CABS Awardee Dr. Matt Redinbo: PXR* and Promiscuous Enzymes
2003 - At this point in his career, Dr. Matt Redinbo might have been teaching Beowulf instead of biochemistry and writing a critique of John Steinbeck rather than a scientific paper on the crystal structure of human carboxylesterase 1. After his undergraduate work in biochemistry and English, the young researcher had to make a tough choice: whether to pursue a Ph.D. in English literature or go on with biochemistry. Already accepted as a biochemistry graduate student at UCLA, Dr. Redinbo remembers talking to English professors for some advice about his dilemma. “The English professors recommended that I go into biochemistry,” says Dr. Redinbo, grinning. “They said at least I’d get paid as a postdoc rather than trying to live on a teaching assistantship.”
Dr. Matt Redinbo says drug metabolizing enzymes are termed promiscuous because they have to take on many different drugs.He took their advice but says at first he was not all that enthused about biochemistry – until he took his first class in structural biology. “Then the lights came on,” he recalls. “In structural biology, you use computers, mathematics, physics; you end up with a detailed picture of what you’re studying.”
Now, he has no doubt he made the right choice. With a BWF Career Award and three subsequent NIH grants, the assistant professor heads up a busy lab at the University of North Carolina at Chapel Hill with a staff of 15 doing research in structural biology. Holding a joint appointment in the Department of Chemistry and in the School of Medicine, he also teaches classes in structural biology methods and DNA biochemistry.
“I enjoy mentoring graduate students,” he says, “because they come in without preconceived notions and can get excited about the science, and their enthusiasm feeds yours.” There’s no lack of enthusiasm in Dr. Redinbo’s demeanor as he talks about his research and what the BWF award has meant to his work and career. “The first thirteen papers from my independent lab were funded partly or completely from my Career Award,” Dr. Redinbo says. “The Career Award has made it possible for me to pursue research I normally couldn’t because it’s risky.”
Currently, Dr. Redinbo is juggling three related research projects in structural biology: how proteins manipulate human DNA to keep it stable; how the human body recognizes drugs (drug receptors); and how the body metabolizes drugs. His findings in the area of drug recognition belie the notion that there is a protein specific to each type of drug. In fact, Dr. Redinbo says, one specific nuclear receptor molecule recognizes a vast majority of drugs we take. This drug patrol protein, called PXR, fingers everything from antibiotics to anti-cancer drugs to herbal supplements. Once PXR recognizes a drug, it signals the liver to metabolize and get rid of the foreign substance. PXR can bind to many types of drugs because it has large cavities—or pockets—that can expand and conform to the shape of different drug molecules.
Dr. Redinbo’s research on metabolites focuses on the crucial step between drug recognition and its excretion by the liver. Enzymes triggered by PXR begin the process of breaking down the drug and can metabolize many different compounds in the liver. “Drug metabolizing enzymes have to be promiscuous,” he says, “because they have to take on a lot of different drugs.” Right now, he’s looking at the enzyme that breaks down heroin and cocaine.With a lab of 15 researchers, Dr. Matt Redinbo is juggling three related research projects in structural biology.
Dr. Redinbo’s research has profound implications for drug efficacy. “For example,” Dr. Redinbo says, “frequently less than five percent of cancer drugs actually makes it to the tumor; the other 95 percent can lead to toxicity and side effects such as hair loss and nausea.” The goal of his research is to understand how to design a drug that can slip by the PXR gatekeeper. “Then we can deliver one-tenth of the dose and get it past the liver,” Dr. Redinbo explains. Consequently, a smaller dose could be more potent with fewer side effects.
His interest in science started as early as the second grade, Dr. Redinbo recalls. “I remember being in the second grade and reading fourth and fifth grade science textbooks,” probably, he thinks, by borrowing those of his older brother, now a physicist. His father is a computer scientist, his mother a speech therapist, and his sister a lawyer. “It’s handy having a lawyer in the family,” he says with a grin. “I pay my sister to go over all my legal contracts.”
Dr. Redinbo met his wife, Liz, a geneticist, during his postdoc in Seattle. They have a two and a half year old son, Andy, and another child on the way in September. When there is spare time, Dr. Redinbo likes to spend it with his family and makes a point of being home in the evenings and on weekends, though his laptop is close at hand and usually gets a workout. Because of his abiding interest in literature, Dr. Redinbo says he usually reads fiction. John Steinbeck’s Cannery Row is his latest choice, though he says he and his wife have been reading Harry Potter. “She got me hooked on Harry Potter,” he says. “So instead of fighting over the books, we read them aloud to each other.”
*pregnane X receptor