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{{enzyme
{{infobox enzyme
| Name = nitric oxide dioxygenase
| Name = nitric oxide dioxygenase
| EC_number = 1.14.12.17
| EC_number = 1.14.12.17
| CAS_number = 214466-78-1
| CAS_number = 214466-78-1
⚫
| GO_code = 0008941
| IUBMB_EC_number = 1/14/12/17
| image = PDB 1gvh.jpg
⚫
| GO_code = 0008941
| image = PDB 1gvh.jpg
| width =
⚫
| caption = ''[[Escherichia coli|E. coli]]'' flavohemoglobin/NOD structure. ''green'' = reductase domain, ''blue'' = hemoglobin domain.<ref name="pmid11964402">{{PDB|1gvh}}; {{cite journal |vauthors=Ilari A, Bonamore A, Farina A, Johnson KA, Boffi A | title = The X-ray structure of ferric ''Escherichia coli'' flavohemoglobin reveals an unexpected geometry of the distal heme pocket | journal = J. Biol. Chem. | volume = 277 | issue = 26 | pages = 23725–32 |date=June 2002 | pmid = 11964402 | doi = 10.1074/jbc.M202228200 | doi-access = free }}</ref>
| width =
⚫
| caption = ''[[Escherichia coli|E. coli]]'' flavohemoglobin/NOD structure. ''green'' = reductase domain, ''blue'' = hemoglobin domain.<ref name="pmid11964402">{{PDB|1gvh}}; {{cite journal | author = Ilari A, Bonamore A, Farina A, Johnson KA, Boffi A | title = The X-ray structure of ferric ''Escherichia coli'' flavohemoglobin reveals an unexpected geometry of the distal heme pocket | journal = J. Biol. Chem. | volume = 277 | issue = 26 | pages = 23725–32 | year = 2002 | month = June | pmid = 11964402 | doi = 10.1074/jbc.M202228200 }}</ref>
}}
}}
'''Nitric oxide dioxygenase''' ({{EC number|1.14.12.17}}) is an [[enzyme]] that catalyzes the conversion of [[nitric oxide]] (NO) to [[nitrate]] (NO{{su|b=3|p=−}})
'''Nitric oxide dioxygenase''' ({{EC number|1.14.12.17}}) is an [[enzyme]] that catalyzes the conversion of [[nitric oxide]] (NO) to [[nitrate]] (NO{{su|b=3|p=−}})
<ref name="pmid22343413">{{cite journal | author = Forrester MT, Foster MW | title = Protection from nitrosative stress: a central role for microbial flavohemoglobin | journal = Free Rad. Biol. Med. | volume = 52 | issue = 9 = |pages = 1620-33 | year = 2012 | month = May | pmid = 22343413 | doi = 10.1016/j.freeradbiomed.2012.01.028}}</ref>. The net reaction for the reaction catalyzed by nitric oxide dioxygenase is shown below:
.<ref name="pmid22343413">{{cite journal |vauthors=Forrester MT, Foster MW | title = Protection from nitrosative stress: a central role for microbial flavohemoglobin | journal = Free Radic. Biol. Med. | volume = 52 | issue = 9 = |pages = 1620–33 |date=May 2012 | pmid = 22343413 | doi = 10.1016/j.freeradbiomed.2012.01.028}}</ref> The net reaction for the reaction catalyzed by nitric oxide dioxygenase is shown below:


* 2NO + 2O<sub>2</sub> + [[Nicotinamide adenine dinucleotide phosphate|NAD(P)H]] → 2NO<sub>3</sub><sup>-</sup> + NAD(P)<sup>+</sup> + H<sup>+</sup>
* 2NO + 2O<sub>2</sub> + [[Nicotinamide adenine dinucleotide phosphate|NAD(P)H]] → 2NO<sub>3</sub><sup>−</sup> + NAD(P)<sup>+</sup> + H<sup>+</sup>


Nitric oxide is a ubiquitous small molecule that is integrated in a wide variety of physiological processes including smooth muscle vasodilation, platelet disaggregation, neurotransmission, and immune response to bacterial infection.<ref name="pmid1852778">{{cite journal | author = Moncada S, Palmer RM, Higgs EA | title = Nitric oxide: physiology, pathophysiology, and pharmacology | journal = Pharmacol. Rev. | volume = 43 | issue = 2 | pages = 109–42 | year = 1991 | month = June | pmid = 1852778 | doi = }}</ref><ref name="pmid15378046">{{cite journal | author = Fang FC | title = Antimicrobial reactive oxygen and nitrogen species: concepts and controversies | journal = Nat. Rev. Microbiol. | volume = 2 | issue = 10 | pages = 820–32 | year = 2004 | month = October | pmid = 15378046 | doi = 10.1038/nrmicro1004 }}</ref> Overproduction of this signaling molecule can be lethal to cells by poisoning cellular energy production. The most sensitive targets of NO are [[aconitase]], an enzyme that catalyzes the isomerization of [[citrate]] to [[isocitrate]] in the citric acid cycle, and [[cytochrome oxidase]], the last enzyme in the respiratory electron transport chain of mitochondria.<ref name="pmid9312115">{{cite journal | author = Gardner PR, Costantino G, Szabó C, Salzman AL | title = Nitric oxide sensitivity of the aconitases | journal = J. Biol. Chem. | volume = 272 | issue = 40 | pages = 25071–6 | year = 1997 | month = October | pmid = 9312115 | doi = 10.1074/jbc.272.40.25071}}</ref> Additionally NO, with its lone radical on the nitrogen atom, is implicated in a number of secondary mechanisms of toxicity, including [[catalase]] inhibition (resulting in hydrogen peroxide toxicity), Fe-S center iron liberation, and the formation of dinitosyl-iron complexes.
Nitric oxide is a ubiquitous small molecule that is integrated in a wide variety of physiological processes including smooth muscle vasodilation, platelet disaggregation, neurotransmission, and immune response to bacterial infection.<ref name="pmid1852778">{{cite journal |vauthors=Moncada S, Palmer RM, Higgs EA | title = Nitric oxide: physiology, pathophysiology, and pharmacology | journal = Pharmacol. Rev. | volume = 43 | issue = 2 | pages = 109–42 |date=June 1991 | pmid = 1852778 }}</ref><ref name="pmid15378046">{{cite journal | author = Fang FC | title = Antimicrobial reactive oxygen and nitrogen species: concepts and controversies | journal = Nat. Rev. Microbiol. | volume = 2 | issue = 10 | pages = 820–32 |date=October 2004 | pmid = 15378046 | doi = 10.1038/nrmicro1004 | s2cid = 11063073 }}</ref> Overproduction of this signaling molecule can be lethal to cells by poisoning cellular energy production. The most sensitive targets of NO are [[aconitase]], an enzyme that catalyzes the isomerization of [[citrate]] to [[isocitrate]] in the citric acid cycle, and [[cytochrome oxidase]], the last enzyme in the respiratory electron transport chain of mitochondria.<ref name="pmid9312115">{{cite journal |vauthors=Gardner PR, Costantino G, Szabó C, Salzman AL | title = Nitric oxide sensitivity of the aconitases | journal = J. Biol. Chem. | volume = 272 | issue = 40 | pages = 25071–6 |date=October 1997 | pmid = 9312115 | doi = 10.1074/jbc.272.40.25071| doi-access = free }}</ref> Additionally NO, with its lone radical on the nitrogen atom, is implicated in a number of secondary mechanisms of toxicity, including [[catalase]] inhibition (resulting in hydrogen peroxide toxicity), Fe-S center iron liberation, and the formation of dinitosyl-iron complexes.


