The mechanisms involving iron toxicity in diabetes mellitus are not completely understood. However, the spontaneous reaction of reducing sugars with protein amino groups, known as glycation, has been shown to compromise the action of Tf (transferrin), the systemic iron transporter. In order to understand the structural alterations that impair its function, Tf was glycated in vitro and the modification sites were determined by MS. Iron binding to glycated Tf was assessed and a computational approach was conducted to study how glycation influences the iron-binding capacity of this protein. Glycated Tf samples were found to bind iron less avidly than non-modified Tf and MS results revealed 12 glycation sites, allowing the establishment of Lys534 and Lys206 as the most vulnerable residues to this modification. Their increased susceptibility to glycation was found to relate to their low side-chain pKa values. Lys534 and Lys206 participate in hydrogen bonding crucial for iron stabilization in the C- and N-lobes of the protein respectively, and their modification is bound to influence iron binding. Furthermore, the orientation of the glucose residues at these sites blocks the entrance to the iron-binding pocket. Molecular dynamics simulations also suggested that additional loss of iron binding capacity may result from the stereochemical effects induced by the glycation of lysine residues that prevent the conformational changes (from open to closed Tf forms) required for metal binding. Altogether, the results indicate that Tf is particularly vulnerable to glycation and that this modification targets spots that are particularly relevant to its function.
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July 2014
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Research Article|
June 13 2014
The glycation site specificity of human serum transferrin is a determinant for transferrin's functional impairment under elevated glycaemic conditions
André M. N. Silva;
André M. N. Silva
1
*Departamento de Química, Universidade de Aveiro, 3810-193 Aveiro, Portugal
1Correspondence may be addressed to either of these authors (email [email protected] or [email protected]).
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Paulo R. H. Sousa;
Paulo R. H. Sousa
*Departamento de Química, Universidade de Aveiro, 3810-193 Aveiro, Portugal
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João T. S. Coimbra;
João T. S. Coimbra
†Requimte/Departamento de Química e Bioquímica, Faculdade de Ciências da Universidade do Porto, Rua do Campo Alegre S/N, 4169-007 Porto, Portugal
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Natércia F. Brás;
Natércia F. Brás
†Requimte/Departamento de Química e Bioquímica, Faculdade de Ciências da Universidade do Porto, Rua do Campo Alegre S/N, 4169-007 Porto, Portugal
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Rui Vitorino;
Rui Vitorino
*Departamento de Química, Universidade de Aveiro, 3810-193 Aveiro, Portugal
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Pedro A. Fernandes;
Pedro A. Fernandes
†Requimte/Departamento de Química e Bioquímica, Faculdade de Ciências da Universidade do Porto, Rua do Campo Alegre S/N, 4169-007 Porto, Portugal
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Maria J. Ramos;
Maria J. Ramos
†Requimte/Departamento de Química e Bioquímica, Faculdade de Ciências da Universidade do Porto, Rua do Campo Alegre S/N, 4169-007 Porto, Portugal
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Maria Rangel;
Maria Rangel
‡Requimte/Instituto de Ciências Biomédicas de Abel Salazar, Rua Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal
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Pedro Domingues
Pedro Domingues
1
*Departamento de Química, Universidade de Aveiro, 3810-193 Aveiro, Portugal
1Correspondence may be addressed to either of these authors (email [email protected] or [email protected]).
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Publisher: Portland Press Ltd
Received:
January 29 2014
Revision Received:
March 19 2014
Accepted:
April 10 2014
Accepted Manuscript online:
April 10 2014
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2014 Biochemical Society
2014
Biochem J (2014) 461 (1): 33–42.
Article history
Received:
January 29 2014
Revision Received:
March 19 2014
Accepted:
April 10 2014
Accepted Manuscript online:
April 10 2014
Citation
André M. N. Silva, Paulo R. H. Sousa, João T. S. Coimbra, Natércia F. Brás, Rui Vitorino, Pedro A. Fernandes, Maria J. Ramos, Maria Rangel, Pedro Domingues; The glycation site specificity of human serum transferrin is a determinant for transferrin's functional impairment under elevated glycaemic conditions. Biochem J 1 July 2014; 461 (1): 33–42. doi: https://doi.org/10.1042/BJ20140133
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