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Theoretical Study of the Nitric Oxide Dioxygenase Reaction of the Truncated Hemoglobin N from Mycobacterium tuberculosis

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Theoretical Study of the Nitric Oxide Dioxygenase Reaction of the Truncated Hemoglobin N from Mycobacterium tuberculosis

Carabet, Lavinia Arielle (2014) Theoretical Study of the Nitric Oxide Dioxygenase Reaction of the Truncated Hemoglobin N from Mycobacterium tuberculosis. Masters thesis, Concordia University.

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Abstract

Tuberculosis (TB) is one of the oldest human afflictions and is still declared a major threat worldwide. The contemporary resurgence of the TB epidemic is due to multidrug-resistant strains of Mycobacterium tuberculosis (Mtb). The success of Mtb as a human lung pathogen is attributed to its capacity to survive in the alveolar macrophages of the host immune system by entering, for a prolonged time, a state of latency where it can resist oxidative and nitrosative species (e.g. O2•- and •NO), and then reactivates to cause TB. •NO plays an important role in the host defense against the pathogen by inhibiting key biological processes. For instance, •NO and its highly reactive derivatives (OONO- and •NO2) inhibit respiration and effect nitration that can lead to cell death. The truncated hemoglobin N (trHbN) of Mtb protects the aerobic respiration of the bacillus from •NO inhibition and prevents its own irreversible nitration, by actively metabolizing •NO to innocuous NO3-, through the rapid nitric oxide dioxygenase reaction (NOD). The NOD reaction is central to the defense system of Mtb, for coping with the toxic effects of •NO under hypoxia. The mechanism of the NOD reaction includes the formation of the OONO- intermediate and its isomerization to a nitrato-complex, followed by the release of the NO3- anion. Discrepancies exist in the literature with respect to the isomerization mechanism and the role of the active site residues in assisting the reaction. These aspects of the NOD reaction have been investigated here using state-of-the-art computational approaches. The results suggest a sequential mechanism with very short-lived intermediates. Distal Gln58, Tyr33, Leu54, Phe46, Phe32 and Val94 residues facilitate and cage the highly reactive FeIV=O2- and •NO2 intermediates that result from OONO- homolysis. Tyr33 is involved in a dynamic H-bonding network with Gln58 and Leu54 backbone. Tyr33 changes conformations and transiently stabilizes the •NO2 radical. Gln58 stabilizes the O-atom of oxo-ferryl species and assists •NO2 rebinding via H-bonding. Phe46 stabilizes the bound product. The H-bonding network between Tyr33, Gln58 and Leu54 prevents the oxidation and nitration of Tyr33 by keeping the hydroxyl and phenyl groups at safe distance and orientation with respect to FeIV=O2- and •NO2. Similar dynamics of the distal site residues have been observed for NO3- release. Tyr33, Gln58, Phe46 and Phe32 stabilize NO3- via H-bonding, and promote the breaking of the FeIII-O bond of the bound NO3-, its dissociation and release.

Divisions:Concordia University > Faculty of Arts and Science > Chemistry and Biochemistry
Item Type:Thesis (Masters)
Authors:Carabet, Lavinia Arielle
Institution:Concordia University
Degree Name:M. Sc.
Program:Chemistry
Date:20 August 2014
Thesis Supervisor(s):Lamoureux, Guillaume
ID Code:978867
Deposited By: LAVINIA CARABET
Deposited On:10 Nov 2014 17:49
Last Modified:18 Jan 2018 17:47
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