New Biological Signaling Agent Identified

Thionitrous acid, HSNO, may be a key molecule in biological signaling and regulation, linking the effects of nitric oxide and hydrogen sulfide, according to a research report (J. Am. Chem. Soc., DOI: 10.1021/ja3009693). The findings may be important for a better understanding of the way cardiac and nerve signals are regulated.

Some effects of nitric oxide are familiar: Nitro­glycerin, for example, releases nitric oxide to open blood vessels to alleviate heart pain. Nitric oxide plays a role in cardiac and neurotransmitter regulation by binding to the heme of a key enzyme. Recent research has also pointed to another signaling path for nitric oxide, in which NO groups add to the thiols of cysteine residues, forming S-nitrosated proteins.

Meanwhile, hydrogen sulfide appears to have signaling roles similar to those of nitric oxide, and scientists have been working to understand the detailed mechanisms of all these signaling processes.

In the new work, a group led by senior research associate Milos R. Filipovic and professor Ivana Ivanović-Burmazović of the University of Erlangen-Nürnberg, in Germany, proposes that HSNO forms from reactions between H₂S and S-nitrosated species, thereby connecting hydrogen sulfide and nitric oxide chemistry in cells.

Their results suggest that HSNO signaling works in two ways. In one, HSNO reacts with additional H₂S to form nitroxyl, HNO, which is involved in cardiac system regulation. This hypothesis is based on detection of H₂S-dependent HNO formation in endothelial cells through use of an HNO-specific dye.

HSNO may also work as a shuttle in S-nitrosation reactions, moving NO from one protein to another in signaling pathways. This hypothesis is based on NO transfer between S-nitrosated albumin in solution and hemoglobin in red blood cells. S-Nitrosated albumin is known not to cross cell membranes, so how its NO group gets transferred to hemoglobin has been a mystery. The researchers found that H₂S enables transfer of NO from albumin to hemoglobin, likely via HSNO, which can freely diffuse into the cells.

The work “expands the repertoire of redox-active signaling molecules,” says Ruma V. Banerjee, a biological chemistry professor at the University of Michigan Medical School. She adds that the convergence of nitric oxide- and hydrogen sulfide-based signaling mechanisms raises questions about how the biogenesis of the two molecules may be coregulated.

Jonathan S. Stamler, director of the Institute for Transformative Molecular Medicine at Case Western Reserve University, notes that the species in question are highly reactive and evanescent, making them difficult to study. The researchers “have done a great job in beginning to make a case” for HSNO having a role in biology, he says. “To me, it’s increasingly clear that NO biology is critically dependent on thiols as the main carriers and conveyors of NO reactivity.” Having a small, easily diffusible molecule such as HSNO play a role in nitric oxide chemistry through transnitrosation reactions would be a nice piece to add to the puzzle, Stamler says.