Due to the potential lethality of NO, cells benefitted greatly from the evolution of an enzyme capable of catalyzing the conversion of toxic NO to nitrate.
Due to the potential lethality of NO, cells benefitted greatly from the evolution of an enzyme capable of catalyzing the conversion of toxic NO to nitrate.
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== Reaction mechanism ==
== Reaction mechanism ==


The mechanism of action has still not been entirely deduced, however, the leading theory suggests that the conversion is carried out through a series of redox reactions involving iron centers as shown in the series of half reactions below:<ref name="Gardner_1998">{{cite journal | author = Gardner PR, Gardner AM, Martin LA, Salzman AL | title = Nitric oxide dioxygenase: an enzymic function for flavohemoglobin | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 95 | issue = 18 | pages = 10378–83 | year = 1998 | month = September | pmid = 9724711 | pmc = 27902 | doi = 10.1073/pnas.95.18.10378| url = }}</ref>
The mechanism of action has still not been entirely deduced, however, the leading theory suggests that the conversion is carried out through a series of redox reactions involving iron centers as shown in the series of half reactions below:<ref name="Gardner_1998">{{cite journal |vauthors=Gardner PR, Gardner AM, Martin LA, Salzman AL | title = Nitric oxide dioxygenase: an enzymic function for flavohemoglobin | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 95 | issue = 18 | pages = 10378–83 |date=September 1998 | pmid = 9724711 | pmc = 27902 | doi = 10.1073/pnas.95.18.10378| doi-access = free }}</ref>


{| class="wikitable"
{| class="wikitable"
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| Iron Reduction 2 || FADH + Fe<sup>3+</sup> → FAD + Fe<sup>2+</sup> + H<sup>+</sup>
| Iron Reduction 2 || FADH + Fe<sup>3+</sup> → FAD + Fe<sup>2+</sup> + H<sup>+</sup>
|-
|-
| O<sub>2</sub> Binding || Fe<sup>2+</sup> + O<sub>2</sub> → Fe<sup>3+</sup>(O<sub>2</sub><sup>-</sup>)
| O<sub>2</sub> Binding || Fe<sup>2+</sup> + O<sub>2</sub> → Fe<sup>3+</sup>(O<sub>2</sub><sup>−</sup>)
|-
|-
| NO dioxygenation || Fe<sup>3+</sup>(O<sub>2</sub><sup>-</sup>) + NO → Fe<sup>3+</sup> + NO<sub>3</sub><sup>-</sup>
| NO dioxygenation || Fe<sup>3+</sup>(O<sub>2</sub><sup>−</sup>) + NO → Fe<sup>3+</sup> + NO<sub>3</sub><sup>−</sup>
|}
|}


Another theory developed more recently (2009) suggests that a NO dioxygenase activity could also proceed through phenolic nitration via a putative heme-peroxynitrite intermediate.<ref name="pmid19627146">{{cite journal | author = Schopfer MP, Mondal B, Lee DH, Sarjeant AA, Karlin KD | title = Heme/O2/*NO nitric oxide dioxygenase (NOD) reactivity: phenolic nitration via a putative heme-peroxynitrite intermediate | journal = J. Am. Chem. Soc. | volume = 131 | issue = 32 | pages = 11304–5 | year = 2009 | month = August | pmid = 19627146 | pmc = 2747244 | doi = 10.1021/ja904832j }}</ref>
Another theory developed more recently (2009) suggests that a NO dioxygenase activity could also proceed through phenolic nitration via a putative heme-peroxynitrite intermediate.<ref name="pmid19627146">{{cite journal |vauthors=Schopfer MP, Mondal B, Lee DH, Sarjeant AA, Karlin KD | title = Heme/O2/*NO nitric oxide dioxygenase (NOD) reactivity: phenolic nitration via a putative heme-peroxynitrite intermediate | journal = J. Am. Chem. Soc. | volume = 131 | issue = 32 | pages = 11304–5 |date=August 2009 | pmid = 19627146 | pmc = 2747244 | doi = 10.1021/ja904832j }}</ref>


The most well studied NO dioxygenase is flavohemoglobin (flavoHb), shown to the right:
The most well studied NO dioxygenase is flavohemoglobin (flavoHb), shown to the right:
<!-- Deleted image removed: [[File: Nitric Oxide Dioxygenase 1.jpg|thumb|right| alt=A cartoon depiction of Nitric Oxide Dioxygenase showing enzyme with FAD.| Flavohemoglobin, a known Nitric Oxide Dioxygenase – Yellow is FAD, Turquoise pocket surrounding FAD is NAD(P)H binding site, area above white (heme) is entry site for NO and exit site for NO<sub>3</sub><sup>-</sup>.]] -->
<!-- Deleted image removed: [[File: Nitric Oxide Dioxygenase 1.jpg|thumb|right| alt=A cartoon depiction of Nitric Oxide Dioxygenase showing enzyme with FAD.| Flavohemoglobin, a known Nitric Oxide Dioxygenase – Yellow is FAD, Turquoise pocket surrounding FAD is NAD(P)H binding site, area above white (heme) is entry site for NO and exit site for NO<sub>3</sub><sup>−</sup>.]] -->
Studies have shown that flavohemoglobins are induced by NO, nitrite, nitrate, and NO-releasing agents in various bacteria and fungi.<ref name="Gardner_1998"/><ref name="Gardner_2000">{{cite journal | author = Gardner PR, Gardner AM, Martin LA, Dou Y, Li T, Olson JS, Zhu H, Riggs AF | title = Nitric-oxide dioxygenase activity and function of flavohemoglobins. sensitivity to nitric oxide and carbon monoxide inhibition | journal = J. Biol. Chem. | volume = 275 | issue = 41 | pages = 31581–7 | year = 2000 | month = October | pmid = 10922365 | doi = 10.1074/jbc.M004141200 | url = }}</ref> Additionally, flavoHbs have been shown to protect bacteria, yeast, and Dictyostelium discoideum against growth inhibition and damage mediated via NO.<ref name="Gardner_2000"/><ref>{{cite journal | author = Hausladen, A., Gow, A. J., and Stamler, J. S. | year = 2001 | title = Flavohemoglobin denitrosylase catalyzes the reaction of a nitroxyl equivalent with molecular oxygen | journal = PNAS | volume = 98 | pages = 10108&ndash;12 | doi = 10.1073/pnas.181199698 | issue = 18 }}</ref><ref name="pmid11139382">{{cite journal | author = Mills CE, Sedelnikova S, Søballe B, Hughes MN, Poole RK | title = Escherichia coli flavohaemoglobin (Hmp) with equistoichiometric FAD and haem contents has a low affinity for dioxygen in the absence or presence of nitric oxide | journal = Biochem. J. | volume = 353 | issue = Pt 2 | pages = 207–13 | year = 2001 | month = January | pmid = 11139382 | pmc = 1221560 | doi = }}</ref>
Studies have shown that flavohemoglobins are induced by NO, nitrite, nitrate, and NO-releasing agents in various bacteria and fungi.<ref name="Gardner_1998"/><ref name="Gardner_2000">{{cite journal |vauthors=Gardner PR, Gardner AM, Martin LA, Dou Y, Li T, Olson JS, Zhu H, Riggs AF | title = Nitric-oxide dioxygenase activity and function of flavohemoglobins. sensitivity to nitric oxide and carbon monoxide inhibition | journal = J. Biol. Chem. | volume = 275 | issue = 41 | pages = 31581–7 |date=October 2000 | pmid = 10922365 | doi = 10.1074/jbc.M004141200 | doi-access = free }}</ref> Additionally, flavoHbs have been shown to protect bacteria, yeast, and Dictyostelium discoideum against growth inhibition and damage mediated via NO.<ref name="Gardner_2000"/><ref>{{cite journal | vauthors = Hausladen A, Gow AJ, Stamler JS | year = 2001 | title = Flavohemoglobin denitrosylase catalyzes the reaction of a nitroxyl equivalent with molecular oxygen | journal = PNAS | volume = 98 | pages = 10108&ndash;12 | doi = 10.1073/pnas.181199698 | issue = 18 | pmid=11517313 | pmc=56923| doi-access = free }}</ref><ref name="pmid11139382">{{cite journal |vauthors=Mills CE, Sedelnikova S, Søballe B, Hughes MN, Poole RK | title = Escherichia coli flavohaemoglobin (Hmp) with equistoichiometric FAD and haem contents has a low affinity for dioxygen in the absence or presence of nitric oxide | journal = Biochem. J. | volume = 353 | issue = Pt 2 | pages = 207–13 |date=January 2001 | pmid = 11139382 | pmc = 1221560 | doi = 10.1042/0264-6021:3530207}}</ref>


