The Balancing of Peroxynitrite Detoxification between Ferric Heme-Proteins and CO2: The Case of Zebrafish Nitrobindin

G, De Simone; Coletta, Andrea; Masi, Alessandra di; Coletta, Massimo; Ascenzi, Paolo

doi:10.3390/antiox11101932

Cited by 3 publications

(6 citation statements)

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“…Specifically, the survival of M . tuberculosis in the host implies the presence of effective detoxification systems, including Nbs, to inactivate RNS and ROS produced by the immune response [ 19 , 25 , 26 ]. In A .…”

Section: Discussionmentioning

confidence: 99%

“…thaliana , Nb has been hypothesized to transport and release NO at the infection site; moreover, NO may reduce the superoxide radical with the generating peroxynitrite that increases pathogen burden [ 16 , 19 ]. Interestingly, Dr -Nb may play a relevant physiological role in peroxynitrite scavenging from poorly oxygenated tissues, such as the retina in fish where blood circulation is critical for adaptation to diving conditions [ 21 , 22 , 26 ]. It is worth remarking that Danio rerio Nb shows the fastest nitrite reductase activity ( Table 1 ), outlining the fact that, in fishes, the O 2 supply to poorly oxygenated tissues, such the retina, occurs by means of a fine regulation of the eye circulation through the rete mirabilis , with NO playing a major role in regulating the blood flow and thus the oxygenation of retinal layers [ 90 ].…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, at alkaline pHs, NO facilitates the reduction of the heme–Fe(III)-atom leading to the nitrosylation of the ferrous metal center (Nb(II)-NO) with a OH − -dependent reaction via the transient formation of ferric nitrosylated Nb (Nb(III)-NO); concomitantly, one equivalent of HNO 2 is produced [ 20 , 22 ]. Furthermore, Nbs catalyze the isomerization of peroxynitrite to NO 3 − and NO 2 − in the absence and presence of CO 2 [ 19 , 25 , 26 ]. Lastly, O 2 scavenging by Nb(II)-NO leads to NO 3 − and Nb(III) via the transient formation of a Nb(III)-NO(O)O adduct [ 24 ].…”

Section: Introductionmentioning

confidence: 99%

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Nitrite Reductase Activity of Ferrous Nitrobindins: A Comparative Study

Masi

Tundo

et al. 2023

IJMS

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Nitrobindins (Nbs) are all-β-barrel heme proteins spanning from bacteria to Homo sapiens. They inactivate reactive nitrogen species by sequestering NO, converting NO to HNO2, and promoting peroxynitrite isomerization to NO3−. Here, the nitrite reductase activity of Nb(II) from Mycobacterium tuberculosis (Mt-Nb(II)), Arabidopsis thaliana (At-Nb(II)), Danio rerio (Dr-Nb(II)), and Homo sapiens (Hs-Nb(II)) is reported. This activity is crucial for the in vivo production of NO, and thus for the regulation of blood pressure, being of the utmost importance for the blood supply to poorly oxygenated tissues, such as the eye retina. At pH 7.3 and 20.0 °C, the values of the second-order rate constants (i.e., kon) for the reduction of NO2− to NO and the concomitant formation of nitrosylated Mt-Nb(II), At-Nb(II), Dr-Nb(II), and Hs-Nb(II) (Nb(II)-NO) were 7.6 M−1 s−1, 9.3 M−1 s−1, 1.4 × 101 M−1 s−1, and 5.8 M−1 s−1, respectively. The values of kon increased linearly with decreasing pH, thus indicating that the NO2−-based conversion of Nb(II) to Nb(II)-NO requires the involvement of one proton. These results represent the first evidence for the NO2 reductase activity of Nbs(II), strongly supporting the view that Nbs are involved in NO metabolism. Interestingly, the nitrite reductase reactivity of all-β-barrel Nbs and of all-α-helical globins (e.g., myoglobin) was very similar despite the very different three-dimensional fold; however, differences between all-α-helical globins and all-β-barrel Nbs suggest that nitrite reductase activity appears to be controlled by distal steric barriers, even though a more complex regulatory mechanism can be also envisaged.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Nitrite Reductase Activity of Ferrous Nitrobindins: A Comparative Study

Masi

Tundo

et al. 2023

IJMS

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“…17−19 Ferric Nbs (Nb(III)) play a role in the isomerization of toxic peroxynitrite to innocuous nitrate, with a second-order rate constant value similar to those of other heme proteins such as myoglobin (Mb) and hemoglobin (Hb). 16,19,20 Binding of external ligands to heme proteins can be rationalized in two distinct steps: first, the ligand needs to migrate from the solvent to the active site, reaching the proximity of the heme iron. Second: ligand exchange reaction in the distal cavity.…”

Section: ■ Introductionmentioning

confidence: 99%

Mechanism of Peroxynitrite Interaction with Ferric M. tuberculosis Nitrobindin: A Computational Study

Messias,

Capece,

De Simone

et al. 2024

Inorg. Chem.

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Nitrobindins (Nbs) are all-β-barrel heme proteins present along the evolutionary ladder. They display a highly solvent-exposed ferric heme group with the iron atom being coordinated by the proximal His residue and a water molecule at the distal position. Ferric nitrobindins (Nb(III)) play a role in the conversion of toxic peroxynitrite (ONOO − ) to harmless nitrate, with the value of the second-order rate constant being similar to those of most heme proteins. The value of the second-order rate constant of Nbs increases as the pH decreases; this suggests that Nb(III) preferentially reacts with peroxynitrous acid (ONOOH), although ONOO − is more nucleophilic. In this work, we shed light on the molecular basis of the ONOO − and ONOOH reactivity of ferric Mycobacterium tuberculosis Nb (Mt-Nb(III)) by dissecting the ligand migration toward the active site, the water molecule release, and the ligand binding process by computer simulations. Classical molecular dynamics simulations were performed by employing a steered molecular dynamics approach and the Jarzynski equality to obtain ligand migration free energy profiles for both ONOO − and ONOOH. Our results indicate that ONOO − and ONOOH migration is almost unhindered, consistent with the exposed metal center of Mt-Nb(III). To further analyze the ligand binding process, we computed potential energy profiles for the displacement of the Fe(III)-coordinated water molecule using a hybrid QM/MM scheme at the DFT level and a nudged elastic band approach. These results indicate that ONOO − exhibits a much larger barrier for ligand displacement than ONOOH, suggesting that water displacement is assisted by protonation of the leaving group by the incoming ONOOH.

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“…However, what little information is currently available points to potential roles in RNS regulation, such as nitric oxide trapping and peroxynitrite scavenging, similar to proposed functions of the classical globins. De Simone et al report on the balance between detoxification of peroxynitrite of ferric Nb from Danio rerio and CO 2 [8]. The pH dependent scavenging of peroxynitrite by Nb leads to nitrite and some nitrite formation.…”

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confidence: 99%