February 25, 2010
Sherket Peterson, a graduate student in the Division of Medicinal Chemistry and Natural Products, has received an NIH award worth approximately $100,000 over three years to support her efforts to create an inhibitor for the enzyme heparanase.
“In our lab, we study heparin and heparan sulfate, but my project is related to heparanase, which is an enzyme that acts on heparan sulfate,” Peterson says. “This enzyme has been linked to a wide array of cancers.”
In cancer and certain other health conditions, heparanase often becomes too abundant or unregulated. In cancer, this enzymatic excess can promote metastasis (the spread of tumors from one organ to another) and angiogenesis (the growth of new blood vessels that feed new and existing tumors). Peterson is seeking a way to rein in heparanase when it starts to get out of control.
“I want to design an inhibitor for this enzyme that is similar to the structure of heparan sulfate, the substrate that heparanase acts upon naturally,” she says. “I have to design a lock to fit the heparanase key.”
However, like the pins hidden inside a lock, scientists haven’t been able to get a good look at the specific sulfate groups on the heparan sulfate molecule that interact with heparanase. The carbohydrates, also called saccharides, that have substituted for heparan sulfate in past testing have too great a variety of sulfate groups, making it difficult to discern which ones actually interact with the enzyme.
“Until now, the substrates used to test the specificity of heparanase have been short, chemically synthesized oligosaccharides,” Peterson says, referring to a carbohydrate made up of only a few simple sugars. “What I need are longer substrates with definite sulfation patterns because they are similar in length and design to heparan sulfate.”
Fortunately, her mentor, associate professor Jian Liu, PhD, has developed a unique process to synthesize the polysaccharide substrates she needs enzymatically instead of chemically.
“With these new substrates, I’ve been able to determine what structures are recognized by the enzyme and identify a potent inhibitor,” Peterson says. Her work is detailed in the article “Unraveling the Specificity of Heparanase Utilizing Synthetic Substrates” published online in the Journal of Biological Chemistry (May 2010).
Peterson’s project, “Enzyme-based approach to probe the specificity of heparanase and its inhibitor,” is being funded by the National Institute of General Medical Services of the National Institutes of Health.
Latest News
RASP poster presentations capture student research
Delesha Carpenter promoted to full professor
