Nature Structural Biology pp 679 - 683

Nitric oxide (NO) has been shown to have a role in a number of conditions, including diabetes, hypertension, cancer, and impotence. This signaling molecule is present at low levels in all parts of the body and is involved in many important functions, including control of blood flow, neurotransmission, and protection from bacterial infection. In pathological condition such as inflammation, however, NO levels increase and become detrimental.

One potential way to decrease NO levels for disease treatment is to inhibit the enzyme NO synthase, which is responsible for creating it. This enzyme uses the amino acid arginine to release NO, so potential inhibitors include molecules that look like arginine and are recognized and bound by the enzyme, but cannot be used to create NO. Efforts are currently being directed toward developing such inhibitors, but it turns out there are naturally-occurring compounds that do this job. The levels of these inhibitory compounds are regulated primarily by another enzyme, 'dimethylarginine dimethylaminohydrolase' (DDAH), which works to eliminate them. Inhibiting DDAH, therefore, would lead to increased levels of natural NO synthase inhibitors, which may represent a new tactic for treating diseases related to increased NO levels.

In the August issue of Nature Structural Biology, Neil McDonald at the Imperial Cancer Research Fund in London and colleagues report the structure of the enzyme DDAH. They find that it looks similar to other enzymes that work on derivatives of arginine, and propose a reaction mechanism for how it works to eliminate the arginine-related NO synthase inhibitors. This structure provides a basis for designing inhibitors for this enzyme, potentially providing a new way of indirectly regulating NO activity.