Nitric oxide dioxygenase: An enzymic function for flavohemoglobin

Gardner, Paul R.; Gardner, Anne M.; Martin, Lori A.; Salzman, Andrew L.

doi:10.1016/s0891-5849(98)90180-0

Cited by 108 publications

(173 citation statements)

References 11 publications

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“…The antimicrobial effect of NO is documented in a number of infectious diseases [7] and appears to be due to a direct reaction of NO with a variety of targets and to the formation of peroxynitrite ONOO - [8] by reaction with O -2 · . In the presence of O 2 , flavohaemoglobins are believed to efficiently scavenge NO by acting as NO-dioxygenases [12], although the in vivo significance of this reaction has been very recently challenged [25]. Under microaerobic conditions, an alternative NO-detoxifying role may be played by ATFs, NADH-dependent enzymes recently discovered to be endowed with a cyanideinsensitive NO-reductase activity [13 -16].…”

Section: Discussionmentioning

confidence: 99%

“…NO can be also metabolized aerobically by flavohaemoglobin [11,12], a ubiquitous enzyme catalysing the reaction: 2NO + 2O 2 + NAD(P)H AE 2NO 3 -+ NAD(P) + + H + The A-type flavoproteins (ATFs) have also been reported to be characterised by NO reductase activity [13 -16]. ATFs are NADH-dependent enzymes containing a nonhaem di-iron active site [17], and are preferentially expressed (e. g. in Escherichia coli) under microaerobic conditions and in response to exposure to NO or NO-related species [18,19].…”

Section: Research Articlementioning

confidence: 99%

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Trichomonas vaginalis degrades nitric oxide and expresses a flavorubredoxin-like protein: a new pathogenic mechanism?

Sarti

Fiori

Forte

et al. 2004

Cellular and Molecular Life Sciences (CMLS)

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Besides possessing many physiological roles, nitric oxide (NO) produced by the immune system in infectious diseases has antimicrobial effects. Trichomoniasis, the most widespread non-viral sexually transmitted disease caused by the microaerophilic protist Trichomonas vaginalis, often evolves into a chronic infection, with the parasite able to survive in the microaerobic, NO-enriched vaginal environment. We relate this property to the finding that T. vaginalis degrades NO under anaerobic conditions, as assessed amperometrically. This activity, which is maximal (133 +/- 41 nmol NO/10(8) cells per minute at 20 degrees C) at low NO concentrations (< or = 1.2 microM), was found to be: (i) NADH dependent, (ii) cyanide insensitive and (iii) inhibited by O(2). These features are consistent with those of the Escherichia coli A-type flavoprotein (ATF), recently discovered to be endowed with NO reductase activity. Using antibodies against the ATF from E. coli, a protein band was immunodetected in the parasite grown in a standard medium. If confirmed, the expression of an ATF in eukaryotes suggests that the genes coding for ATFs were transferred during evolution from anaerobic Prokarya to pathogenic protists, to increase their fitness for the microaerobic, parasitic life style. Thus the demonstration of an ATF in T. vaginalis would appear relevant to both pathology and evolutionary biology. Interestingly, genomic analysis has recently demonstrated that Giardia intestinalis and other pathogenic protists have genes coding for ATFs.

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Section: Discussionmentioning

confidence: 99%

Section: Research Articlementioning

confidence: 99%

Trichomonas vaginalis degrades nitric oxide and expresses a flavorubredoxin-like protein: a new pathogenic mechanism?

Sarti

Fiori

Forte

et al. 2004

Cellular and Molecular Life Sciences (CMLS)

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“…The source of NO remains to be identified, as a transient induction of the FhpA in A. fumigatus was also observed in the absence of external NO 3 − und NO 2 − ). Flavohemoglobins, like FhpA have NO dioxygenase activity and are generally regarded as part of an NO detoxification system catalyzing the NADPH-dependant oxidation of toxic NO to NO 3 − (Gardner et al 1998). Respective null mutants showed indeed NO-sensitive phenotypes in A. nidulans and A. fumigatus (Schinko et al 2010;Lapp et al 2014).…”

