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Microbiology and Molecular Biology Reviews, March 2005, p. 51-78, Vol. 69, No. 1
1092-2172/05/$08.00+0     doi:10.1128/MMBR.69.1.51-78.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Diversifying Carotenoid Biosynthetic Pathways by Directed Evolution

Daisuke Umeno ,{dagger},{ddagger} Alexander V. Tobias,{ddagger} and Frances H. Arnold*

Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California

Microorganisms and plants synthesize a diverse array of natural products, many of which have proven indispensable to human health and well-being. Although many thousands of these have been characterized, the space of possible natural products—those that could be made biosynthetically—remains largely unexplored. For decades, this space has largely been the domain of chemists, who have synthesized scores of natural product analogs and have found many with improved or novel functions. New natural products have also been made in recombinant organisms, via engineered biosynthetic pathways. Recently, methods inspired by natural evolution have begun to be applied to the search for new natural products. These methods force pathways to evolve in convenient laboratory organisms, where the products of new pathways can be identified and characterized in high-throughput screening programs. Carotenoid biosynthetic pathways have served as a convenient experimental system with which to demonstrate these ideas. Researchers have mixed, matched, and mutated carotenoid biosynthetic enzymes and screened libraries of these "evolved" pathways for the emergence of new carotenoid products. This has led to dozens of new pathway products not previously known to be made by the assembled enzymes. These new products include whole families of carotenoids built from backbones not found in nature. This review details the strategies and specific methods that have been employed to generate new carotenoid biosynthetic pathways in the laboratory. The potential application of laboratory evolution to other biosynthetic pathways is also discussed.

* Corresponding author. Mailing address: Division of Chemistry and Chemical Engineering, California Institute of Technology, 210-41, 1200 E. California Blvd., Pasadena, CA 91125. Phone: (626) 395-4162. Fax: (626) 568-8743. E-mail: frances{at}cheme.caltech.edu.

{ddagger} Present address: Department of Applied Chemistry and Biotechnology, Chiba University, 1-33 Yayoi-machi, Inage-Ku, Chiba, Japan 263-8522.

{ddagger} D.U. and A.V.T. contributed equally to this work.

Microbiology and Molecular Biology Reviews, March 2005, p. 51-78, Vol. 69, No. 1
1092-2172/05/$08.00+0     doi:10.1128/MMBR.69.1.51-78.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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