Copper + love chemical = big sulfur stink

When Hiroaki Matsunami, PhD, associate professor at Duke University, set out to study a chemical in male mouse urine called MTMT that attracts female mice, he didn't think he would stumble into a new field of study. But the research has led scientists at Duke University Medical Center and the University of Albany to the discovery that it's the copper in our bodies that makes mammals recoil from sulfurous chemical smells.

Working with Eric Block, PhD, the Carla Rizzo Delray Distinguished Professor of Chemistry at the University of Albany, the team looked at reasons why mammals, including people, can detect even trace amounts of sulfur-containing substances, like MTMT.

"While we were doing our experiments, on even very dilute specimens of MTMT, our neighbors on the lab hallway complained," Matsunami said with a laugh. He is an associate professor in the Duke Department of Molecular Genetics and Microbiology and the Department of Neurobiology.

The Duke laboratory ran a high-throughput test of several hundred mammalian odor receptors, and found that one receptor that bound copper ions resulted in superior detection of even trace amounts of sulfur.

Underarm odors from bacteria, skunk spray, volcanic gases and odorized natural gas (for leak detection) are examples of sulfurous substances.

The work was published in the Proceedings of the National Academy of Sciences online the week of Feb. 6.

"We learned that copper was the metal that allowed for detection of all the sulfur-containing compounds we tested, and it was Eric Block's idea that metal ions must be involved," Matsunami said. "Further, I see no reason why the mouse receptor activity would be different from human receptors, because we have the same kind of olfactory receptors."

Block and colleagues created several dozen sulfur-containing compounds for testing.

The odor impact of the sulfur-containing molecule MTMT can be attenuated by manipulating the copper concentration in the nasal mucus. The team did experiments using a chemical that binds to copper in the mouse nose, so that copper wasn't available to the receptors, and the mice didn't detect the MTMT, Matsunami said.

"This study establishes for the first time the key role of a metal, namely copper, in the activity of an olfactory receptor," Eric Block said. "What's also exciting is that, because olfactory receptors are transmembrane G protein-coupled receptors (GPCRs) of the same type as receptors for drugs, our discovery suggests a possibility that some drug-receptor responses may also be enhanced in the presence of copper or other metal ions."

Other authors include Siji Thomas and Shaozhong Zhang, of the University of Albany Department of Chemistry; Timothy Connelly, Qiuyi Chi and Minghong Ma of the Department of Neurobiology, University of Pennsylvania School of Medicine; and Xufang Duan, Zhen Li, Lifang Wu, Guo-Qiang Chen and Hanyi Zhuang, all of the Ruijin Hospital in China. The senior authors on the paper were Dr. Matsunami and Dr. Zhuang, formerly of Duke, who is also with the Institute of Health Sciences, Shanghai Institutes for Biological Sciences of Chinese Academy of Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai.

This research is supported by National Natural Science Foundation of China Grants, Shanghai Pujiang Program Grant, the Program for Innovative Research Team of Shanghai Municipal Education Commission grant from the Chen Guang Project funded by Shanghai Municipal Education Commission and Shanghai Education Development Foundation, and a grant from the Program for Professor of Special Appointment (Eastern Scholar) at Shanghai Institutions of Higher Learning, from the Leading Academic Discipline Project of Shanghai Municipal Education Commission. The U.S. National Institutes of Health (NIH), National Basic Research Program of China, U.S. National Science Foundation, and NIH/National Institute on Deafness and Other Communication Disorders also funded the work.

This article is dedicated to the memory of Dr. Lawrence C. Katz of Duke, who worked on related studies and with Eric Block found the first evidence of neurons that respond to social odors.

Source: Duke University Medical Center