Diversity of Globin Function: Enzymatic, Transport, Storage, and Sensing

Vinogradov, Serge N.; Moëns, Luc

doi:10.1074/jbc.r700029200

Cited by 178 publications

(144 citation statements)

References 48 publications

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“…As THB8 interacts with NO, THB8-knockdown strains cannot grow hypoxically when NO is scavenged by PTIO, and NO itself can trigger transcript accumulation of otherwise anaerobically induced genes, we suggest that THB8 participates in an NO-dependent signaling pathway operative upon oxygen limitation in C. reinhardtii. Reactions of Hbs with the NO molecule are manifold and have roles in NO scavenging, fermentation, and signaling (4,21,30,38). The THB8 protein might trigger responses upon its reaction with NO and could be a yet unclassified mediator between the NO signal and the cellular responses reported here.…”

Section: Resultsmentioning

confidence: 99%

“…3B), also speaking for the signal being due to S-nitrosothiol formation (20). Most heme-catalyzed reactions resulting in S-nitrosothiol formation occur in the presence of oxygen, usually upon reactions of oxy-ferrous Hb or Mb (4,19,21). However, the reaction of ferric human Hb with NO and subsequent S-nitrosothiol formation is possible, too (22), and a similar mechanism might be operable in recombinant THB8.…”

Section: Resultsmentioning

confidence: 99%

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Hypoxic survival requires a 2-on-2 hemoglobin in a process involving nitric oxide

Hemschemeier

Düner

Casero

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Hemoglobins are recognized today as a diverse family of proteins present in all kingdoms of life and performing multiple reactions beyond O 2 chemistry. The physiological roles of most hemoglobins remain elusive. Here, we show that a 2-on-2 ("truncated") hemoglobin, termed THB8, is required for hypoxic growth and the expression of anaerobic genes in Chlamydomonas reinhardtii. THB8 is 1 of 12 2-on-2 hemoglobins in this species. It belongs to a subclass within the 2-on-2 hemoglobin class I family whose members feature a remarkable variety of domain arrangements and lengths. Posttranscriptional silencing of the THB8 gene results in the misregulation of several genes and a growth defect under hypoxic conditions. The latter is intensified in the presence of an NO scavenger, which also impairs growth of wild-type cells. As recombinant THB8 furthermore reacts with NO, the results of this study indicate that THB8 is part of an NO-dependent signaling pathway.gene expression | hypoxia

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Hypoxic survival requires a 2-on-2 hemoglobin in a process involving nitric oxide

Hemschemeier

Düner

Casero

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…The functions of these proteins differ significantly, ranging from oxygen storage and transport, NO dioxygenation, and nitrite reduction to sensing intracellular levels of diatomic gases for transcriptional regulation and chemotaxis (2). The central chemical events for these functions are movement of ligands into the distal portion of the heme pocket, internal bond formation with the heme iron, and electrostatic stabilization or steric hindrance of the bound ligand by surrounding active site amino acids.…”

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confidence: 99%

Blocking the Gate to Ligand Entry in Human Hemoglobin

Birukou

Soman

Olson

2011

Journal of Biological Chemistry

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His(E7) to Trp replacements inHemoglobins represent a very diverse protein family with members occurring in all six kingdoms of life (1). The functions of these proteins differ significantly, ranging from oxygen storage and transport, NO dioxygenation, and nitrite reduction to sensing intracellular levels of diatomic gases for transcriptional regulation and chemotaxis (2). The central chemical events for these functions are movement of ligands into the distal portion of the heme pocket, internal bond formation with the heme iron, and electrostatic stabilization or steric hindrance of the bound ligand by surrounding active site amino acids. Although the quantum mechanical details of bond formation remain to be resolved, there is general agreement on the biophysical mechanisms governing steric hindrance and hydrogen bonding between amino acid side chains and the bound ligand (3-10). In contrast, the pathways for ligands movement from solvent through the protein and into the active site are still under debate.As recently reviewed by Elber (11), molecular dynamics simulations and other computational approaches have almost uniformly suggested that there are multiple routes for ligand entry into and escape from the active sites of hemoglobins and myoglobins (12-27). Many of these pathways are coincident with apolar cavities, which have been identified as xenon docking sites (16, 17, 28 -30). However, as also pointed out by Elber (11), there is little or no direct experimental evidence in support of multiple pathways (31, 32). In the cases of mammalian myoglobins, human hemoglobin, and HbI from Scapharca inaequivalvis, almost all of the experimental evidence suggests that Ն75% of ligands enter and exit the distal pocket through a transient channel between the heme propionates, which is produced by outward rotation of the distal histidine (His(E7)). 2Although ligands do migrate into internal cavities immediately after photodissociation, they appear to return to the distal pocket and escape through the E7 gate (33-41).The structures of the active sites and the E7 channels in Mb and the subunits of human HbA are very similar, and thus analogous mechanisms for ligand binding are inferred. Until very recently, there were little experimental and computational data regarding the pathways of ligand migration into HbA. Mouawad et al. (15) observed the formation of transient cavities in the ␣ and ␤ subunits of human HbA during simulations of the T to R conformational change and postulated these cavities could allow ligands to diffuse through the globin matrix. Sottini et al. (16,17) used molecular modeling approaches to find potential xenon binding cavities in human HbA and suggested that ligands could use these apolar voids as pathways to enter or escape the active site. Savino et al. (30) reported crystal structures of Tyr(B10)/Gln(E7) deoxyHbA with xenon atoms partially occupying the sites identified in molecular modeling experiments. Thus, if only the theoretical and structural litera-* This work was supported, in whole or...

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“…Even though leukocyte peroxi-dases are believed to play a dominant role in the consumption of NO-derived oxidants at sites of inflammation (as a part of host defenses against oxidative tissue injury), ferrous oxygenated Hb and Mb (HbO 2 and MbO 2 , respectively) indeed are involved in the major pathway for NO removal from the vascular compartment and in the protection of mitochondrial respiration (4,6,10,12,14,26), respectively. Hereafter, we deal with these reactions under aerobic and anaerobic conditions, discriminating between reducing environmental conditions and oxidative conditions.…”

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confidence: 99%

“…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)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15).…”

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confidence: 99%

Catalytic peroxidation of nitrogen monoxide and peroxynitrite by globins

et al. 2008

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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).

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Diversity of Globin Function: Enzymatic, Transport, Storage, and Sensing

Cited by 178 publications

References 48 publications

Hypoxic survival requires a 2-on-2 hemoglobin in a process involving nitric oxide

Hypoxic survival requires a 2-on-2 hemoglobin in a process involving nitric oxide

Blocking the Gate to Ligand Entry in Human Hemoglobin

Catalytic peroxidation of nitrogen monoxide and peroxynitrite by globins

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