Nitrite and Nitrite Reductases: From Molecular Mechanisms to Significance in Human Health and Disease

Abstract

Nitrite, previously considered physiologically irrelevant and a simple end product of endogenous nitric oxide (NO) metabolism, is now envisaged as a reservoir of NO to be activated in response to oxygen (O(2)) depletion. In the first part of this review, we summarize and compare the mechanisms of nitrite-dependent production of NO in selected bacteria and in eukaryotes. Bacterial nitrite reductases, which are copper or heme-containing enzymes, play an important role in the adaptation of pathogens to O(2) limitation and enable microrganisms to survive in the human body. In mammals, reduction of nitrite to NO under hypoxic conditions is carried out in tissues and blood by an array of metalloproteins, including heme-containing proteins and molybdenum enzymes. In humans, tissues play a more important role in nitrite reduction, not only because most tissues produce more NO than blood, but also because deoxyhemoglobin efficiently scavenges NO in blood. In the second part of the review, we outline the significance of nitrite in human health and disease and describe the recent advances and pitfalls of nitrite-based therapy, with special attention to its application in cardiovascular disorders, inflammation, and anti-bacterial defence. It can be concluded that nitrite (as well as nitrate-rich diet for long-term applications) may hold promise as therapeutic agent in vascular dysfunction and ischemic injury, as well as an effective compound able to promote angiogenesis.

Inorganic nitrite attenuates NADPH oxidase-derived superoxide generation in activated macrophages via a nitric oxide-dependent mechanism

“…It has been shown that the biological functions of inorganic nitrate and nitrite are mediated, at least in part, by the formation of NO [9,10,13]. Our data shows that the effect of nitrite in reducing O 2 •-production in LPS activated macrophages is mimicked by the NO donor DETA-NONOate, and could be abolished by cPTIO but not by L-NAME.…”

“…Increased production of ROS is considered a major contributing factor to the development and progression of various diseases, including kidney diseases, type 2 diabetes, cardiovascular diseases and neurodegenerative diseases [3][4][5][6]. where these anions may undergo bioconversion to form NO and other bioactive nitrogen oxides [8][9][10]. Nitrate is converted to nitrite by oral bacteria, and subsequent reduction of nitrite to NO can be achieved by a variety of proteins and enzymes in blood and tissues, including xanthine oxidase (XO) [11][12][13].…”

NADPH Oxidase in the Renal Microvasculature Is a Primary Target for Blood Pressure–Lowering Effects by Inorganic Nitrate and Nitrite

“…Several enzymes and proteins have been implicated in nitrite reduction in the vasculature, including heme proteins such as hemoglobin and myoglobin, enzymes of the respiratory chain, aldehyde oxidase, and XO. 15,37 Our findings emphasize XO as a major nitrite reducer in the renal microvasculature, because XO was highly expressed and inhibitors of the enzyme completely inhibited the nitrite response. The generated NO operates partly by stimulating a NO-soluble guanylyl cyclase-cGMP pathway, but more importantly by inhibiting vascular NADPH oxidase-dependent superoxide signaling.…”

Origin and Impact of Nitric Oxide in Pseudomonas aeruginosa Biofilms

“…1) is cytochrome cd 1 nitrite reductase (hereinafter NIR), a homodimer containing one c-heme and one d 1 -heme group in each subunit (58), belonging to the NirS family of nitrite reductases (59). The d 1 -heme is a partially saturated macrocycle, unique to this enzyme and synthesized by a specialized pathway present only in denitrifiers (strongly induced in P. aeruginosa upon nitrite treatment): this specialized cofactor is required for the efficient release of NO (60).…”