Physiological Roles of Nitrite and Nitric Oxide in Bacteria: Similar Consequences from Distinct Cell Targets, Protection, and Sensing Systems

Abstract

sodium nitrite) is currently in a phase 2b clinical trial as a drug for pulmonary hypertension treatment on the basis of the finding that it could be safely applied to reach millimolar concentrations in the airway surface liquid. [6] In the broad nitrogen biogeochemical cycle, nitrite serves as the central molecule linking nitrate (NO 3 − ) to dinitrogen gas (N 2 ) or ammonia (NH 3 ). [7] As a nitrogen oxo-anion, nitrite per se is crucial to life on earth because it participates in diverse key biological processes, especially in bacteria because they are renowned for their ability to carry out biological transformation of nitrite (Maia and Moura, 2014). Nitrite can be oxidized to nitrate or reduced to various nitrogen species such as nitric oxide (NO), nitrous oxide (N 2 O), N 2 , and NH 3 . [8] Although nitrite transformation is regarded as an effective means for detoxification, it brings out new threats. [7] Apart from an intermediate in the nitrogen cycle, NO, whose physiological concentrations are suggested to be up to ≈5 nM in cells, is a well-recognized bacteriostatic agent the same as nitrite. [9] It should be noted that concentrations of NO generated from nitrite reduction vary drastically in different bacteria, for example, less than 20 nM and up to 38 µM in cultures of two denitrifiers Paracoccus denitrificans and Agrobacterium tumefaciens, respectively. [10] In bacteria, a variety of enzymes are implicated in generation of NO from nitrite, and consistently, multiple enzymes contribute to transformation of NO to other nitrogen species for detoxification. [7,11] It is worth noting that in contrast to nitrite, whose transformation is exclusively conducted by enzymes involved in the nitrogen biogeochemical cycle, NO can be generated and scavenged by proteins outside the cycle, bacterial NO synthases (bNOSs) and flavohemoglobin Hmp, respectively. [12] Both nitrite and NO are bacteriostatic agents due to their ability to inhibit protein activity. In vitro studies show that nitrite and NO display similar, albeit not identical, biochemical properties, and therefore proteins susceptible to them are similar, mainly those containing redox-active centers such as heme, iron-sulfur clusters, mono-/di-nuclear iron, thiol, and so on. [13] Consistently, most of cellular targets identified in vivo are metabolic and respiratory enzymes depending on their redox-active centers for catalysis and/or oxi-reduction. [11] Despite this, cellular targets of nitrite and NO in any given bacterial species are Nitrite and nitric oxide (NO) are two active nitrogen oxides that display similar biochemical properties, especially when interacting with redox-sensitive proteins (i.e., hemoproteins), an observation serving as the foundation of the notion that the antibacterial effect of nitrite is largely attributed to NO formation. However, a growing body of evidence suggests that they are largely treated as distinct molecules by bacterial cells. Although both nitrite and NO are formed and decomposed by enzymes participating in the trans...

Complex Interplay of Heme-Copper Oxidases with Nitrite and Nitric Oxide

“…Similar to NO, nitrite also displays inhibitory effects on HCOs [22]. As nitrite can be transformed by a variety of proteins, including HCO, into other nitrogen oxides, especially NO, its inhibition has been attributed to NO for decades [124].…”

“…In addition to the NO-independent inhibition of HCOs by nitrite, recent advances have revealed an array of physiological aspects in which nitrite and NO function independently from each other. These include enzymes for their formation and detoxification and novel biological activities such as the lowing effect of nitrite on blood pressure [22,160]. In addition, nitrite and NO as signal molecules at very low concentrations are perceived by completely different sensing systems, through which they are linked to different biological processes [22,161].…”

“…Given that bacteria are able to catalyze all steps of the nitrogen cycle, they are crucial for the inter-conversion of different nitrogen oxides [21]. Both nitrite and NO are involved in diverse physiological processes in bacteria functioning as important cellular signaling molecules, substrates of metabolic enzymes, and inhibitory agents modulating protein activity [19,22]. Although a significant portion of phenotypic changes caused by nitrite are NO-independent, it is widely accepted that NO is the molecule largely underpinning the physiological influences; nitrite impacts the physiology of living organisms in part by serving as a biochemical circulating reservoir for NO [19].…”

“…On the other hand, both nitrite and NO are bacteriostatic agents due to their ability to inhibit proteins, especially hemoproteins [36,37]. A great body of evidence has been accumulated showing that nitrite and NO react with purified HCOs and bd QOs in vitro and inhibit cell respiration in vivo [22,30,31,[38][39][40][41][42]. While there are common reaction mechanisms involved in the inhibition by nitrite and NO, considerable discrepancies have been observed between their cellular targets identified to date [22].…”

“…A great body of evidence has been accumulated showing that nitrite and NO react with purified HCOs and bd QOs in vitro and inhibit cell respiration in vivo [22,30,31,[38][39][40][41][42]. While there are common reaction mechanisms involved in the inhibition by nitrite and NO, considerable discrepancies have been observed between their cellular targets identified to date [22]. Thus, the extent of the effective mechanisms elucidated by in vitro analyses is in living cells is still a matter of study.…”