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Designer Proteins that Control Enzyme Activity

2015-09-02
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    Enzymes are macromolecular biological catalysts. Enzymes accelerate, or catalyze, chemical reactions.  The molecules at the beginning of the process are called substrates and the enzyme converts these into different molecules, called products. Enzymes are used in a wide range of commercial applications, such as the preparation of foods, dietary supplements, therapeutics, and chemical materials. The ability to precisely tune enzymatic reactions with small biomolecules holds enormous potential for industrial manufacturing, analytical science, and drug therapeutics.

 

    Scientists from the University of Chicago have developed a novel approach to control the activity of enzymes through the use of synthetic, antibody-like proteins known as monobodies. A team led by Shohei Koide, PhD, professor of biochemistry and molecular biophysics, was able to change the specificity of an enzyme, widely used in the food industry, without altering the enzyme itself – establishing a new route for enzyme engineering and demonstrating the versatility of these synthetic proteins. The findings, detailed online in Nature Chemical Biology on Aug. 31, 2015, have widespread implications for a broad range of industrial, scientific and medical applications in which enzymes are used.

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“This is the first time that synthetic accessory molecules have been engineered to change the specificity of an enzyme in order to achieve a desired end-product,” explained senior author Dr. Shohei Koide. “In this paper, we demonstrated their efficacy on sugars, but one can envision applications of this concept with enzymes acting on other types of molecules such as lipids and peptides—there are literally hundreds of enzymes currently used in industry and millions that are potentially useful.”

 

    The findings from this study were published recently in Nature Chemical Biology through an article entitled “Monobody-mediated alteration of enzyme specificity.”

 

    Dr. Koide and his team used their expertise in designing monobodies to engineer the small molecules to recognize and bind a specific target in order to affect function. Specifically, the researchers focused their attention on the enzyme beta-galactosidase (β-Gal), looking to design a monobody that would cause the enzyme to only act on small sugar chains.

 

    The investigators started with a pool of about 10 billion unique monobodies and used directed evolution techniques to identify molecules that bound near the active site of β-Gal, eventually “culling the herd” and homing in on a single molecule that had the desired activity.

 

    “We were able to design one monobody that prevents β-Gal from using certain sugars as starting material and produce only small oligosaccharides, making it a much more valuable catalyst for use in industry,” Dr. Koide stated. “Our collaborators generated over 1,000 mutants of this enzyme in previous attempts to achieve the same goal and none of them did what this monobody accomplished. We are quite pleased with the outcome.”

 

    Surprisingly, monobodies are relatively economical to produce in large quantities and are already in use as a platform for other applications by biotechnology companies. The University of Chicago team is currently investigating other enzymes that might benefit from monobody technology, as well as working with an industry partner to develop monobody-modified β-Gal for commercial use.

 

    “For now, this technology is most useful when restricting the starting material that enzymes use from larger to smaller,” Dr. Koide noted. “There are many cases in which one would like to produce only smaller products, and many more interesting possibilities that we are excited to explore.”

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