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• W2068689095 abstract "Enzymes catalyse virtually all metabolic reactions under mild conditions with high substrate specificities and stereoselectivities as well as enormous rate enhancements. For almost a century, biochemists have been attempting to find out how the structure, function and stability of this important class of proteins are interrelated. The ultimate proof for our understanding of the highly complex interplay between these molecular properties would be to design enzymes with a preconceived combination of catalytic activity, conformational flexibility and robustness. Beyond basic research, tailored enzymes provide novel and important tools for the chemical and pharmaceutical industry because they have the potential to contribute to the generation of fine chemicals in environmentally friendly and energy-saving production processes. Over the past years, impressive progress has been made in the rational design of enzymes, partly due to the development of sophisticated computational methods that integrate comprehensive structure and sequence analyses with molecular dynamics simulations and quantum mechanical calculations. However, the catalytic proficiency of de novo-designed enzymes is still poor compared to that of natural enzymes.1–3 This finding does not diminish the achievements of computational biologists, but rather reflects, among other things, the fact that nature has had millions of years to optimise molecular biocatalysts by trial and error. Taking this into account, it is not surprising that directed evolution, which mimics the principles of natural evolution on a laboratory timescale, has become a successful alternative and valuable addition to rational design for the generation of enzymes with desired properties.4–7 In a directed evolution experiment, random mutagenesis is used to generate large gene libraries from which variants with desired properties can be isolated by iterative rounds of screening or selection, followed by the biochemical characterisation of the purified proteins. In contrast to rational design, directed evolution does not require a detailed a priori knowledge of the structure or mechanism of a biocatalyst. It is, therefore, particularly instructive because it can provide unexpected solutions that go beyond the original hypothesis. These considerations were pivotal when the German Research Foundation (Deutsche Forschungsgemeinschaft) decided to sponsor a Priority Program (Schwerpunktprogramm 1170) entitled “Directed evolution to optimise and understand molecular biocatalysts”. Within the framework of this program, over the past six years more than 20 research groups from German universities and research institutions have been involved in projects that aimed at reshaping enzymes. The current special issue of ChemBioChem contains examples from various laboratories, in the form of original papers and reviews, that reflect the broad range of biological systems that have been analysed and optimised by different kinds of directed evolution approaches. One major focus of the program was on enzymes that replicate or modify DNA and RNA. The contributions by Obeid et al., Söte et al., Jurkowska et al., Pingoud and Wende, and Li et al. illustrate how the manipulation and optimisation of translesion polymerases, viral polymerases, methyltransferases, rare-cutting restriction endonucleases and RNAse P ribozymes, as well as the modification of their nucleic acid substrates, can help to elucidate the structure–function relationships of these complicated molecular machineries and provide insights into their natural evolution. Two superior properties of enzymes compared to nonbiological catalysts are high substrate specificity and stereoselectivity. The articles by Samland et al., Reetz and Zheng, Jochens et al., and Schöpfel et al. show how the catalytic machineries of various aldolases, α/β-hydrolases and proteases can be reprogrammed to accept alternative substrates and to interconvert non-natural substrates with high enantioselectivity; this paves the way for many important applications in biotechnology. Natural enzymes are usually not very stable because they need a certain degree of flexibility for substrate binding, catalysis and product release. The Minireview by Schmid and the paper by Sterner and Schwab present various screening and selection systems that may be applied to increase the thermal stability of enzymes. The analysis of similar directed evolution studies in many laboratories has provided profound insights into the structural basis of protein stability, which is better understood than enzyme catalysis. Based on this knowledge, computational methods can predict the stability effects of mutations with certain reliability, and Fischer et al. present a new approach in this field. It is generally recognised that the analysis of natural enzyme evolution is instructive for directed evolution approaches.8, 9 Using the versatile (βα)8-barrel fold as a paradigm, List et al. show that, on the other hand, laboratory evolution experiments can help to test the plausibility of hypotheses on how stable and active biocatalysts have emerged and diversified over the course of natural evolution. The success of directed evolution crucially depends on the continuous optimisation of the techniques for generating gene libraries, for screening and for selection. Along these lines, Mundaha et al. present the further development of a saturation mutagenesis method that allows for the homogeneous distribution of nucleotide exchanges and for the introduction of consecutive mutations, which is generally difficult to achieve. Jaeger and Kolmar show that certain autotransporters can be used as vehicles to display lipases and hydrolases on the surface of Escherichia coli cells, and illustrate how these systems can be applied to the high-throughput screening of highly active and enantioselective enzyme variants by flow cytometry. In order to take full advantage of the instructive potential of directed evolution, it is crucial to analyse the isolated optimised variants in great detail. An example of such analysis is provided by Schweizer et al., who used sophisticated kinetic methods to characterise a chaperone variant with improved folding-assistance capabilities. This special issue is completed by a Highlight article from Lalli et al. on a recent and elegant directed evolution approach by which a toxic protease was encapsulated into an intracellular “protein container”.10 I would like to thank the Deutsche Forschungsgemeinschaft for generous support of the Priority Program 1170, and its representatives Drs. Ilka Suelmann, Andreas Strecker and Nikolai Raffler for their continuous support. Moreover, I am grateful to the members of the international reviewing board for their time and valuable advice and to ChemBioChem for their interest in publishing this special issue.1 1" @default.
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• W2068689095 date "2011-06-09" @default.
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• W2068689095 title "Editorial: Directed Evolution: A Powerful Approach to Optimising and Understanding Enzymes" @default.
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• W2068689095 doi "https://doi.org/10.1002/cbic.201100285" @default.
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