Sulfide Signal In Sight

Infamous for being the source of rotten-egg stench, hydrogen sulfide (H₂S) has a rather complicated place in biology. The human body makes it. It is both poisonous—linked to diseases such as type 1 diabetes—and beneficial to activities such as immune signaling. Researchers would like to know more about how H₂S is made and how it exerts its effects, but they have lacked tools to noninvasively monitor the compound in living beings.

Enter Christopher J. Chang’s team at the University of California, Berkeley, which has developed molecules to track H₂S in live cells (Proc. Natl. Acad. Sci. USA, DOI: 10.1073/pnas.1302193110).

Chang’s lab first reported fluorescent probes for H₂S two years ago. The probes selectively light up in the presence of H₂S because they contain an aryl azide group that only H₂S can reduce to a fluorescent product. Those probes, however, weren’t sensitive enough to detect biologically relevant levels of H₂S.

To fix that, Chang lab members Vivian S. Lin and Alexander R. Lippert made two improvements. They increased the probes’ sensitivity by adding a second aryl azide group. They also added two acetoxymethyl ester groups, which are lipophilic and help the probe enter cells. Once inside, the groups get cleaved by esterases, rendering the probe incapable of leaving. The probes accumulate inside cells, further boosting sensitivity.

With the improved probes, the team followed H₂S production in cells from umbilical cords. They found evidence to back a hunch held by members of several other labs—H₂S production depends on a signal from hydrogen peroxide. That’s a fascinating relationship, Chang says, because H₂O₂ is an oxidant and H₂S is a reductant. The biochemistry linking those chemical opposites is far from clear, so “it’s going to be exciting to learn more about that cross talk,” he says.

“This work presages many exciting new directions in both redox and chemical biology,” says Kate Carroll, who maps redox signaling at Scripps Research Institute Florida. “A central goal for future studies will be to define the molecular targets of H₂O₂, H₂S, and other redox-based signaling molecules.”