Section: Oxidative and Nitrosative Stress Defenses During Oxygen Limimentioning

confidence: 99%

Insights into the cellular responses to hypoxia in filamentous fungi

2015

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Most eukaryotes require molecular oxygen for growth. In general, oxygen is the terminal electron acceptor of the respiratory chain and represents an important substrate for the biosynthesis of cellular compounds. However, in their natural environment, such as soil, and also during the infection, filamentous fungi are confronted with low levels of atmospheric oxygen. Transcriptome and proteome studies on the hypoxic response of filamentous fungi revealed significant alteration of the gene expression and protein synthesis upon hypoxia. These analyses discovered not only common but also species-specific responses to hypoxia with regard to NAD(+) regeneration systems and other metabolic pathways. A surprising outcome was that the induction of oxidative and nitrosative stress defenses during oxygen limitation represents a general trait of adaptation to hypoxia in many fungi. The interplay of these different stress responses is poorly understood, but recent studies have shown that adaptation to hypoxia contributes to virulence of pathogenic fungi. In this review, results on metabolic changes of filamentous fungi during adaptation to hypoxia are summarized and discussed.

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“…In microorganisms, NO is metabolized by NO dioxygenase, a flavohemoglobin possessing NAD(P)Hdependent enzymatic activity (Gardner et al 1998(Gardner et al , 2000. In animal tissues, dioxygen-dependent metabolism of NO is likely connected with heme-and flavoprotein (Gardner et al 2001); however, a particular Hb and flavin has not been identified.…”

Section: Introductionmentioning

confidence: 99%

NADH-dependent metabolism of nitric oxide in alfalfa root cultures expressing barley hemoglobin

Igamberdiev

Seregélyes

Manac′h

et al. 2004

Planta

138

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Transgenic alfalfa ( Medicago sativa L.) root cultures expressing sense and antisense barley ( Hordeum vulgare L.) hemoglobin were examined for their ability to metabolize NO. Extracts from lines overexpressing hemoglobin had approximately twice the NO conversion rate of either control or antisense lines under normoxic conditions. Only the control line showed a significant increase in the rate of NO degradation when placed under anaerobic conditions. The decline in NO was dependent on the presence of reduced pyridine nucleotide, with the NADH-dependent rate being about 2.5 times faster than the NADPH-dependent rate. Most of the activity was found in the cytosolic fraction of the extracts, while only small amounts were found in the cell wall, mitochondria, and 105,000- g membrane fraction. The NADH-dependent NO conversion exhibited a broad pH optimum in the range 7-8 and a strong affinity to NADH and NADPH ( K(m) 3 microM for both). It was sensitive to diphenylene iodonium, an inhibitor of flavoproteins. The activity was strongly reduced by applying antibodies raised against recombinant barley hemoglobin. Extracts of Escherichia coli overexpressing barley hemoglobin showed a 4-fold higher rate of NO metabolism as compared to non-transformed cells. The NADH/NAD and NADPH/NADP ratios were higher in lines underexpressing hemoglobin, indicating that the presence of hemoglobin has an effect on these ratios. They were increased under hypoxia and antimycin A treatment. Alfalfa root extracts exhibited methemoglobin reductase activity, using either cytochrome c or recombinant barley hemoglobin as substrates. There was a correspondence between NO degradation and nitrate formation. The activity was eluted from a Superose 12 column as a single peak with molecular weight of 35+/-4 kDa, which corresponds to the size of the hemoglobin dimer. The results are consistent with an NO dioxygenase-like activity, with hemoglobin acting in concert with a flavoprotein, to metabolize NO to nitrate utilizing NADH as the electron donor.

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Nitric oxide dioxygenase: An enzymic function for flavohemoglobin

Cited by 108 publications

References 11 publications

Trichomonas vaginalis degrades nitric oxide and expresses a flavorubredoxin-like protein: a new pathogenic mechanism?

Trichomonas vaginalis degrades nitric oxide and expresses a flavorubredoxin-like protein: a new pathogenic mechanism?

Insights into the cellular responses to hypoxia in filamentous fungi

NADH-dependent metabolism of nitric oxide in alfalfa root cultures expressing barley hemoglobin

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