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Human nitrobindin: the first example of an all-?-barrel ferric heme-protein that catalyzes peroxynitrite detoxification.

ABSTRACT: Nitrobindins (Nbs), constituting a heme-protein family spanning from bacteria to Homo sapiens, display an all-?-barrel structural organization. Human Nb has been described as a domain of the nuclear protein named THAP4, whose physiological function is still unknown. We report the first evidence of the heme-Fe(III)-based detoxification of peroxynitrite by the all-?-barrel C-terminal Nb-like domain of THAP4. Ferric human Nb (Nb(III)) catalyzes the conversion of peroxynitrite to NO3- and impairs the nitration of free l-tyrosine. The rate of human Nb(III)-mediated scavenging of peroxynitrite is similar to those of all-?-helical horse heart and sperm whale myoglobin and human hemoglobin, generally taken as the prototypes of all-?-helical heme-proteins. The heme-Fe(III) reactivity of all-?-barrel human Nb(III) and all-?-helical prototypical heme-proteins possibly reflects the out-to-in-plane transition of the heme-Fe(III)-atom preceding peroxynitrite binding. Human Nb(III) not only catalyzes the detoxification of peroxynitrite but also binds NO, possibly representing a target of reactive nitrogen species.

SUBMITTER: De Simone G

PROVIDER: S-EPMC6275384 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Human nitrobindin: the first example of an all-β-barrel ferric heme-protein that catalyzes peroxynitrite detoxification.

De Simone Giovanna G di Masi Alessandra A Polticelli Fabio F Ascenzi Paolo P

FEBS open bio 20181109 12

Nitrobindins (Nbs), constituting a heme-protein family spanning from bacteria to <i>Homo sapiens</i>, display an all-β-barrel structural organization. Human Nb has been described as a domain of the nuclear protein named THAP4, whose physiological function is still unknown. We report the first evidence of the heme-Fe(III)-based detoxification of peroxynitrite by the all-β-barrel <i>C</i>-terminal Nb-like domain of THAP4. Ferric human Nb (Nb(III)) catalyzes the conversion of peroxynitrite to NO 3 ...[more]

PMID: 30524950

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Project description:Human serum albumin (HSA) participates in heme scavenging; in turn, heme endows HSA with myoglobin-like reactivity and spectroscopic properties. Here, the allosteric effect of ibuprofen on peroxynitrite isomerization to NO(3)(-) catalyzed by ferric human serum heme-albumin (HSA-heme-Fe(III)) is reported. Data were obtained at 22.0 degrees C. HSA-heme-Fe(III) catalyzes peroxynitrite isomerization in the absence and presence of CO(2); the values of the second order catalytic rate constant (k(on)) are 4.1 x 10(5) and 4.5 x 10(5) m(-1) s(-1), respectively. Moreover, HSA-heme-Fe(III) prevents peroxynitrite-mediated nitration of free added l-tyrosine. The pH dependence of k(on) (pK(a) = 6.9) suggests that peroxynitrous acid reacts preferentially with the heme-Fe(III) atom, in the absence and presence of CO(2). The HSA-heme-Fe(III)-catalyzed isomerization of peroxynitrite has been ascribed to the reactive pentacoordinated heme-Fe(III) atom. In the absence and presence of CO(2), ibuprofen impairs dose-dependently peroxynitrite isomerization by HSA-heme-Fe(III) and facilitates the nitration of free added l-tyrosine; the value of the dissociation equilibrium constant for ibuprofen binding to HSA-heme-Fe(III) (L) ranges between 7.7 x 10(-4) and 9.7 x 10(-4) m. Under conditions where [ibuprofen] is >>L, the kinetics of HSA-heme-Fe(III)-catalyzed isomerization of peroxynitrite is superimposable to that obtained in the absence of HSA-heme-Fe(III) or in the presence of non-catalytic HSA-heme-Fe(III)-cyanide complex and HSA. Ibuprofen binding impairs allosterically peroxynitrite isomerization by HSA-heme-Fe(III), inducing the hexacoordination of the heme-Fe(III) atom. These results represent the first evidence for peroxynitrite isomerization by HSA-heme-Fe(III), highlighting the allosteric modulation of HSA-heme-Fe(III) reactivity by heterotropic interaction(s), and outlining the role of drugs in modulating HSA functions. The present results could be relevant for the drug-dependent protective role of HSA-heme-Fe(III) in vivo.

Dataset Information

Human nitrobindin: the first example of an all-?-barrel ferric heme-protein that catalyzes peroxynitrite detoxification.

Publications

Human nitrobindin: the first example of an all-β-barrel ferric heme-protein that catalyzes peroxynitrite detoxification.

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