Structure & Function of the Bile acid transporter

Brian Kloss and Renato Bruni from NYCOMPS worked with Columbia University’s Ming Zhou, Matthias Quick and colleagues to elucidate the mechanism of transport of bile acids in the body. The groups cloned, expressed, and solved the X-ray crystal structure of ASBTYf, a close relative of the human protein that transports bile acids from the small intestine back to the bloodstream, where they are returned to the liver. This important function had not been previously understood.

“These structural details could point to ways to design more specifically targeted drugs,” said Wayne Hendrickson, the Scientific Director of NYSBC, director of NYCOMPS, and of Columbia and Brookhaven as well as a senior author on the paper.

But even more interesting, Hendrickson said, was a series of biochemical assays the team performed to try to decipher the physiological function of TSPO. These studies revealed that TSPO breaks down a compound found in red blood cells to produce a novel product (which the scientists named bilindigin) that is similar to a chemical important for scavenging reactive forms of oxygen.

“These ‘reactive oxygen species’ contribute to a variety of disease processes—including inflammation and programed cell death, which play roles in cardiovascular disease and cancer,” said Youzhong Guo, a postdoctoral research fellow working with Hendrickson and the first author on the paper. “Our findings therefore suggest that TSPO may help regulate the levels of potentially damaging oxygen compounds in cells.”

While the team does not yet fully understand the physiological role of TSPO, or whether it is related to side effects of Valium and other benzodiazepine drugs, studies to explore these questions could potentially offer insight, and possibly help identify new targets for drugs designed to mitigate these effects.

Research article: Zhou et al. Nature 505:569 (2013).