== Discovery ==
== Discovery ==


Nitric oxide dioxygenase was discovered, and first reported in 1998, as an inducible O<sub>2</sub>-dependent enzymatic activity that protected bacteria against [[nitric oxide]] toxicity.<ref>{{cite journal | author = Gardner PR, Costantino G, Salzman AL | year = 1998 | title = Constitutive and adaptive detoxification of nitric oxide in ''Escherichia coli''. Role of nitric-oxide dioxygenase in the protection of aconitase | journal = J. Biol. Chem. | volume = 273 | pages = 26528&ndash;33 | pmid = 9756889 | doi = 10.1074/jbc.273.41.26528 | issue = 41 }}</ref> The enzyme was identified with the ''[[Escherichia coli|E. coli]]'' flavohemoglobin.<ref>{{cite journal | author = Gardner PR, Gardner AM, Martin LA, Salzman AL | year = 1998 | title = Nitric oxide dioxygenase: an enzymic function for flavohemoglobin | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 95 | pages = 10378&ndash;83 | pmid = 9724711 | doi = 10.1073/pnas.95.18.10378 | issue = 18 | pmc = 27902 }}</ref>
Nitric oxide dioxygenase was discovered, and first reported in 1998, as an inducible O<sub>2</sub>-dependent enzymatic activity that protected bacteria against [[nitric oxide]] toxicity.<ref>{{cite journal |vauthors=Gardner PR, Costantino G, Salzman AL | year = 1998 | title = Constitutive and adaptive detoxification of nitric oxide in ''Escherichia coli''. Role of nitric-oxide dioxygenase in the protection of aconitase | journal = J. Biol. Chem. | volume = 273 | pages = 26528&ndash;33 | pmid = 9756889 | doi = 10.1074/jbc.273.41.26528 | issue = 41 | doi-access = free }}</ref> The enzyme was identified with the ''[[Escherichia coli|E. coli]]'' flavohemoglobin.<ref>{{cite journal |vauthors=Gardner PR, Gardner AM, Martin LA, Salzman AL | year = 1998 | title = Nitric oxide dioxygenase: an enzymic function for flavohemoglobin | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 95 | pages = 10378&ndash;83 | pmid = 9724711 | doi = 10.1073/pnas.95.18.10378 | issue = 18 | pmc = 27902 | doi-access = free }}</ref>


More recently, another protein has been identified as a NO dioxygenase - rhodobacter sphaeroides haem protein (SHP), a novel cytochrome with NO dioxygenase activity.<ref name="Li_2008">{{cite journal | author = Li BR, Anderson JL, Mowat CG, Miles CS, Reid GA, Chapman SK | title = Rhodobacter sphaeroides haem protein: a novel cytochrome with nitric oxide dioxygenase activity | journal = Biochem. Soc. Trans. | volume = 36 | issue = Pt 5 | pages = 992–5 | year = 2008 | month = October | pmid = 18793176 | doi = 10.1042/BST0360992 }}</ref><ref name="pmid9171397">{{cite journal | author = Bartnikas TB, Tosques IE, Laratta WP, Shi J, Shapleigh JP | title = Characterization of the nitric oxide reductase-encoding region in Rhodobacter sphaeroides 2.4.3 | journal = J. Bacteriol. | volume = 179 | issue = 11 | pages = 3534–40 | year = 1997 | month = June | pmid = 9171397 | pmc = 179145 | doi = }}</ref> Although the biological function of SHP has yet to be identified, SHP has been shown, that with oxygen bound, it can react rapidly with nitric oxide to form nitrate.<ref name="Li_2008"/>
More recently, another protein has been identified as a NO dioxygenase - rhodobacter sphaeroides haem protein (SHP), a novel cytochrome with NO dioxygenase activity.<ref name="Li_2008">{{cite journal |vauthors=Li BR, Anderson JL, Mowat CG, Miles CS, Reid GA, Chapman SK | title = Rhodobacter sphaeroides haem protein: a novel cytochrome with nitric oxide dioxygenase activity | journal = Biochem. Soc. Trans. | volume = 36 | issue = Pt 5 | pages = 992–5 |date=October 2008 | pmid = 18793176 | doi = 10.1042/BST0360992 }}</ref><ref name="pmid9171397">{{cite journal |vauthors=Bartnikas TB, Tosques IE, Laratta WP, Shi J, Shapleigh JP | title = Characterization of the nitric oxide reductase-encoding region in Rhodobacter sphaeroides 2.4.3 | journal = J. Bacteriol. | volume = 179 | issue = 11 | pages = 3534–40 |date=June 1997 | pmid = 9171397 | pmc = 179145 | doi = 10.1128/jb.179.11.3534-3540.1997}}</ref> Although the biological function of SHP has yet to be identified, SHP has been shown, that with oxygen bound, it can react rapidly with nitric oxide to form nitrate.<ref name="Li_2008"/>


