Nitric oxide dioxygenase: Difference between revisions
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== Physiological function == |
== Physiological function == |
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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. Shown below is a cartoon of microbial flavohemoglobin (Hb domain) |
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| ⚫ | NODs serve two important physiological functions in diverse life forms. They prevent NO toxicity and regulate NO signalling. NODs belong to the larger family of well-established free radical and reactive oxygen detoxifying enzymes that includes [[superoxide dismutase]], [[catalase]], and [[peroxidase]]. |
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Garnder et al. (1998) reported that the first hemoglobin/myoglobin probably functioned as an enzyme utilizing bound ‘activated’ oxygen gas to dioxygenate NO or other substrates in microbes.1 |
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The wide diversity of multicellular organisms benefitting from the oxygen storage and transport functions of myoglobin/hemoglobin appeared much later (approximately 3.0 billion years ago). For structural comparison with microbial flavohemoglobin, a cartoon of RBC hemoglobin is shown. |
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| ⚫ | NODs are now known to serve two important physiological functions in diverse life forms. They prevent NO toxicity and regulate NO signalling. NODs belong to the larger family of well-established free radical and reactive oxygen detoxifying enzymes that includes [[superoxide dismutase]], [[catalase]], and [[peroxidase]]. |
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== Distribution in nature == |
== Distribution in nature == |
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Revision as of 12:07, 17 May 2011
| nitric oxide dioxygenase | |||||||||
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| Identifiers | |||||||||
| EC no. | 1.14.12.17 | ||||||||
| CAS no. | 214466-78-1 | ||||||||
| Databases | |||||||||
| IntEnz | IntEnz view | ||||||||
| BRENDA | BRENDA entry | ||||||||
| ExPASy | NiceZyme view | ||||||||
| KEGG | KEGG entry | ||||||||
| MetaCyc | metabolic pathway | ||||||||
| PRIAM | profile | ||||||||
| PDB structures | RCSB PDB PDBe PDBsum | ||||||||
| Gene Ontology | AmiGO / QuickGO | ||||||||
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Nitric oxide (NO) is a widespread 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. 14,15 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. 2 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 nitrates. A nitric oxide dioxygenase (EC 1.14.12.17) 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. The net reaction for this conversion is shown below:
Net Reaction: 2NO + 2O2 + NAD(P)H → 2NO3- + NAD(P)+ + H+
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:3
FAD reduction: NAD(P)H + FAD + H+ → NAD(P)+ + FADH2
Iron reduction 1(in presence of CN-): FADH2 + Fe3+ → Fe2+ + FADH + H+
Iron Reduction 2 (in presence of CN-): FADH + Fe3+ → FAD + Fe2+ + H+
O2 Binding (in presence of NO & CO): Fe2+ + O2 → Fe3+(O2-)
NO dioxygenation: Fe3+(O2-) + NO → Fe3+ + NO3-
Another theory developed more recently (2009) suggests that NO dioxygenase activity could also proceed through phenolic nitration via a putative heme-peroxynitrite intermediate.8
The most well studied NO dioxygenase is flavohemoglobin (flavoHb). Studies have shown that flavohemoglobins are induced by NO, nitrite, nitrate, and NO-releasing agents in various bacteria.4,5 Additionally, FlavoHbs have been shown to protect bacteria, yeast, and Dictyostelium discoideum against growth inhibition and damage mediated via NO.4,6,7
Discovery
Nitric oxide dioxygenase was discovered, and first reported in 1998, as an inducible O2-dependent enzymatic activity that protected bacteria against nitric oxide toxicity.[2] The enzyme was identified with the E. coli flavohemoglobin.[3]
More recently, another protein has been identified as a NO dioxygenase - rhodobacter sphaeroides haem protein (SHP), a novel cytochrome with NO dioxygenase activity,12,13 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 nitrite.12
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. 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 [4][5] 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.[6] 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
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. Shown below is a cartoon of microbial flavohemoglobin (Hb domain)
Garnder et al. (1998) reported that the first hemoglobin/myoglobin probably functioned as an enzyme utilizing bound ‘activated’ oxygen gas to dioxygenate NO or other substrates in microbes.1
The wide diversity of multicellular organisms benefitting from the oxygen storage and transport functions of myoglobin/hemoglobin appeared much later (approximately 3.0 billion years ago). For structural comparison with microbial flavohemoglobin, a cartoon of RBC hemoglobin is shown.
NODs are now known to serve two important physiological functions in diverse life forms. They prevent NO toxicity and regulate NO signalling. 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
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 O2 transport-storage function of red cell hemoglobin[7] which was first investigated and reported over a century earlier by Felix Hoppe-Seyler and others.[8] Other proteins that may act as NODs include mammalian microsomal cytochrome P450(s)[9] and a novel O2-binding cytochrome b from Rhodobacter sphaeroides.[10]
Technologies
Inhibitors of the NODs are being developed for application as microbial antibiotics[11][12], anti-tumor agents and modulators of NO signalling. 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.
References
- ^ PDB: 1gvh; Ilari A, Bonamore A, Farina A, Johnson KA, Boffi A (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.
{{cite journal}}: Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link) - ^ 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.
{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link) - ^ 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.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ Gardner AM, Cook MR, Gardner PR (2010). "Nitric-oxide dioxygenase function of human cytoglobin with cellular reductants and in rat hepatocytes". J. Biol. Chem. 285 (31): 23850–57. doi:10.1074/jbc.M110.132340. PMID 20511233.
{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link) - ^ Halligan KE, Jourd'heuil FL, Jourd'heuil D (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. PMID 19147491.
{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link) - ^ Gardner PR (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.
- ^ Vinogradov SN, Moens L (2008). "Diversity of globin function: Enzymatic, transport, storage and sensing". J. Biol. Chem. 283 (14): 8773–77. doi:10.1074/jbc.R700029200. PMID 18211906.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - ^ Hoppe-Seyler F (1866). "Über die Oxydation in lebenden Blute". Med.-Chem. Untersuch Lab. 1: 133–40.
- ^ Hallstrom CK, Gardner AM, Gardner PR (2004). "Nitric oxide metabolism in mammalian cells: Substrate and inhibitor profiles of a NADPH-cytochrome P450 oxidoreductase-coupled microsomal nitric oxide dioxygenase". Free Radical Biol. Med. 37 (2): 216–28. doi:10.1016/j.freeradbiomed.2004.04.031. PMID 15203193.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ Li BR, Ross Anderson JL, Mowat CG, Miles CS, Reid GA, Chapman SK (2008). "Rhodobacter sphaeroides haem protein: a novel cytochrome with nitric oxide dioxygenase activity". Biochem. Soc. Trans. 36: 992–93. doi:10.1042/BST0360992. PMID 18793176.
{{cite journal}}: Unknown parameter|part=ignored (help)CS1 maint: multiple names: authors list (link) - ^ Helmick RA, Fletcher AE, Gardner AM, Gessner CR, Hvitved, AN, Gustin MC, Gardner PR (2005). "Imidazole antibiotics inhibit the nitric oxide dioxygenase function of microbial flavohemoglobin". Antimicrob. Agents Chemotherap. 49 (5): 1837–43. doi:10.1128/AAC.49.5.1837-1843.2005. PMID 15855504.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ El Hammi E, Warkentin E, Demmer U, Limam F, Marzouki NM, Ermler U, Baciou L (2011). "Structure of Ralstonia eutropha flavohemoglobin in complex with three antibiotic azole compounds". Biochemistry. 50: ePub ahead of print. doi:10.1021/bi101650q. PMID 21210640.
{{cite journal}}: CS1 maint: multiple names: authors list (link)