Human Neuroglobin Functions as a Redox-regulated Nitrite Reductase

• DOI: 10.1074/jbc.m110.159541
• Publication Date: 2011-02-05T02:42:52Z
• Authors: Mauro Tiso; Jesús Tejero; Swati Basu; Ivan Azarov; Xunde Wang; Virgil Simplaceanu; Sheila Frizzell; Thottala Jayaraman; Lisa Geary; Calli Shapiro; Chien Ho; Sruti Shiva; Daniel B. Kim-Sha...; Mark T. Gladwin
• Keywords: Male; 0303 health sciences; Nitrite Reductases; Mutation, Missense; Neuroglobin; Nerve Tissue Proteins; Nitric Oxide; Globins; Rats; 3. Good health; Rats, Sprague-Dawley; Oxidative Stress; 03 medical and health sciences; Oxygen Consumption; Amino Acid Substitution; FOS: Biological sciences; Animals; Humans; Oxidation-Reduction; Nitrites; 69999 Biological Sciences not elsewhere classified

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.