Glucose reacts with proteins nonenzymatically under physiological conditions. Such glycation is exacerbated in diabetic patients with high levels of blood sugar and induces various complications. Human albumin serum (HSA) is the most abundant protein in plasma and is glycated by glucose. The glycation sites on HSA remain controversial among different studies. Here, we report two protein crystal structures of HSA in complex with either glucose or fructose. These crystal structures reveal the presence of linear forms of sugar for both monosaccharides. The linear form of glucose forms a covalent bond to Lys-195 of HSA, but this is not the case for fructose. Based on these structures, we propose a mechanism for glucose ring opening involving both residues Lys-195 and Lys-199. These results provide mechanistic insights to understand the glucose ring-opening reaction and the glycation of proteins by monosaccharides.
Background: Glucose can glycate human serum albumin (HSA), but the mechanism is unknown.
Results: Crystal structures of rHSA in the presence of glucose show that glucose is linearized and covalently linked to rHSA.
Conclusion: The residues Lys-195 and Lys-199 of rHSA are involved in glucose ring opening.
Significance: This work provides a structural mechanism of protein glycation.
Albumin
Fructose
Glucose
Serum
X-ray Crystallography
Crystal Structure
Glycation
Human Serum Albumin
Ring Opening
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The atomic coordinates and structure factors (codes4IW2and4IW1) have been deposited in the Protein Data Bank (http://wwpdb.org/).