Endogenous nitrate- and nitrite-reducing enzymatic systems (Nitrate-nitrite-NO pathway)

The endogenous nitrate- and nitrite-reducing enzymatic systems constitute a secondary pathway for nitric oxide (NO) production that operates independently of the oxygen-dependent nitric oxide synthase (NOS) enzymes (Lundberg et al., 2008). This pathway involves the sequential reduction of nitrate to nitrite, primarily by commensal oral bacteria, and the subsequent reduction of nitrite to NO by various mammalian proteins (Gladwin et al., 2005). Key enzymes and proteins involved in this process include xanthine oxidoreductase, deoxyhemoglobin, deoxymyoglobin, and certain mitochondrial enzymes (Weitzberg et al., 2010). A unique feature of this system is that its activity is significantly enhanced under conditions of hypoxia and low pH, where the conventional NOS pathway is often impaired (Zweier et al., 1995). In disease states such as hypertension, myocardial infarction, and peripheral artery disease, these systems serve as a crucial backup for maintaining NO bioavailability and vascular homeostasis (Hord et al., 2009). Therapeutic interventions often involve the administration of inorganic nitrate or nitrite salts to provide substrates for these enzymes, thereby promoting vasodilation and cytoprotection. Research into these systems has expanded the understanding of how dietary nitrate influences cardiovascular health and exercise performance. However, pharmacological targeting must be carefully managed to avoid excessive NO production or the formation of methemoglobin.

Other names

Nitrate-nitrite-nitric oxide pathwayMammalian nitrate and nitrite reductasesNon-canonical nitric oxide synthesis pathwayNitrate reductase systemNitrite reductase system

The primary mechanism involves the enzymatic reduction of inorganic nitrate to nitrite and then to nitric oxide (NO), providing an alternative source of NO that is particularly active during hypoxia and acidosis, thereby bypassing dysfunctional nitric oxide synthase (NOS) pathways (Lundberg et al., 2008).