INVESTIGADORES
ISSOGLIO Federico Matias
congresos y reuniones científicas
Título:
Computer Simulation Study of the Catalytic mechanism of Human Glutamine Synthetase
Autor/es:
FEDERICO M. ISSOGLIO; NICOLAS CAMPOLO; ARI ZEIDA; RAFAEL RADI; SILVINA BARTESAGHI; DARIO ESTRIN
Lugar:
Salto
Reunión:
Congreso; Latin American Crosstalk in Biophysics and Physiology. Sociedad Argentina de Biofísica (SAB) ? Seccional Biofísica, Sociedad Uruguaya de Biociencias (SBF.uy); 2015
Resumen:
Glutamine synthetase (GS) catalyzes the formation of glutamine from glutamate and ammonia, using ATP as a cofactor. In plants and bacteria it is essential in nitrogen metabolism, making it a good target for herbicides and antimicrobial drug design. In human's brain it prevents glutamate dependent excitotoxicity and detoxifies ammonia. The loss of GS activity as been related with neurodegenerative disorders, such as Alzheimer's disease. The human enzyme has 373 aminoacids (M.W. 44 kDa.) and exists as a decamer, formed by two stacked pentamers, with the active sites located at the interface between two subunits of the pentamer. Mainly from crystallographic results a reaction mechanism has been proposed1, but since there is no information regarding the enzyme structure with its three natural substrates, a detailed study of the catalytic mechanism has still not been reported.In the present work we used molecular dynamics simulations (MD), and combined quantum mechanics and molecular mechanics simulations (QM/MM)2, to examine human GS structural properties, as well as the reaction mechanism at an atomic level. The results provide an accurate study of human GS dynamics, and establishes the groundwork to further analysis regarding changes in GS activity, as occur in natural variants and post-translational modifications, aiding to understand the molecular basis that govern these changes.