Combinatorial biosynthesis—Potential and problems

• Published in: Journal of biotechnology Vol. 124; no. 1; pp. 242 - 257
• Main Author: Floss, Heinz G.
• Format: Journal Article
• Language: English
• Published: Lausanne Elsevier B.V 25.06.2006; Amsterdam Elsevier; New York, NY
• Subjects: Anti-Bacterial Agents - biosynthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Antineoplastic Agents, Phytogenic - chemical synthesis; Antineoplastic Agents, Phytogenic - chemistry; Antineoplastic Agents, Phytogenic - pharmacology; Biological and medical sciences; Biotechnology; Combinatorial biosynthesis; Combinatorial Chemistry Techniques; Drug Design; Fundamental and applied biological sciences. Psychology; Genetic Engineering - methods; Maytansine - chemical synthesis; Maytansine - chemistry; Maytansine - pharmacology; Maytansinoids; Metabolic engineering; Molecular Structure; Natural products; Polyketide Synthases - biosynthesis; Polyketide Synthases - chemistry; Polyketide Synthases - genetics; Polyketide Synthases - pharmacology; Polyketides; Rifabutin - chemical synthesis; Rifabutin - chemistry; Rifabutin - pharmacology; Rifamycin; Combinatorial biosynthesis; Metabolic engineering; Polyketides; Rifamycin; Natural products; Maytansinoids; Polyketide; Natural product; Biosynthesis; Maytansinoids: Polyketides
• ISSN: 0168-1656; 1873-4863
• DOI: 10.1016/j.jbiotec.2005.12.001

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.