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HUMAN NEUROGLOBIN FUNCTIONS AS A REDOX REGULATED NITRITE REDUCTASE
Author(s) -
Tiso Mauro,
Tejero Jesus,
Basu Swati,
Azarov Ivan,
Wang Xunde,
Simplaceanu Virgil,
Frizzell Sheila,
Jayaraman Thottala,
Geary Lisa,
Shapiro Calli,
Ho Chien,
Shiva Sruti,
KimShapiro Daniel B,
Gladwin Mark T
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.959.6
Subject(s) - neuroglobin , heme , chemistry , nitrite reductase , myoglobin , nitrite , biochemistry , nitric oxide , redox , histidine , hemeprotein , hemoglobin , globin , amino acid , enzyme , nitrate reductase , inorganic chemistry , organic chemistry , nitrate
Neuroglobin (Ngb) is a highly conserved hemoprotein of uncertain physiological function that evolved from a common ancestor to hemoglobin and myoglobin. Ngb shows a six‐coordinate heme iron with proximal and distal histidines in the heme pocket directly bound to the heme iron however coordination of the sixth ligand is reversible. Deoxygenated human neuroglobin reacts with nitrite to form nitric oxide (NO). This reaction is regulated by redox sensitive surface thiols, cysteine 55 and 46, which regulate the open probability of heme pocket, nitrite binding and NO formation. Replacement of the distal histidine by leucine (H64L) leads to a stable five‐coordinated geometry; the Ngb H64L mutant reduces nitrite to NO approximately 2000‐times faster than the wild type, while mutation of either C55 or C46 to alanine stabilizes the six‐coordinate structure and slows the reaction. Using lentivirus expression systems we show that the nitrite‐reductase activity of Ngb inhibits cellular respiration via NO binding to cytochrome c oxidase and confirm that the six‐to‐five coordinate status of Ngb regulates intracellular hypoxic NO signaling pathways. These studies suggest that Ngb may function as a physiological oxidative stress sensor and a post‐translationally redox regulated nitrite reductase, that generates NO under six‐to‐five coordinate heme pocket control.