Research by a Michigan State University chemist could eventually lead to a quicker and easier way of developing protein-based drugs which are key to treating a number of diseases, including cancer, diabetes and hepatitis.
Proteins used in drug manufacture and research often are made within genetically modified Escherichia coli, a one-cell bacteria. That protein tends to collect into what scientists call inclusion bodies. Those hard-to-separate clumps render up to 95 percent of the protein unusable, according to associate chemistry professor David P. Weliky.
Some can be recovered by breaking down the protein to separate it, but because protein structure determines its function, another step must be added to “refold” it into its original configuration.
Weliky and colleagues took a closer look at the structure of the proteins that make up these inclusion bodies. Learning what makes them stick together might yield some clues as to how to separate them, he said, and that could make the manufacturing process more efficient.
Instead of employing more commonly used infrared spectroscopy to look at dehydrated samples, the researchers used nuclear magnetic resonance spectroscopy using whole cells. That technology analyzes the magnetic properties of an atom’s nucleus.
While best known as medical diagnostic imaging technology, Weliky and colleagues view NMR as a powerful approach to analyzing biological molecules, including bacterial inclusion bodies. Because the inclusion body protein appeared to be predominantly folded rather than unfolded, it might be possible to extract protein without separating and then refolding, Weliky said.
“This study highlights our ability to probe the molecular structure of a single protein in whole cells and to apply advanced analytical and biochemical methods to a problem of general significance in biotechnology,” Weliky said.
This research by Weliky and students Jaime Curtis-Fisk and Ryan M. Spencer was recently featured in Chemical and Engineering News, the membership publication of the American Chemical Society.
Proteins have been called the workhorses of biological macromolecules, forming enzymes critical for metabolism, giving cells structural support and comprising key parts of cell signaling, immune response and other life activities. In other words, whatever happens within a living organism, proteins probably make it happen or regulate it.
The world protein therapeutics market totaled $63 billion in 2007, according to market research firm Kalorama Information, and could reach $87 billion by 2010. It amounts to some $39 billion in the United States alone, propelled by recombinant insulin and other drugs. As protein drug use has increased, so has the need for manufacturing capacity and ways to streamline the production of protein.
- Curtis-Fisk et al. Native Conformation at Specific Residues in Recombinant Inclusion Body Protein in Whole Cells Determined with Solid-State NMR Spectroscopy. Journal of the American Chemical Society, 2008; 130 (38): 12568 DOI: 10.1021/ja8039426
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