== Structure and molecular function ==
== Structure and molecular function ==


The flavohemoglobin protein contains two domains: an [[oxidoreductase FAD-binding domain]], and a ''b''-type heme-containing "[[globin]]" domain and optionally an [[oxidoreductase NAD-binding domain]]. The reductase domain supplies an electron to the heme iron to achieve a high rate of catalytic NO dioxygenation.
The flavohemoglobin protein contains two domains: an [[oxidoreductase FAD-binding domain]], and a ''b''-type heme-containing "[[globin]]" domain and optionally an [[oxidoreductase NAD-binding domain]]. The reductase domain supplies an electron to the heme iron to achieve a high rate of catalytic NO dioxygenation.
In addition to numerous flavohemoglobins, many distantly related members of the [[hemoglobin]] superfamily including the muscle [[myoglobin]], the non-symbiotic plant hemoglobin and symbiotic plant [[leghemoglobin]], the neuronal [[neuroglobin]], and the mammalian cytoplasmic [[cytoglobin]]<ref name="pmid20511233">{{cite journal | author = Gardner AM, Cook MR, Gardner PR | title = Nitric-oxide dioxygenase function of human cytoglobin with cellular reductants and in rat hepatocytes | journal = J. Biol. Chem. | volume = 285 | issue = 31 | pages = 23850–7 | year = 2010 | month = July | pmid = 20511233 | doi = 10.1074/jbc.M110.132340 | pmc = 2911317 }}</ref><ref name="pmid19147491">{{cite journal | author = Halligan KE, Jourd'heuil FL, Jourd'heuil D | title = Cytoglobin is expressed in the vasculature and regulates cell respiration and proliferation via nitric oxide dioxygenation | journal = J. Biol. Chem. | volume = 284 | issue = 13 | pages = 8539–47 | year = 2009 | month = March | pmid = 19147491 | pmc = 2659212 | doi = 10.1074/jbc.M808231200 }}</ref> appear to function as nitric oxide dioxygenases (NODs), although the cellular electron donor(s) for many globins have yet to be defined. Electron donors may include ascorbate, cytochrome b<sub>5</sub> or ferredoxin reductase.<ref name="pmid15598505">{{cite journal | author = Gardner PR | title = Nitric oxide dioxygenase function and mechanism of flavohemoglobin, hemoglobin, myoglobin and their associated reductases | journal = J. Inorg. Biochem. | volume = 99 | issue = 1 | pages = 247–66 | year = 2005 | month = January | pmid = 15598505 | doi = 10.1016/j.jinorgbio.2004.10.003 }}</ref> The catalytic NO dioxygenation can be written in its simplest form:
In addition to numerous flavohemoglobins, many distantly related members of the [[hemoglobin]] superfamily including the muscle [[myoglobin]], the non-symbiotic plant hemoglobin and symbiotic plant [[leghemoglobin]], the neuronal [[neuroglobin]], and the mammalian cytoplasmic [[cytoglobin]]<ref name="pmid20511233">{{cite journal |vauthors=Gardner AM, Cook MR, Gardner PR | title = Nitric-oxide dioxygenase function of human cytoglobin with cellular reductants and in rat hepatocytes | journal = J. Biol. Chem. | volume = 285 | issue = 31 | pages = 23850–7 |date=July 2010 | pmid = 20511233 | doi = 10.1074/jbc.M110.132340 | pmc = 2911317 | doi-access = free }}</ref><ref name="pmid19147491">{{cite journal |vauthors=Halligan KE, Jourd'heuil FL, Jourd'heuil D | title = Cytoglobin is expressed in the vasculature and regulates cell respiration and proliferation via nitric oxide dioxygenation | journal = J. Biol. Chem. | volume = 284 | issue = 13 | pages = 8539–47 |date=March 2009 | pmid = 19147491 | pmc = 2659212 | doi = 10.1074/jbc.M808231200 | doi-access = free }}</ref> appear to function as nitric oxide dioxygenases (NODs), although the cellular electron donor(s) for many globins have yet to be defined. Electron donors may include ascorbate, cytochrome b<sub>5</sub> or ferredoxin reductase.<ref name="pmid15598505">{{cite journal | author = Gardner PR | title = Nitric oxide dioxygenase function and mechanism of flavohemoglobin, hemoglobin, myoglobin and their associated reductases | journal = J. Inorg. Biochem. | volume = 99 | issue = 1 | pages = 247–66 |date=January 2005 | pmid = 15598505 | doi = 10.1016/j.jinorgbio.2004.10.003 }}</ref> The catalytic NO dioxygenation can be written in its simplest form:


: NO + O<sub>2</sub> + e<sup>-</sup> <math>\rightleftharpoons</math> NO<sub>3</sub><sup>-</sup>
: NO + O<sub>2</sub> + e<sup>−</sup> <math>\rightleftharpoons</math> NO<sub>3</sub><sup>−</sup>


Catalysis is very efficient. The reported bimolecular NO dioxygenation rate constants range from 2 x 10<sup>7</sup> M<sup>−1</sup>s<sup>−1</sup> for cytoglobin to 3 x 10<sup>9</sup> M<sup>−1</sup>s<sup>−1</sup> for flavohemoglobin, and turnover rates range from 1 to 700 s<sup>−1</sup>. Structure, O<sub>2</sub> binding, and reduction of globins appear optimized for a NO dioxygenase function.
Catalysis is very efficient. The reported bimolecular NO dioxygenation rate constants range from 2 x 10<sup>7</sup> M<sup>−1</sup>s<sup>−1</sup> for cytoglobin to 3 x 10<sup>9</sup> M<sup>−1</sup>s<sup>−1</sup> for flavohemoglobin, and turnover rates range from 1 to 700 s<sup>−1</sup>. Structure, O<sub>2</sub> binding, and reduction of globins appear optimized for a NO dioxygenase function.
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== Physiological function ==
== Physiological function ==
<!-- Deleted image removed: [[File: Nitric Oxide Evolution.jpg|thumb| alt= Microbial flavohemoglobin (Hb domain).| Microbial flavohemoglobin (Hb domain) – Oxygen gas would be activated and bound by the enzyme to dioxygenate NO or other substrates in microbes.]] -->
<!-- Deleted image removed: [[File: Nitric Oxide Evolution.jpg|thumb| alt= Microbial flavohemoglobin (Hb domain).| Microbial flavohemoglobin (Hb domain) – Oxygen gas would be activated and bound by the enzyme to dioxygenate NO or other substrates in microbes.]] -->
Historically, nitric oxide dioxygenase (around 1.8 billion years ago) served to provide the modern day analogue of hemoglobin/myoglobin function for oxygen storage and transport. Gardner et al. (1998) suggested that the first hemoglobin/myoglobin probably functioned as an enzyme utilizing bound ‘activated’ oxygen gas to dioxygenate NO in microbes.<ref name="pmid9724711">{{cite journal | author = Gardner PR, Gardner AM, Martin LA, Salzman AL | title = Nitric oxide dioxygenase: an enzymic function for flavohemoglobin | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 95 | issue = 18 | pages = 10378–83 | year = 1998 | month = September | pmid = 9724711 | pmc = 27902 | doi = 10.1073/pnas.95.18.10378}}</ref>
Historically, nitric oxide dioxygenase (around 1.8 billion years ago) served to provide the modern day analogue of hemoglobin/myoglobin function for oxygen storage and transport. Gardner et al. (1998) suggested that the first hemoglobin/myoglobin probably functioned as an enzyme utilizing bound ‘activated’ oxygen gas to dioxygenate NO in microbes.<ref name="Gardner_1998"/>


The wide diversity of multicellular organisms benefitting from the oxygen storage and transport functions of myoglobin/hemoglobin appeared much later (approximately 0.5 billion years ago).
The wide diversity of multicellular organisms benefitting from the oxygen storage and transport functions of myoglobin/hemoglobin appeared much later (approximately 0.5 billion years ago).
<!-- Deleted image removed: [[File: Nitric oxide Evolution 2 Hemoglobin.jpg|thumb|right| alt= RBC Hemoglobin.| Muscle Myoglobin – This enzyme is much better equipped for oxygen storage, allowing more stable binding of O<sub>2</sub> gas at the heme center.]] -->
<!-- Deleted image removed: [[File: Nitric oxide Evolution 2 Hemoglobin.jpg|thumb|right| alt= RBC Hemoglobin.| Muscle Myoglobin – This enzyme is much better equipped for oxygen storage, allowing more stable binding of O<sub>2</sub> gas at the heme center.]] -->
NODs are now known to serve two important physiological functions in diverse life forms: they prevent NO toxicity (otherwise known as "nitrosative stress") and regulate NO signalling<ref name="pmid22343413">{{cite journal | author = Forrester MT, Foster MW | title = Protection from nitrosative stress: a central role for microbial flavohemoglobin | journal = Free Rad. Biol. Med. | volume = 52 | issue = 9 = |pages = 1620-33 | year = 2012 | month = May | pmid = 22343413 | doi = 10.1016/j.freeradbiomed.2012.01.028}}</ref>. NODs belong to the larger family of well-established free radical and reactive oxygen detoxifying enzymes that includes [[superoxide dismutase]], [[catalase]], and [[peroxidase]].
NODs are now known to serve two important physiological functions in diverse life forms: they prevent NO toxicity (otherwise known as "nitrosative stress") and regulate NO signalling.<ref name="pmid22343413"/> NODs belong to the larger family of well-established free radical and reactive oxygen detoxifying enzymes that includes [[superoxide dismutase]], [[catalase]], and [[peroxidase]].


