CHAPTER 17: Lessons from Denitrification for the Human Metabolism of Signalling Nitric Oxide

The nitric oxide radical NO (NO) is a signalling molecule involved in several physiological processes in humans, including vasodilation, immune response, neurotransmission, platelet aggregation, apoptosis and gene expression. Undue normal conditions, NO synthases catalyse the formation of NO from l-arginine and dioxygen. Yet, upon a hypoxic event, when the decreased dioxygen concentration compromises NO synthase activity, cells can generate NO from another source: nitrite. Since the late 1990s, it has become clear that nitrite can be reduced back to NO under hypoxic/anoxic conditions. Simultaneously, it was realised that nitrite can exert a significant cytoprotective action in vivo during ischaemia and other pathological conditions. Presently, blood and tissue nitrite are recognised as NO "storage forms" that can be made available in order to maintain NO formation and ensure cell signalling and survival under challenging conditions. To reduce nitrite to NO, human cells can use different metalloproteins that are present in cells for carrying out other functions, including several haemic proteins and molybdoenzymes, forming what we refer to as "non-dedicated nitrite reductases". In this chapter, two non-dedicated nitrite reductases - xanthine oxidase and myoglobin - will be described, and the human nitrate/nitrite/NO signalling pathway will be discussed within the cellular context and the nitrogen cycle scenario.