Metals’ Role In Odor Sensing

The metal copper allows mice to detect some particularly stinky thiols and related compounds, according to a new report (Proc. Natl. Acad. Sci. USA, DOI: 10.1073/pnas.1111297109). The results put on firm ground long-held suspicions that metals might help humans and animals smell certain volatile chemicals and may force scientists to rethink traditional models of how ligands activate biological receptors.

Humans can smell some thiols, which have odors reminiscent of rotten eggs, at levels approaching 1 ppb. Because of this extreme sensitivity, chemists have in the past proposed that metal ions somehow mediate the interaction between these odorants and protein receptors in the nose that send olfactory information to the brain. “They knew that chemicals that bind with metals smell stronger than those that don’t,” explains Hiroaki Matsunami, a neurobiologist at Duke University Medical Center and coauthor of the new study. “This made them think that metal coordination is important to the odor detection process.”

In 1978, for instance, Robert H. Crabtree of Yale University published a paper in the Journal of Inorganic & Nuclear Chemistry stating that copper(I), an ion present inside cells, has a high affinity for malodorous thiol compounds and that it is “the most likely candidate for a metallo-receptor site in olfaction” (DOI: 10.1016/0022-1902(78)80071-2). In 2003, Kenneth S. Suslick of the University of Illinois, Urbana-Champaign, also suggested that metal ions would help thiols activate olfactory receptors embedded in cell membranes by binding to particular peptide sequences on their surfaces (Proc. Natl. Acad. Sci. USA, DOI: 10.1073/pnas.262792899).

Matsunami and coworkers confirmed these chemists’ suspicions by first screening for and identifying an olfactory receptor in mice, called MOR244-3, that is responsible for binding the volatile chemical (methylthio)methanethiol (MTMT). They then showed that MTMT and some of its analogs could not activate MOR244-3 in the absence of copper ion. MTMT is a compound that male mice excrete in their urine to signal females that they are fertile, says Eric Block, a chemist at the State University of New York, Albany, and a member of the research team.

On the basis of mutation and modeling studies, the researchers, who also include Hanyi Zhuang of China’s Shanghai Jiao Tong University School of Medicine, believe that copper binds to MTMT and other odorant compounds before interacting with the receptor. They hypothesize that the copper alters the conformation of the odorant, enabling the whole complex to nestle snugly into the receptor’s active site, switching the protein on.

Ever since scientists discovered that mice were extremely sensitive to MTMT, question has been, “How does the nose do it?” says Leslie B. Vosshall, a neuroscientist at Rockefeller University, in New York City. “How can it possibly detect something that isn’t even a detectable peak on a gas chromatography/mass spectrometry instrument? This paper solves it in a big way.” The new results, she adds, will make scientists “rethink the whole process of ligand-receptor interaction.”

The next step for the team, both Block and Matsunami say, is to see whether, as suspected, humans also need copper to sense thiols.