INQUIMAE   12526
INSTITUTO DE QUIMICA, FISICA DE LOS MATERIALES, MEDIOAMBIENTE Y ENERGIA
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
Understanding the molecular basis of Nitric oxide detoxification by M.tuberculosis Truncated Hemoglobin N.
Autor/es:
MARCELO A MARTI
Lugar:
Pretoria South Africa
Reunión:
Workshop; Workshop on Advanced Design and Development of potential Drugs against Tuberculosis.; 2009
Institución organizadora:
ICS-UNIDO
Resumen:
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Mycobacterium
tuberculosis,
the causative agent of human tuberculosis, encodes a small haeme
protein named Truncated Haemoglobin N (trHbN), which in its active
site transforms nitric oxide (NO) to nitrate anion NO3-.
The NO-dioxygenase activity of trHbN seems to be crucial for the
bacillus, which can survive under the nitrosative stress conditions
that occur upon infection of the host. As a defense mechanism against
the copious amounts of NO produced by macrophages upon infection, the
protein must achieve a high level of NO-dioxygenase activity to
eliminate NO, activity which is modulated by its efficiency in
capturing both susbtrates O2
and NO. To fulfill this task, migration of these small diatomic
ligands through the protein matrix relies on the presence of a doubly
branched tunnel system connecting the surface and the haem active
site. Using state of the art computer simulation techniques we have
studied the structural and dynamical factors that controls small
ligand migration and affinity, NO oxidation reaction, and the
product release steps. The results support a dual path mechanism for
migration of O2 and NO through distinct branches of the tunnel, where
migration of NO is allosterically facilitated upon binding of O2 to
the haem group. The NO oxidation reaction occurs almost barrierless
highlighting the importance of entry rate. Finally, egression of NO3
is preceded by the entrance of water to the haem cavity and occurs
through a different pathway. Overall, the results highlight the
intimate relationship between structure, dynamical behavior and
biological function of trHbN.