How Biology Handles Nitrite Luisa B
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This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes. Review pubs.acs.org/CR How Biology Handles Nitrite Luisa B. Maia and JoséJ. G. Moura* REQUIMTE/CQFB, Departamento de Química, Faculdade de Cienciaŝ e Tecnologia, Universidade Nova de Lisboa, 2829-516 Caparica, Portugal Biographies 5328 Acknowledgments 5329 Abbreviations 5329 References 5329 Note Added in Proof 5357 1. INTRODUCTION Nitrite is one of the players in the broad nitrogen biogeochemical cycle. This nitrogen oxo-anion is involved in key pathways crucial to life on Earth and to the planetary “recycling” of nitrogen. From a human perspective, nitrite (and CONTENTS nitrate) is an important food preservative that has been used for the last five millennia.1 This successful nitrite utilization was, 1. Introduction 5273 however, overshadowed in the 1970s, when it was suggested 2. Biological Fate of Nitrite 5274 that nitrite might increase the incidence of cancer, through the 2.1. Biological Fate of Nitrite − Nitrite in the − formation of N-nitrosamines.2 8 Recently, another twist took Nitrogen Cycle 5274 place, and nitrite is now being rediscovered as a beneficial 2.1.1. Classic and New Pathways 5274 molecule, endogenously formed or therapeutically added, 2.1.2. Nitrite and Nitrogen “Recycling” 5277 involved in cell survival during hypoxic events, as will be here 2.2. Biological Fate of Nitrite − Nitrite in Signal- discussed. ing Pathways 5277 In this Review, we will review the physiological role of nitrite 2.2.1. Nitrite in Signaling Pathways in Mam- in the biochemical cycle of nitrogen (section 2.1) and in mals 5277 mammalian and plant signaling pathways (sections 2.2.1 and 2.2.2. Nitrite in Signaling (and Other) Path- 2.2.2). A very brief description of potential bacterial signaling ways in Plants 5297 (section 2.2.3) will also be included. In the “Nitrite in the 2.2.3. Nitrite in Signaling (and Other) Path- Nitrogen Cycle” section, the main, well-established, pathways ways in Bacteria 5303 will be briefly described, with emphasis on the nitrite-mediated 3. Biological Mechanistic Strategies To Handle reactions. In the “Nitrite in Signaling Pathways” section, the Nitrite 5305 nitrite-mediated reactions will be discussed with a deeper detail: 3.1. Nitrite Reduction to Ammonium 5306 the nitrite-mediated signaling and damaging pathways are a 3.1.1. Dissimilatory Nitrite Reduction to Am- (comparatively) recent and controversial area, and the Review monium 5307 will be oriented to discuss the feasibility of these novel 3.1.2. Assimilatory Nitrite Reduction to Am- pathways mainly from the chemical point of view. As will be monium 5312 described in section 2, the living organisms use nitrite for 3.1.3. Nitrite Reduction to Ammonium by remarkably different purposes, oxidizing and reducing it. Other Enzymes 5313 Subsequently (section 3), several key reaction mechanisms 3.2. Nitrite Reduction to Nitric Oxide 5314 will be analyzed at a molecular level of detail, and structure/ 3.2.1. Dissimilatory Nitrite Reduction to Nitric activity relationships will be, as much as possible, systematically Oxide by an Iron-Dependent Enzyme 5315 explored to discuss the mechanistic strategies that biology 3.2.2. Dissimilatory Nitrite Reduction to Nitric developed to reduce and oxidize nitrite. Oxide by a Copper-Dependent Enzyme 5319 The global aim is to review the present functional, structural, 3.2.3. Signaling Nitrite Reduction to Nitric and mechanistic knowledge of nitrite reduction/oxidation, to Oxide by a Molybdenum-Dependent assess in what extent we understand how nitrite is handled by Enzyme 5322 living organisms. Nitrite formation is outside the scope of this 3.3. Nitrite Oxidation to Nitrate 5326 Review. This knowledge is essential for the comprehension of 3.3.1. Dissimilatory Nitrite Oxidation to Nitrate 5326 the global nitrogen biochemical cycle and, consequently, for the 4. Outlook 5327 comprehension of the impressive changes the human activities Author Information 5328 Corresponding Author 5328 Notes 5328 Received: September 20, 2013 Published: April 2, 2014 © 2014 American Chemical Society 5273 dx.doi.org/10.1021/cr400518y | Chem. Rev. 2014, 114, 5273−5357 Chemical Reviews Review are introducing in the cycle. Furthermore, the wealth of environmentally (soils, oceans, and crust) available ammonium information gathered and discussed enables one to further and nitrate/nitrite. The nitrate assimilation is dependent on evaluate the feasibility and physiological significance of the two sequential reactions (assimilatory ammonification, Figure presently accepted “avenues” of NO formation in humans and 1, orange arrows): first, the reduction of nitrate to nitrite, plants and to