== Distribution in nature ==
== Distribution in nature ==


NODs, as well as many hemoglobins that function as NODs, are distributed to most life forms including bacteria, fungi, protists, worms, plants and animals. In fact, nitric oxide dioxygenation appears to be a primal function for members of the hemoglobin superfamily. Moreover, it is becoming increasingly evident that the NOD function of globins is much more common than the paradigmatic O<sub>2</sub> transport-storage function of red cell [[hemoglobin]]<ref name="pmid18211906">{{cite journal | author = Vinogradov SN, Moens L | title = Diversity of globin function: enzymatic, transport, storage, and sensing | journal = J. Biol. Chem. | volume = 283 | issue = 14 | pages = 8773–7 | year = 2008 | month = April | pmid = 18211906 | doi = 10.1074/jbc.R700029200 }}</ref> which was first investigated and reported over a century earlier by [[Felix Hoppe-Seyler]] and others.<ref>{{cite journal | author = Hoppe-Seyler F | year = 1866 | title = Über die Oxydation in lebenden Blute | journal = Med.-Chem. Untersuch Lab. | volume = 1 | pages = 133&ndash;40 }}</ref> Other proteins that may act as NODs include mammalian microsomal cytochrome P450(s)<ref name="pmid15203193">{{cite journal | author = Hallstrom CK, Gardner AM, Gardner PR | title = Nitric oxide metabolism in mammalian cells: substrate and inhibitor profiles of a NADPH-cytochrome P450 oxidoreductase-coupled microsomal nitric oxide dioxygenase | journal = Free Radic. Biol. Med. | volume = 37 | issue = 2 | pages = 216–28 | year = 2004 | month = July | pmid = 15203193 | doi = 10.1016/j.freeradbiomed.2004.04.031 }}</ref> and a novel O<sub>2</sub>-binding cytochrome ''b'' from ''[[Rhodobacter sphaeroides]]''.<ref name="Li_2008" />
NODs, as well as many hemoglobins that function as NODs, are distributed to most life forms including bacteria, fungi, protists, worms, plants and animals. In fact, nitric oxide dioxygenation appears to be a primal function for members of the hemoglobin superfamily. Moreover, it is becoming increasingly evident that the NOD function of globins is much more common<ref>{{cite journal | author = Gardner PR | title = Hemoglobin: A Nitric-Oxide Dioxygenase | journal = Scientifica | volume = 2012 | pages = 34 |date=October 2012 | doi = 10.6064/2012/683729 | pmid = 24278729 | pmc = 3820574 | doi-access = free }}</ref> than the paradigmatic O<sub>2</sub> transport-storage function of red cell [[hemoglobin]]<ref name="pmid18211906">{{cite journal |vauthors=Vinogradov SN, Moens L | title = Diversity of globin function: enzymatic, transport, storage, and sensing | journal = J. Biol. Chem. | volume = 283 | issue = 14 | pages = 8773–7 |date=April 2008 | pmid = 18211906 | doi = 10.1074/jbc.R700029200 | doi-access = free }}</ref> which was first investigated and reported over a century earlier by [[Felix Hoppe-Seyler]] and others.<ref>{{cite journal | author = Hoppe-Seyler F | year = 1866 | title = Über die Oxydation in lebenden Blute | journal = Med.-Chem. Untersuch Lab. | volume = 1 | pages = 133&ndash;40 }}</ref> Other proteins that may act as NODs include mammalian microsomal cytochrome P450(s)<ref name="pmid15203193">{{cite journal |vauthors=Hallstrom CK, Gardner AM, Gardner PR | title = Nitric oxide metabolism in mammalian cells: substrate and inhibitor profiles of a NADPH-cytochrome P450 oxidoreductase-coupled microsomal nitric oxide dioxygenase | journal = Free Radic. Biol. Med. | volume = 37 | issue = 2 | pages = 216–28 |date=July 2004 | pmid = 15203193 | doi = 10.1016/j.freeradbiomed.2004.04.031 }}</ref> and a novel O<sub>2</sub>-binding cytochrome ''b'' from ''[[Rhodobacter sphaeroides]]''.<ref name="Li_2008" />


== Technologies ==
== Technologies ==


Inhibitors of the NODs are being developed for application as microbial antibiotics,<ref name="pmid15855504">{{cite journal | author = Helmick RA, Fletcher AE, Gardner AM, Gessner CR, Hvitved AN, Gustin MC, Gardner PR | title = Imidazole antibiotics inhibit the nitric oxide dioxygenase function of microbial flavohemoglobin | journal = Antimicrob. Agents Chemother. | volume = 49 | issue = 5 | pages = 1837–43 | year = 2005 | month = May | pmid = 15855504 | pmc = 1087630 | doi = 10.1128/AAC.49.5.1837-1843.2005 }}</ref><ref name="pmid21210640">{{cite journal | author = El Hammi E, Warkentin E, Demmer U, Limam F, Marzouki NM, Ermler U, Baciou L | title = Structure of Ralstonia eutropha flavohemoglobin in complex with three antibiotic azole compounds | journal = Biochemistry | volume = 50 | issue = 7 | pages = 1255–64 | year = 2011 | month = February | pmid = 21210640 | doi = 10.1021/bi101650q }}</ref> anti-tumor agents and modulators of NO signalling. The most prominent class of inhibitor of NO dioxygenase to date is [[imidazole]] antibiotics. Imidazoles have been shown to coordinate with the heme iron atom of microbial flavohemoglobin, impair ferric heme reduction, produce uncompetitive inhibition with respect to O<sub>2</sub> and NO, and inhibit NO metabolism by yeasts and bacteria.<ref name="Helmick_2005">{{cite journal | author = Helmick RA, Fletcher AE, Gardner AM, Gessner CR, Hvitved AN, Gustin MC, Gardner PR | title = Imidazole antibiotics inhibit the nitric oxide dioxygenase function of microbial flavohemoglobin | journal = Antimicrob. Agents Chemother. | volume = 49 | issue = 5 | pages = 1837–43 | year = 2005 | month = May | pmid = 15855504 | pmc = 1087630 | doi = 10.1128/AAC.49.5.1837-1843.2005 | url = }}</ref> Specifically, imidazoles bearing bulky aromatic substituents have been shown to have potential for selective and high-affinity inhibition of NO dioxygenase function by coordinating the catalytic heme iron and "fitting" within the large hydrophobic distal heme pocket.<ref name="Helmick_2005"/><ref name="pmid8557026">{{cite journal | author = Ermler U, Siddiqui RA, Cramm R, Friedrich B | title = Crystal structure of the flavohemoglobin from Alcaligenes eutrophus at 1.75 Å resolution | journal = EMBO J. | volume = 14 | issue = 24 | pages = 6067–77 | year = 1995 | month = December | pmid = 8557026 | pmc = 394731 | doi = | url = }}</ref><ref name="pmid10336624">{{cite journal | author = Ollesch G, Kaunzinger A, Juchelka D, Schubert-Zsilavecz M, Ermler U | title = Phospholipid bound to the flavohemoprotein from Alcaligenes eutrophus | journal = Eur. J. Biochem. | volume = 262 | issue = 2 | pages = 396–405 | year = 1999 | month = June | pmid = 10336624 | doi = 10.1046/j.1432-1327.1999.00381.x}}</ref> As a result, imidazole engineering has been suggested as a means to specifically inhibit NO dioxygenases.
Inhibitors of the NODs are being developed for application as microbial antibiotics,<ref name="Helmick_2005">{{cite journal |vauthors=Helmick RA, Fletcher AE, Gardner AM, Gessner CR, Hvitved AN, Gustin MC, Gardner PR | title = Imidazole antibiotics inhibit the nitric oxide dioxygenase function of microbial flavohemoglobin | journal = Antimicrob. Agents Chemother. | volume = 49 | issue = 5 | pages = 1837–43 |date=May 2005 | pmid = 15855504 | pmc = 1087630 | doi = 10.1128/AAC.49.5.1837-1843.2005 }}</ref><ref name="pmid21210640">{{cite journal |vauthors=El Hammi E, Warkentin E, Demmer U, Limam F, Marzouki NM, Ermler U, Baciou L | title = Structure of Ralstonia eutropha flavohemoglobin in complex with three antibiotic azole compounds | journal = Biochemistry | volume = 50 | issue = 7 | pages = 1255–64 |date=February 2011 | pmid = 21210640 | doi = 10.1021/bi101650q }}</ref> anti-tumor agents and modulators of NO signalling. The most prominent class of inhibitor of NO dioxygenase to date is [[imidazole]] antibiotics. Imidazoles have been shown to coordinate with the heme iron atom of microbial flavohemoglobin, impair ferric heme reduction, produce uncompetitive inhibition with respect to O<sub>2</sub> and NO, and inhibit NO metabolism by yeasts and bacteria.<ref name="Helmick_2005"/> Specifically, imidazoles bearing bulky aromatic substituents have been shown to have potential for selective and high-affinity inhibition of NO dioxygenase function by coordinating the catalytic heme iron and "fitting" within the large hydrophobic distal heme pocket.<ref name="Helmick_2005"/><ref name="pmid8557026">{{cite journal |vauthors=Ermler U, Siddiqui RA, Cramm R, Friedrich B | title = Crystal structure of the flavohemoglobin from Alcaligenes eutrophus at 1.75 Å resolution | journal = EMBO J. | volume = 14 | issue = 24 | pages = 6067–77 |date=December 1995 | pmid = 8557026 | pmc = 394731 | doi = 10.1002/j.1460-2075.1995.tb00297.x}}</ref><ref name="pmid10336624">{{cite journal |vauthors=Ollesch G, Kaunzinger A, Juchelka D, Schubert-Zsilavecz M, Ermler U | title = Phospholipid bound to the flavohemoprotein from Alcaligenes eutrophus | journal = Eur. J. Biochem. | volume = 262 | issue = 2 | pages = 396–405 |date=June 1999 | pmid = 10336624 | doi = 10.1046/j.1432-1327.1999.00381.x| doi-access = free }}</ref> As a result, imidazole engineering has been suggested as a means to specifically inhibit NO dioxygenases.


