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Seminar by Dr. Federico Ortiz

Universidad de la República (UdelaR), Montevideo (Uruguay)

07 Sep 2015 16:00
07 Sep 2015 17:00
Lecture room 2009, Jülich GRS building (16.15)

Insights on the Mechanism of Early Glycation of Human Serum Albumin (HSA): from Glucopyranose Opening to Lys195 Schiff Base Formation

The increase of glucose in the blood of diabetic organisms notably accelerates non-enzymatic glycosylation (aka glycation) of biological amines [1]. Accumulation of glycation products has been related for years to diabetes-derived pathologies among others [2]. From a chemical point of view, glycation involves a complex cascade of reactions triggered by nucleophilic addition of primary amino groups -mainly from Lys/Arg or N-term residues- on reactive carbonyls from sugars and other species.
Through such processes Early Glycation Products (Schiff Bases–SB and Amadori Products) and Advanced Glycation/Glycoxidation End Products (AGEs) are respectively formed by reversible and irreversible steps. A very detailed understanding of the mechanism of early glycation of key proteins such as human serum albumin (HSA) may lead to the identification of new molecular targets for early diagnosing diabetic patients and contribute to the rational design of specific drugs to inhibit/reverse glycation and its deleterious effects in the organism.
The first 3D structure of HSA glycated by glucose obtained by X-Ray diffraction was reported in 2013, showing Lys195 modified into a SB (hereto HSA-SBK195) [3]. From the structural evidence the authors proposed a mechanism for glucopyranose opening in HSA involving assistance by a Lys199 neighbouring residue and assigning a crucial role to the hydrogen-bond (HB) network established within the Sudlow Site I of the protein, where Lys195/Lys199 are placed [3].
Different computational strategies and models were applied by us to gather further evidence to support/reject the mechanism of glucopyranose ring-opening proposed by Wang et al. [3], also examining the subsequent formation of HSA-SBK195. Our work included the use of reduced models of the real system in aqueous solution, described at a quantum mechanics level with DFT/PCM methods. Molecular dynamics
simulations were also performed under quasi-physiological conditions on both native/glycated HSA structures and for predicting the structure of HSA:Glucose initial complexes. Reactivity of both Lys residues was assessed at the ONIOM(DFT:AMBER) level. A comparative analysis on the nature and strength of the HB network at the glycation site was done using Wiberg bond indices from a Weinhold NBO analysis.


[1] Kisugi R, Kouzuma T, Yamamoto T, et al. Structural and glycation site changes of albumin in diabetic patient with very high glycated albumin. Clinica Chim Acta 2007, 382: 59-64.
[2] Furusyo N, Hayashi J. Glycated albumin and diabetes mellitus. Biochim Biophys Acta 2013, 1830: 5509-5514.
[3] Wang Y, Yu H, Shi X, et al. Structural mechanism of ring opening reaction of glucose by human serum albumin. J Biol Chem 2013, 288: 15980-15987.