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Biologically produced nitric oxide (NO) originates from oxygen and
L-arginine in the reaction catalyzed by NO synthase (NOS) enzymes (NOS, EC 1.14.13.39), first reported in the late 1980s. It was soon discovered that these enzymes have different biochemical properties depending on the tissue from which they are isolated. This suggested that there are special regulatory mechanisms that match the supply of NO exactly to its function in each tissue where it is produced. Subsequent research has confirmed that indeed these enzymes are subject to sophisticated and complex regulation. It is indispensable to understand this regulation better, both to understand the physiology of NO, and to pick targets for new therapeutic strategies.