Catalytic peroxidation of nitrogen monoxide and peroxynitrite by globins

Abstract

SummaryGlobins are generally considered as carriers of diatomic gaseous ligands (e.g., O 2 and NO) in metazoa. Recently, the (pseudo-)enzymatic activity of globins towards reactive nitrogen and oxygen species has been elucidated. In particular, some globins (e.g., hemoglobin and myoglobin) catalyze the enzymatic scavenging of NO and peroxynitrite in the presence of H 2 O 2 . Indeed, H 2 O 2 oxidizes some globins leading to the formation of water and of the heme-protein ferryl derivative, which, in turn, oxidizes NO and peroxynitrite leading to the formation of the globin ferric species, NO 2 2 , and NO 3 2 . Here, we hypothesize that NO, peroxynitrite, and H 2 O 2 are co-substrates for the peroxidase activity of some globins, this catalytic activity was reported in 1900 for the first time, even though the substrates have never been identified firmly up to now. The hemoglobin (Hb) superfamily includes several hemeproteins, generally referred to as globins, which are found in all kingdoms of living organisms (1, 2). Globin functions have been the subject of active debate, in addition to dioxygen transport and storage. Several functions have been proposed recently, including control of nitrogen monoxide levels, O 2 sensing, and dehaloperoxidase activity (3-15).Globins share physical, spectroscopic, and chemical similarities with peroxidases (16,17). In fact, as demonstrated first in 1900 (18), Hb reacts readily with hydrogen peroxide (H 2 O 2 ). In 1923, the peroxidase activity of Hb has been reported (19), and in 1938, the modulation of the peroxidase activity of Hb by haptoglobin has been demonstrated (20). The reaction of myoglobin (Mb) with H 2 O 2 , on the other hand, apparently was not considered until 1952 (21), and the ability of Mb to catalyze peroxide oxidation of substrates was not reported until 1955 (22). Upon reaction with H 2 O 2 , Mb and Hb form the cytotoxic ferryl derivative (heme-Fe(IV)¼ ¼O), which is similar to compound II formed by peroxidases (23, 24). Heme-Fe(IV)¼ ¼O is able to oxidize a wide range of reducing substrates, such as phenols and aromatic amines, even though substrate peroxidation by Hb and Mb is far less efficient than that of peroxidases (24, 25), ruling out the possibility that the potential peroxidase activity of Hb and Mb is exerted on this class of substrates under normal conditions.Here, we hypothesize that the capability of some globins (e.g., Hb and Mb) to form a compound II-like species under oxidative stress may be actually exploited to avoid the building up of NO and peroxynitrite, 1 which can be then identified as the 'true' substrates for the peroxidase activity of Hb and Mb.Heme-proteins share the ability of detoxifying nitrogen reactive species, for example, NO. Even though leukocyte peroxi- 1 The term peroxynitrite is used in the text to refer generically to both ONOO 2 and its conjugated acid HOONO (38).

Peroxynitrite detoxification by ferryl Mycobacterium leprae truncated hemoglobin O

“…Ferrous oxygenated and nitrosylated Ml-trHbO (Ml-trHbOAFe(II)AO 2 and Ml-trHbOAFe(II)ANO, respectively) has been reported to facilitate Å NO, O 2 , and peroxynitrite detoxification, moreover ferryl Ml-trHbO (Ml-trHbOAFe(IV)@O) acts as a Å NO, nitrite (NO 2 À ), and H 2 O 2 scavenger [9,20,21,[23][24][25]. Peroxynitrite scavenging by ferrous oxygenated and nitrosylated heme-proteins (heme-Fe(II)AO 2 and hemeFe(II)ANO, respectively), leading to the ferric heme-protein derivative (heme-Fe(III)), needs a specific reductase(s) to restore the ferrous species (heme-Fe(II)) in order to start a new catalytic cycle (see [26]). Since a reductase system(s) has been identified only for hemoglobin (Hb), flavohemoglobin, and myoglobin (Mb) (see [27][28][29] E-mail address: ascenzi@uniroma3.it (P. Ascenzi).…”

“…The term peroxynitrite is used in the text to refer generically to both ONOO À and its conjugate acid ONOOH (see [14]). [25,26,[30][31][32]). …”

The key role of water in the dioxygenase function of Escherichia coli flavohemoglobin

“…The NOD activity carried out by heme proteins consists in the conversion of nitric oxide (NO), which is toxic for the bacteria, into innocuous nitrate according to the NO detoxification reaction cycle, shown in Scheme 1 [9,[13][14][15][16].…”

Characterization of THB1, a Chlamydomonas reinhardtii Truncated Hemoglobin: Linkage to Nitrogen Metabolism and Identification of Lysine as the Distal Heme Ligand

“…14 The reactions include oxidation, e.g., generation of nitrate from nitric oxide by oxy Hb; reduction, e.g., formation of nitric oxide from nitrite by deoxy Hb; and isomerization, e.g., conversion of peroxynitrite to nitrate by ferric (met) Hb, each process depending on the redox and ligation state of the protein. Such chemical versatility can be attained by alterations of the heme environment without disruption of the fold.…”