In addition, genetically modified plants with heterologous flavohemoglobin-NODs are being developed to limit NO toxicity created by metabolism of nitrogen fertilizers by soil microbes and as a means towards plant self-fertilization through absorption of environmental NO.
In addition, genetically modified plants with heterologous flavohemoglobin-NODs are being developed to limit NO toxicity created by metabolism of nitrogen fertilizers by soil microbes and as a means towards plant self-fertilization through absorption of environmental NO.


Recently a lentiviral vector that allows for expression of <I>E. coli</I> flavoHb in mammalian cells has been described. This approach demonstrated that flavoHb is indeed enzymatically active within human and murine cells and potently blocks exogenous and endogenous sources of nitrosative stress.<ref name="pmid21231921">{{cite journal | author = Forrester MT, Eyler CE, Rich, JN | title = Bacterial flavohemoglobin: a molecular tool to probe mammalian nitric oxide biology | journal = Biotechniques | volume = 50 | issue = 1 = |pages = 41-45 | year = 2011 | month = January | pmid = 21231921 | pmc = 3096140 | doi = 10.2144/000113586}}</ref> This technology was then extended to interrogate the role of NO synthesis in the highly tumorigenic cancer stem cells (CSCs) from human glioblastoma (brain tumor) samples. Expression of flavoHb within xenografted tumors led to depletion of NO generated by iNOS/NOS2. The phenotypic result was loss of tumorigenicity of the CSCs and improved mouse survival.<ref name="pmid21729780">{{cite journal | author = Eyler CE, Wu Q, Yan K, MacSwords JM, Chandler-Militello D, Misuraca KL, Lathia JD, Forrester MT, Lee J, Stamler JS, Goldman SA, Bredel M, McLendon RE, Sloan AE, Hjelmeland AB, Rich JN | title = Glioma stem cell proliferation and tumor growth are promoted by nitric oxide synthase-2 | journal = Cell | volume = 146 | issue = 1 = |pages = 53-66 | year = 2011 | month = July | pmid = 21729780 | pmc = 3144745 | doi = 10.1016/j.cell.2011.06.006}}</ref> These experiments demonstrate that flavoHb can be employed for <I>in vivo</I> studies of nitric oxide biology and suggest that therapeutic NO-depletion may be achieved via heterologous expression of bacterial flavoHbs.
Recently a lentiviral vector that allows for expression of ''E. coli'' flavoHb in mammalian cells has been described. This approach demonstrated that flavoHb is indeed enzymatically active within human and murine cells and potently blocks exogenous and endogenous sources of nitrosative stress.<ref name="pmid21231921">{{cite journal | vauthors = Forrester MT, Eyler CE, Rich JN | title = Bacterial flavohemoglobin: a molecular tool to probe mammalian nitric oxide biology | journal = BioTechniques | volume = 50 | issue = 1 = |pages = 41–45 |date=January 2011 | pmid = 21231921 | pmc = 3096140 | doi = 10.2144/000113586}}</ref> This technology was then extended to interrogate the role of NO synthesis in the highly tumorigenic cancer stem cells (CSCs) from human [[glioblastoma]] (brain tumor) samples. Expression of flavoHb within xenografted tumors led to depletion of NO generated by iNOS/NOS2. The phenotypic result was loss of tumorigenicity of the CSCs and improved mouse survival.<ref name="pmid21729780">{{cite journal |vauthors=Eyler CE, Wu Q, Yan K, MacSwords JM, Chandler-Militello D, Misuraca KL, Lathia JD, Forrester MT, Lee J, Stamler JS, Goldman SA, Bredel M, McLendon RE, Sloan AE, Hjelmeland AB, Rich JN | title = Glioma stem cell proliferation and tumor growth are promoted by nitric oxide synthase-2 | journal = Cell | volume = 146 | issue = 1 = |pages = 53–66 |date=July 2011 | pmid = 21729780 | pmc = 3144745 | doi = 10.1016/j.cell.2011.06.006}}</ref> These experiments demonstrate that flavoHb can be employed for ''in vivo'' studies of nitric oxide biology and suggest that therapeutic NO-depletion may be achieved via heterologous expression of bacterial flavoHbs.


==References==
==References==
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{{Dioxygenases}}
{{Enzymes}}
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[[Category:NADH-dependent enzymes]]
[[Category:NADH-dependent enzymes]]
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[[it:Ossido nitrico diossigenasi]]
[[ja:一酸化窒素ジオキシゲナーゼ]]

Latest revision as of 04:10, 17 September 2023

nitric oxide dioxygenase
E. coli flavohemoglobin/NOD structure. green = reductase domain, blue = hemoglobin domain.[1]
Identifiers
EC no.1.14.12.17
CAS no.214466-78-1
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Nitric oxide dioxygenase (EC 1.14.12.17) is an enzyme that catalyzes the conversion of nitric oxide (NO) to nitrate (NO−
3) .[2] The net reaction for the reaction catalyzed by nitric oxide dioxygenase is shown below:

  • 2NO + 2O2 + NAD(P)H → 2NO3− + NAD(P)+ + H+

Nitric oxide is a ubiquitous small molecule that is integrated in a wide variety of physiological processes including smooth muscle vasodilation, platelet disaggregation, neurotransmission, and immune response to bacterial infection.[3][4] Overproduction of this signaling molecule can be lethal to cells by poisoning cellular energy production. The most sensitive targets of NO are aconitase, an enzyme that catalyzes the isomerization of citrate to isocitrate in the citric acid cycle, and cytochrome oxidase, the last enzyme in the respiratory electron transport chain of mitochondria.[5] Additionally NO, with its lone radical on the nitrogen atom, is implicated in a number of secondary mechanisms of toxicity, including catalase inhibition (resulting in hydrogen peroxide toxicity), Fe-S center iron liberation, and the formation of dinitosyl-iron complexes.

