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Article

Crystal Structure of Escherichia coli Agmatinase: Catalytic Mechanism and Residues Relevant for Substrate Specificity

1
Departamento de Biología, Facultad de Ciencias, Universidad de Chile, Ñuñoa 7800003, Santiago, Chile
2
Facultad de Ciencias de la Vida, Universidad Andres Bello, Santiago 8370251, Santiago, Chile
3
Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias Biológicas, Universidad de Concepción, Casilla 160-C, Concepción 4070386, Concepción, Chile
*
Authors to whom correspondence should be addressed.
Academic Editors: Francesco Malatesta and Roberto Contestabile
Int. J. Mol. Sci. 2021, 22(9), 4769; https://doi.org/10.3390/ijms22094769
Received: 6 March 2021 / Revised: 18 April 2021 / Accepted: 28 April 2021 / Published: 30 April 2021
(This article belongs to the Special Issue Ligand Binding in Enzyme Systems)
Agmatine is the product of the decarboxylation of L-arginine by the enzyme arginine decarboxylase. This amine has been attributed to neurotransmitter functions, anticonvulsant, anti-neurotoxic, and antidepressant in mammals and is a potential therapeutic agent for diseases such as Alzheimer’s, Parkinson’s, and cancer. Agmatinase enzyme hydrolyze agmatine into urea and putrescine, which belong to one of the pathways producing polyamines, essential for cell proliferation. Agmatinase from Escherichia coli (EcAGM) has been widely studied and kinetically characterized, described as highly specific for agmatine. In this study, we analyze the amino acids involved in the high specificity of EcAGM, performing a series of mutations in two loops critical to the active-site entrance. Two structures in different space groups were solved by X-ray crystallography, one at low resolution (3.2 Å), including a guanidine group; and other at high resolution (1.8 Å) which presents urea and agmatine in the active site. These structures made it possible to understand the interface interactions between subunits that allow the hexameric state and postulate a catalytic mechanism according to the Mn2+ and urea/guanidine binding site. Molecular dynamics simulations evaluated the conformational dynamics of EcAGM and residues participating in non-binding interactions. Simulations showed the high dynamics of loops of the active site entrance and evidenced the relevance of Trp68, located in the adjacent subunit, to stabilize the amino group of agmatine by cation-pi interaction. These results allow to have a structural view of the best-kinetic characterized agmatinase in literature up to now. View Full-Text
Keywords: agmatine; agmatinase; ureohydrolase; enzyme specificity; arginase agmatine; agmatinase; ureohydrolase; enzyme specificity; arginase
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MDPI and ACS Style

Maturana, P.; Orellana, M.S.; Herrera, S.M.; Martínez, I.; Figueroa, M.; Martínez-Oyanedel, J.; Castro-Fernandez, V.; Uribe, E. Crystal Structure of Escherichia coli Agmatinase: Catalytic Mechanism and Residues Relevant for Substrate Specificity. Int. J. Mol. Sci. 2021, 22, 4769. https://doi.org/10.3390/ijms22094769

AMA Style

Maturana P, Orellana MS, Herrera SM, Martínez I, Figueroa M, Martínez-Oyanedel J, Castro-Fernandez V, Uribe E. Crystal Structure of Escherichia coli Agmatinase: Catalytic Mechanism and Residues Relevant for Substrate Specificity. International Journal of Molecular Sciences. 2021; 22(9):4769. https://doi.org/10.3390/ijms22094769

Chicago/Turabian Style

Maturana, Pablo, María S. Orellana, Sixto M. Herrera, Ignacio Martínez, Maximiliano Figueroa, José Martínez-Oyanedel, Victor Castro-Fernandez, and Elena Uribe. 2021. "Crystal Structure of Escherichia coli Agmatinase: Catalytic Mechanism and Residues Relevant for Substrate Specificity" International Journal of Molecular Sciences 22, no. 9: 4769. https://doi.org/10.3390/ijms22094769

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