foresee new potential pathways. catalyzed by molybdenum-dependent nitrate reductases (NaR; described in refs 1667,1679), and then the reduction of nitrite 2. BIOLOGICAL FATE OF NITRITE to ammonium, catalyzed by sirohaem-containing nitrite 34−41 2.1. Biological Fate of Nitrite − Nitrite in the Nitrogen Cycle reductases (CSNiR; described in section 3.1.2). The electron source to carry out the nitrite reduction to ammonium Nitrogen is absolutely essential for life, being the fourth most is (i) the photosynthetically reduced ferredoxin, in photo- abundant element in living organisms (behind hydrogen, synthetic organisms (e.g., cyanobacteria and chloroplasts of 9 oxygen, and carbon). Nitrogen is used by all organisms for photosynthetic eukaryotes36,39,42), or (ii) the reduced pyridine the biosynthesis of amino acids, nucleosides, and other nucleotide pool, in most heterotrophs, but also in some fundamental compounds, and two nitrogen assimilatory phototrophs (e.g., nonphotosynthetic tissues of higher plants42 pathways were developed to provide the necessary reduced and Rhodobacter capsulatus,43,44 respectively). For that reason, “ ” “ nitrogen. This is then recycled in a universal organic there are two types of assimilatory CSNiR: ferredoxin- ” nitrogen pool . In addition, some organisms also use nitrogen dependent and NAD(P)H-dependent enzymes. Within each “ ” compounds as substrates for respiration , and for that purpose type, the enzymes share sequence and structural similarity, several nitrogen dissimilatory pathways have also evolved. The regardless of their prokaryotic or eukaryotic origin. Both types nitrogen biochemical cycle (Figure 1, Table 1) keeps this hold a sirohaem, where the nitrite reduction takes place, and an iron−sulfur center (Fe/S). Yet NAD(P)H-dependent enzymes contain an additional FAD domain that is involved in the − NAD(P)H binding and oxidation.34 44 Ammonium then enters the “organic nitrogen pool” (Figure 1, pink arrows) in the form of two amino acids, glutamine and glutamate, through the concerted action of glutamine synthase (eq 1) and glutamate synthase (eq 2) of bacteria, fungi, and plants. Ammonium can also be directly incorporated into glutamate through the glutamate dehydrogenase enzyme present in all forms of life (eq 3). However, under most physiological conditions, glutamate dehydrogenase catalyzes instead the reverse reaction, yielding ammonium in amino acid catabolism. Hence, the key enzyme that controls the entrance of the “organic nitrogen pool” is the glutamine synthase, not surprisingly one of the most complex regulatory enzymes. Besides this crucial role, glutamine synthase is also of main importance in animals, where it is responsible for the removal of toxic ammonium. Figure 1. Biochemical cycle of nitrogen. Dinitrogen fixation, yellow arrow; assimilatory ammonification, orange arrows; “organic nitrogen pool”, pink arrows; denitrification, blue arrows; dissimilatory nitrate reduction to ammonium (DNRA), green arrows; nitrification, black arrows; anaerobic ammonium oxidation (AnAmmOx), gray arrows; “denitrification/intra-aerobic methane oxidation”, violet arrows. element in forms available to support live on Earth, “starting” with fixation from the atmosphere (the largest nitrogen source) − and “recycling” it through the dissimilatory pathways.10 17 2.1.1. Classic and New Pathways. Two nitrogen The organic nitrogen, in the form of amino and amide assimilatory pathways provide the reduced nitrogen (ammo- groups, can now be transferred to other amino acids and several nium) essential for biosynthetic purposes (Figure 1, yellow and other nitrogen-containing biomolecules, supporting the vital orange arrows, Table 1). The organisms capable of dinitrogen biosynthetic needs. The organic nitrogen is then “recycled” fixation (some free-living archea and bacteria, e.g., Azotobacter, between all living organism, through chain foods, waste and symbiotic bacteria, e.g., Rhizobium) possess a unique products, and organic decay. Eventually, the organic nitrogen pathway, where the atmospheric dinitrogen is directly reduced is converted back to ammonium and returned to the to ammonium, in a reaction catalyzed by molybdenum/iron- environment, in a process called mineralization, thus closing − dependent nitrogenases18 (Figure 1, yellow arrow).22 33 All of the “organic” part of the nitrogen cycle ((Figure 1, pink the other organisms, prokaryotic and eukaryotic, depend on arrows). 5274 dx.doi.org/10.1021/cr400518y | Chem. Rev. 2014, 114, 5273−5357 Chemical Reviews Review Table 1. Main Pathways of the Biochemical Cycle of Nitrogen aFigures where the reaction and/or enzyme is represented. bSections where the reaction and/or enzyme is discussed. − The biochemical cycle of nitrogen continues