Due to the potential lethality of NO, cells benefitted greatly from the evolution of an enzyme capable of catalyzing the conversion of toxic NO to nitrate. A 'nitric oxide dioxygenase' is an enzyme that is capable of carrying out this reaction. NO dioxygenase belongs to the family of oxidoreductases, more specifically those acting on paired donors, with O2 as oxidant and with incorporation of two atoms of oxygen into the other donor.

Reaction mechanism

[edit]

The mechanism of action has still not been entirely deduced, however, the leading theory suggests that the conversion is carried out through a series of redox reactions involving iron centers as shown in the series of half reactions below:[6]

Step Reaction
FAD reduction NAD(P)H + FAD + H+ → NAD(P)+ + FADH2
Iron reduction 1 FADH2 + Fe3+ → Fe2+ + FADH + H+
Iron Reduction 2 FADH + Fe3+ → FAD + Fe2+ + H+
O2 Binding Fe2+ + O2 → Fe3+(O2−)
NO dioxygenation Fe3+(O2−) + NO → Fe3+ + NO3−

Another theory developed more recently (2009) suggests that a NO dioxygenase activity could also proceed through phenolic nitration via a putative heme-peroxynitrite intermediate.[7]

The most well studied NO dioxygenase is flavohemoglobin (flavoHb), shown to the right: Studies have shown that flavohemoglobins are induced by NO, nitrite, nitrate, and NO-releasing agents in various bacteria and fungi.[6][8] Additionally, flavoHbs have been shown to protect bacteria, yeast, and Dictyostelium discoideum against growth inhibition and damage mediated via NO.[8][9][10]

Discovery

[edit]

Nitric oxide dioxygenase was discovered, and first reported in 1998, as an inducible O2-dependent enzymatic activity that protected bacteria against nitric oxide toxicity.[11] The enzyme was identified with the E. coli flavohemoglobin.[12]

More recently, another protein has been identified as a NO dioxygenase - rhodobacter sphaeroides haem protein (SHP), a novel cytochrome with NO dioxygenase activity.[13][14] Although the biological function of SHP has yet to be identified, SHP has been shown, that with oxygen bound, it can react rapidly with nitric oxide to form nitrate.[13]

Structure and molecular function

[edit]

The flavohemoglobin protein contains two domains: an oxidoreductase FAD-binding domain, and a b-type heme-containing "globin" domain and optionally an oxidoreductase NAD-binding domain. The reductase domain supplies an electron to the heme iron to achieve a high rate of catalytic NO dioxygenation. In addition to numerous flavohemoglobins, many distantly related members of the hemoglobin superfamily including the muscle myoglobin, the non-symbiotic plant hemoglobin and symbiotic plant leghemoglobin, the neuronal neuroglobin, and the mammalian cytoplasmic cytoglobin[15][16] appear to function as nitric oxide dioxygenases (NODs), although the cellular electron donor(s) for many globins have yet to be defined. Electron donors may include ascorbate, cytochrome b5 or ferredoxin reductase.[17] The catalytic NO dioxygenation can be written in its simplest form:

NO + O2 + e− NO3−

Catalysis is very efficient. The reported bimolecular NO dioxygenation rate constants range from 2 x 107 M−1s−1 for cytoglobin to 3 x 109 M−1s−1 for flavohemoglobin, and turnover rates range from 1 to 700 s−1. Structure, O2 binding, and reduction of globins appear optimized for a NO dioxygenase function.

Physiological function

[edit]

Historically, nitric oxide dioxygenase (around 1.8 billion years ago) served to provide the modern day analogue of hemoglobin/myoglobin function for oxygen storage and transport. Gardner et al. (1998) suggested that the first hemoglobin/myoglobin probably functioned as an enzyme utilizing bound ‘activated’ oxygen gas to dioxygenate NO in microbes.[6]

The wide diversity of multicellular organisms benefitting from the oxygen storage and transport functions of myoglobin/hemoglobin appeared much later (approximately 0.5 billion years ago).

NODs are now known to serve two important physiological functions in diverse life forms: they prevent NO toxicity (otherwise known as "nitrosative stress") and regulate NO signalling.[2] NODs belong to the larger family of well-established free radical and reactive oxygen detoxifying enzymes that includes superoxide dismutase, catalase, and peroxidase.

Distribution in nature

[edit]

NODs, as well as many hemoglobins that function as NODs, are distributed to most life forms including bacteria, fungi, protists, worms, plants and animals. In fact, nitric oxide dioxygenation appears to be a primal function for members of the hemoglobin superfamily. Moreover, it is becoming increasingly evident that the NOD function of globins is much more common[18] than the paradigmatic O2 transport-storage function of red cell hemoglobin[19] which was first investigated and reported over a century earlier by Felix Hoppe-Seyler and others.[20] Other proteins that may act as NODs include mammalian microsomal cytochrome P450(s)[21] and a novel O2-binding cytochrome b from Rhodobacter sphaeroides.[13]

Technologies

[edit]

Inhibitors of the NODs are being developed for application as microbial antibiotics,[22][23] anti-tumor agents and modulators of NO signalling. The most prominent class of inhibitor of NO dioxygenase to date is imidazole antibiotics. Imidazoles have been shown to coordinate with the heme iron atom of microbial flavohemoglobin, impair ferric heme reduction, produce uncompetitive inhibition with respect to O2 and NO, and inhibit NO metabolism by yeasts and bacteria.[22] Specifically, imidazoles bearing bulky aromatic substituents have been shown to have potential for selective and high-affinity inhibition of NO dioxygenase function by coordinating the catalytic heme iron and "fitting" within the large hydrophobic distal heme pocket.[22][24][25] As a result, imidazole engineering has been suggested as a means to specifically inhibit NO dioxygenases.

In addition, genetically modified plants with heterologous flavohemoglobin-NODs are being developed to limit NO toxicity created by metabolism of nitrogen fertilizers by soil microbes and as a means towards plant self-fertilization through absorption of environmental NO.

Recently a lentiviral vector that allows for expression of E. coli flavoHb in mammalian cells has been described. This approach demonstrated that flavoHb is indeed enzymatically active within human and murine cells and potently blocks exogenous and endogenous sources of nitrosative stress.[26] This technology was then extended to interrogate the role of NO synthesis in the highly tumorigenic cancer stem cells (CSCs) from human glioblastoma (brain tumor) samples. Expression of flavoHb within xenografted tumors led to depletion of NO generated by iNOS/NOS2. The phenotypic result was loss of tumorigenicity of the CSCs and improved mouse survival.[27] These experiments demonstrate that flavoHb can be employed for in vivo studies of nitric oxide biology and suggest that therapeutic NO-depletion may be achieved via heterologous expression of bacterial flavoHbs.

