Enhancing Biological Products

BY ROBIN HUIRAS @UMN, 1999

WHEN CHEMISTRY PROFESSOR HUNG-Wen Liu was younger and had more time on his hands, he used to build model airplanes, configuring miniature pieces into perfect replicas of real aircraft. Through careful construction he could understand the mechanics of a large plane, replicate it, and even alter the model to suit his purposes. Liu no longer has much time for his hobby, but he still configures and replicates models-Mother Nature’s models, that is. Now he spends most of his time studying the catalysis of enzymes, the biosynthesis of natural products, the regulation of protein functions. Using genes and enzymes as his modeling components, Liu is working to alter and improve natural products with bio-logical activity, such as antibiotics.

As a Distinguished McKnight University Professor, Liu will receive $100,000 over five years to support his research efforts. Liu received the coveted award for his accomplishments as a University faculty member, an honor endorsed by his colleagues in the chemistry department. He says his family and associates have been very supportive, encouraging him to pursue what he enjoys. “I alone couldn’t have accomplished the achievements recognized by the award,” Liu says. “In fact, I owe this award to my coworkers in the laboratory and to years of hard work by my dedicated graduate students and postdoctoral associates. “With the McKnight grant and support from the National Institutes of Health, he has the financial support necessary to continue and expand his research. “He is a very excellent critical thinker and outstanding experimentalist, and he’s very deserving of the McKnight professorship,” says David Sherman, University microbiology professor and Liu’s frequent collaborator. Sherman first met Liu 20 years ago at Columbia University, when they were graduate students in the chemistry department, Liu, whose research activities satisfy his intense creative drive, says one of his goals is to find a lead compound, new chemical with bacteria-fighting potential.

After studying the fundamental mechanistic properties involved in the synthesis of a specific natural product-an antibiotic, for example-Liu can manipulate the “machinery” of the producing organism and generate new molecules that may demonstrate novel bioactivity. “By simply changing the way it made, we alter the structure of the natural product and possibly generate new or improved activity,” Liu explains “For example, resistant bacteria the are immune to currently available antibiotics have never encountered these new compounds before, so their mode of resistance may not work, leaving them vulnerable.” The first step is to study the functions and catalysts of enzymes that manufacture antibiotics from simple molecules. Once the researchers determine how and why a reaction occurs, the team can then mimic or change it. The researchers also examine the overall pathways of natural product biosynthesis-how plants and microorganisms produce secondary metabolites. “You can always learn a lesson from Mother Nature, and as a chemist, Mother Nature is much better,” Liu says. Once the biosynthetic pathway is established, Liu and his coworkers attempt to manipulate it in various ways. “You can manipulate the biosynthetic machinery at the genetic level, you can shut down certain steps by turning off specific genes, or shuffle the biosynthetic genes with others, to construct hybrid gene clusters and create new compounds,” Liu says. “Its quite exciting-you don’t even have to do chemistry anymore. We try to use natures biosynthetic machinery, modify it, and produce a new compound.” He explains that the ability to create tailor-made compounds is one of the last steps in a long process, one that demands training in various disciplines.

Liu’s complex research requires knowledge of organic chemistry, molecular biology, mechanistic enzymology, biosynthesis of natural products, and protein regulation areas that Liu has been studying ever since he arrived at the University 15 years ago. “The unique problems we address are at the interface of chemistry and biology,” says Liu, who began his training in the United States 23 years ago at Columbia. Liu continued his postdoctoral of the research interests he continues to pursue today. “I wanted to carry on my independent research after MIT. I always wanted to be a professor, so I responded to some ads and applied for academic positions. I got a few offers, but considered Minnesota to be the best for me to carry out what I wanted to do. The salary was the lowest,” Liu says with a laugh, “but the reason I chose it was because the chemistry department here had an excellent faculty and a lot of potential.

Financed by the McKnight grant, the third phase of Liu’s research project will investigate the regulation of protein function in nature. According to Liu, many proteins must be activated, much like turning on a switch. By understanding how nature regulates the activation, researchers hope to gain the ability to turn a protein “on” or “off” at will. “There are many interesting and amazing things to learn when you study those biological systems, especially proteins which have catalytic activity. Our challenge is to use what we learn to develop a strategy to control or mimic the natural bioprocesses,” Liu says. His research also examines the design and synthesis of enzyme inhibitors. He identifies proteins essential to human health, thoroughly studies their mechanisms, and then develops specific compounds to control them. To illustrate how this strategy can ultimately advance the treatment of disease, Liu uses the example of his research in the metabolism of fatty acids. A vital process involving several enzymes, the metabolism of fatty acids produces much of the energy needed by human beings, but it is also closely linked to Type II diabetes. If researchers can learn how natural metabolism works including the enzyme processes and the functions of the specific proteins involved-then it will be possible to manipulate the enzymes’ functions precisely, thereby controlling the disease. “If the properties of the target enzyme are known in detail, we can design a more efficient drug,” Liu says.