Determining the glycation site specificity of human holo-transferrin

• Type: Article in International Scientific Journal
• Date: 2018

Authors

Silva, AMN (Author) Other; Coimbra, JTS (Author) Other; Castro, MM (Author) Other; Oliveira, A (Author) Other; Natercia F Bras (Author) FCUP; Pedro A Fernandes (Author) FCUP; Ramos, MJ (Author) FCUP; Maria Rangel (Author) ICBAS

Journal

Title: Journal of Inorganic Biochemistry

Vol. 186

Pages: 95-102

ISSN: 0162-0134

Publisher: Elsevier

Indexing

ISI Web of Knowledge - 3 Citations

Scopus - 3 Citations

Other information

Authenticus ID: P-00P-HCK

DOI: 10.1016/j.jinorgbio.2018.05.016

Abstract (EN): Understanding the effect of glycation on the function of transferrin, the systemic iron transporter, is fundamental to fully grasp the mechanisms leading to the loss of iron homeostasis observed in diabetes mellitus (DM). The spontaneous reaction with protein amino groups is one of the main causes of glucose toxicity, but the site specificity of this reaction is still poorly understood. Here in, an in vitro approach was used to study human holotransferrin glycation in detail. Lysine residues 103, 312 and 380 proved to be the most reactive sites, and overall glycation specificity was found to be remarkably different from that described for apo-transferrin. A computational biochemistry approach was subsequently applied to rationalize lysine reactivity. Even though pK(a) values, solvent accessible surface area, hydrogen bonds or the presence of nearby charged/polar residues could be related to lysine reactivity, these parameters do not suffice to describe glycation site specificity in holo-transferrin. Furthermore, analysis of the most reactive residues suggests that the correct lysine side chain orientation may play a fundamental role in reactivity. Nevertheless, in holo-transferrin, glycation occurs away from the iron binding sites and, despite the observed iron release, the modification of apo-transferrin should play a more relevant role for the loss of iron-binding capacity observed in the blood serum of DM patients.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 8