References

[edit]
  1. ^ PDB: 1gvh​; Ilari A, Bonamore A, Farina A, Johnson KA, Boffi A (June 2002). "The X-ray structure of ferric Escherichia coli flavohemoglobin reveals an unexpected geometry of the distal heme pocket". J. Biol. Chem. 277 (26): 23725–32. doi:10.1074/jbc.M202228200. PMID 11964402.
  2. ^ a b Forrester MT, Foster MW (May 2012). "Protection from nitrosative stress: a central role for microbial flavohemoglobin". Free Radic. Biol. Med. 52 (9 =): 1620–33. doi:10.1016/j.freeradbiomed.2012.01.028. PMID 22343413.
  3. ^ Moncada S, Palmer RM, Higgs EA (June 1991). "Nitric oxide: physiology, pathophysiology, and pharmacology". Pharmacol. Rev. 43 (2): 109–42. PMID 1852778.
  4. ^ Fang FC (October 2004). "Antimicrobial reactive oxygen and nitrogen species: concepts and controversies". Nat. Rev. Microbiol. 2 (10): 820–32. doi:10.1038/nrmicro1004. PMID 15378046. S2CID 11063073.
  5. ^ Gardner PR, Costantino G, Szabó C, Salzman AL (October 1997). "Nitric oxide sensitivity of the aconitases". J. Biol. Chem. 272 (40): 25071–6. doi:10.1074/jbc.272.40.25071. PMID 9312115.
  6. ^ a b c Gardner PR, Gardner AM, Martin LA, Salzman AL (September 1998). "Nitric oxide dioxygenase: an enzymic function for flavohemoglobin". Proc. Natl. Acad. Sci. U.S.A. 95 (18): 10378–83. doi:10.1073/pnas.95.18.10378. PMC 27902. PMID 9724711.
  7. ^ Schopfer MP, Mondal B, Lee DH, Sarjeant AA, Karlin KD (August 2009). "Heme/O2/*NO nitric oxide dioxygenase (NOD) reactivity: phenolic nitration via a putative heme-peroxynitrite intermediate". J. Am. Chem. Soc. 131 (32): 11304–5. doi:10.1021/ja904832j. PMC 2747244. PMID 19627146.
  8. ^ a b Gardner PR, Gardner AM, Martin LA, Dou Y, Li T, Olson JS, Zhu H, Riggs AF (October 2000). "Nitric-oxide dioxygenase activity and function of flavohemoglobins. sensitivity to nitric oxide and carbon monoxide inhibition". J. Biol. Chem. 275 (41): 31581–7. doi:10.1074/jbc.M004141200. PMID 10922365.
  9. ^ Hausladen A, Gow AJ, Stamler JS (2001). "Flavohemoglobin denitrosylase catalyzes the reaction of a nitroxyl equivalent with molecular oxygen". PNAS. 98 (18): 10108–12. doi:10.1073/pnas.181199698. PMC 56923. PMID 11517313.
  10. ^ Mills CE, Sedelnikova S, Søballe B, Hughes MN, Poole RK (January 2001). "Escherichia coli flavohaemoglobin (Hmp) with equistoichiometric FAD and haem contents has a low affinity for dioxygen in the absence or presence of nitric oxide". Biochem. J. 353 (Pt 2): 207–13. doi:10.1042/0264-6021:3530207. PMC 1221560. PMID 11139382.
  11. ^ Gardner PR, Costantino G, Salzman AL (1998). "Constitutive and adaptive detoxification of nitric oxide in Escherichia coli. Role of nitric-oxide dioxygenase in the protection of aconitase". J. Biol. Chem. 273 (41): 26528–33. doi:10.1074/jbc.273.41.26528. PMID 9756889.
  12. ^ Gardner PR, Gardner AM, Martin LA, Salzman AL (1998). "Nitric oxide dioxygenase: an enzymic function for flavohemoglobin". Proc. Natl. Acad. Sci. U.S.A. 95 (18): 10378–83. doi:10.1073/pnas.95.18.10378. PMC 27902. PMID 9724711.
  13. ^ a b c Li BR, Anderson JL, Mowat CG, Miles CS, Reid GA, Chapman SK (October 2008). "Rhodobacter sphaeroides haem protein: a novel cytochrome with nitric oxide dioxygenase activity". Biochem. Soc. Trans. 36 (Pt 5): 992–5. doi:10.1042/BST0360992. PMID 18793176.
  14. ^ Bartnikas TB, Tosques IE, Laratta WP, Shi J, Shapleigh JP (June 1997). "Characterization of the nitric oxide reductase-encoding region in Rhodobacter sphaeroides 2.4.3". J. Bacteriol. 179 (11): 3534–40. doi:10.1128/jb.179.11.3534-3540.1997. PMC 179145. PMID 9171397.
  15. ^ Gardner AM, Cook MR, Gardner PR (July 2010). "Nitric-oxide dioxygenase function of human cytoglobin with cellular reductants and in rat hepatocytes". J. Biol. Chem. 285 (31): 23850–7. doi:10.1074/jbc.M110.132340. PMC 2911317. PMID 20511233.
  16. ^ Halligan KE, Jourd'heuil FL, Jourd'heuil D (March 2009). "Cytoglobin is expressed in the vasculature and regulates cell respiration and proliferation via nitric oxide dioxygenation". J. Biol. Chem. 284 (13): 8539–47. doi:10.1074/jbc.M808231200. PMC 2659212. PMID 19147491.
  17. ^ Gardner PR (January 2005). "Nitric oxide dioxygenase function and mechanism of flavohemoglobin, hemoglobin, myoglobin and their associated reductases". J. Inorg. Biochem. 99 (1): 247–66. doi:10.1016/j.jinorgbio.2004.10.003. PMID 15598505.
  18. ^ Gardner PR (October 2012). "Hemoglobin: A Nitric-Oxide Dioxygenase". Scientifica. 2012: 34. doi:10.6064/2012/683729. PMC 3820574. PMID 24278729.
  19. ^ Vinogradov SN, Moens L (April 2008). "Diversity of globin function: enzymatic, transport, storage, and sensing". J. Biol. Chem. 283 (14): 8773–7. doi:10.1074/jbc.R700029200. PMID 18211906.
  20. ^ Hoppe-Seyler F (1866). "Über die Oxydation in lebenden Blute". Med.-Chem. Untersuch Lab. 1: 133–40.
  21. ^ Hallstrom CK, Gardner AM, Gardner PR (July 2004). "Nitric oxide metabolism in mammalian cells: substrate and inhibitor profiles of a NADPH-cytochrome P450 oxidoreductase-coupled microsomal nitric oxide dioxygenase". Free Radic. Biol. Med. 37 (2): 216–28. doi:10.1016/j.freeradbiomed.2004.04.031. PMID 15203193.
  22. ^ a b c Helmick RA, Fletcher AE, Gardner AM, Gessner CR, Hvitved AN, Gustin MC, Gardner PR (May 2005). "Imidazole antibiotics inhibit the nitric oxide dioxygenase function of microbial flavohemoglobin". Antimicrob. Agents Chemother. 49 (5): 1837–43. doi:10.1128/AAC.49.5.1837-1843.2005. PMC 1087630. PMID 15855504.
  23. ^ El Hammi E, Warkentin E, Demmer U, Limam F, Marzouki NM, Ermler U, Baciou L (February 2011). "Structure of Ralstonia eutropha flavohemoglobin in complex with three antibiotic azole compounds". Biochemistry. 50 (7): 1255–64. doi:10.1021/bi101650q. PMID 21210640.
  24. ^ Ermler U, Siddiqui RA, Cramm R, Friedrich B (December 1995). "Crystal structure of the flavohemoglobin from Alcaligenes eutrophus at 1.75 Å resolution". EMBO J. 14 (24): 6067–77. doi:10.1002/j.1460-2075.1995.tb00297.x. PMC 394731. PMID 8557026.
  25. ^ Ollesch G, Kaunzinger A, Juchelka D, Schubert-Zsilavecz M, Ermler U (June 1999). "Phospholipid bound to the flavohemoprotein from Alcaligenes eutrophus". Eur. J. Biochem. 262 (2): 396–405. doi:10.1046/j.1432-1327.1999.00381.x. PMID 10336624.
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