UMBC’s Songon An is on a quest to explain how enzymes direct sugar metabolism through research with implications for cancer treatment. Scientists already know a great deal about how individual enzymes work in a test tube, but “once we move into the living cell system, we barely know about the enzymes,” says An, assistant professor of chemistry and biochemistry. With a new $1.5 million NIH grant, his lab is working to change that.
To explore how enzymes interact and form complex biochemical pathways in the body, An is using various biochemical and imaging techniques from biochemists and biophysicists. New, three-dimensional imaging techniques developed by Minjoung Kyoung, assistant professor of chemistry and biochemistry, will help examine the pathways at work inside living cells. A mathematical model developed by Hye-Won Kang, assistant professor of mathematics and statistics, supports the project.
The research focuses on two processes related to glucose metabolism: One produces energy for the cell to use, and the other generates compounds that assist in building the components of proteins and DNA, supporting the organism’s growth and repair. These two processes start out with the same first steps, and then diverge to generate different small molecules referred to as “metabolites.”
“What decides the direction of the pathway flux?” An is asking. His hypothesis, which his lab will test with the new grant, has to do with the physical arrangement of the enzymes in living cells. The enzymes that catalyze glucose metabolism physically group together, forming complexes that An has dubbed “glucosomes.” Each glucosome contains at least four critical enzymes, and the glucosomes further group together in the cell, forming glucosome clusters.
An hypothesizes that the enzymes present within the clusters and communication among the enzymes determines which metabolic process a given region in the cell favors at a given time. Interestingly, the size of the glucosome clusters also appears to play a role in determining which metabolic pathway dominates, and An intends to test that idea as well. Preliminary data suggest that single-enzyme concentrations (separate from the glucosomes) promote energy production, and multi-enzyme glucosome clusters favor churning out building blocks to grow the organism.
“Eventually, what I’d like to do, if technology allows, is to pinpoint individual clusters in the live cell, and put in some sort of probe to measure the level of the metabolites,” An says. “Then, if this hypothesis is correct, we will see different concentrations of metabolites in clusters of different sizes.”
Most imaging techniques only allow a researcher to detect where an enzyme is, not how much of a given metabolite a reaction is producing. An is hoping to use a more refined technique called secondary ion mass spectrometry (SIMS) to examine cells’ metabolite concentrations. This technique has been successfully applied to detect lipids on the surface of cells, but never metabolites inside cells or related to glucose metabolism. In addition to incorporating Kyoung’s imaging expertise, An is collaborating with researchers outside UMBC who have experience with this challenging, new technique.
Beyond gaining a more complete understanding of the fundamental regulation of glucose metabolism, An seeks to contribute to cancer treatment. Preliminary data suggest that the largest glucosome clusters appear only in cancerous cells, and An is applying for another grant to further test that hypothesis. Patients who donated cancerous cells also donated healthy ones, so An’s team will be able to look for differences between them.
If An’s hypotheses are confirmed, the next challenge will be translating the new knowledge into a treatment that will break up the large clusters without interrupting the function of individual enzymes. “If small molecules inhibit the enzyme activity in diseased cells, they will inhibit the same enzymes in healthy ones as well,” An explains. “So what we’re trying to find is a small molecule that will simply dissociate the cancer-relevant large clusters, without inhibiting the enzyme activity.”
This new area of research is the reason An came to UMBC in 2011. “I’m hoping that in the future many people will be working in this area of cellular biochemistry, studying many metabolic enzymes in living cells,” and, eventually, “connecting the cellular level to the animal level, so we don’t have a scientific gap of understanding metabolism from a test tube to the human body,” he says.
By using fresh imaging techniques in new ways and employing mathematical modeling, An is moving past assumptions of what biochemistry can be, and he’s excited about the possible breakthroughs ahead. “We are opening up a new chapter for biochemistry in the cell,” he says. “This is the next stage of biochemistry.”
Image: Songon An, assistant professor of chemistry and biochemistry, and Danielle Schmitt, Ph.D. ’17, biochemistry, working in the lab; photo by Marlayna Demond ’11 for UMBC.
Tags: ChemBiochem, CNMS, MathStat, Research