods*; D008453:Maytansine / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015394:Molecular Structure; D048630:Polyketide Synthases / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology; D017828:Rifabutin / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D000972:Antineoplastic Agents, Phytogenic; D008453:Maytansine; D017828:Rifabutin; D048630:Polyketide Synthases