Glycolaldehyde Exhibits Superior Protein-Denaturing Potency among Reactive Carbonyl Compounds: Structural and Thermal Stability Analysis of Major Vascular Proteins

Reactive carbonyl compounds generated under hyperglycemic conditions -including glyoxal (GO), methylglyoxal (MGO), glyceraldehyde (GA), and glycolaldehyde (GC) -are well-established mediators of protein glycation and advanced glycation end product (AGE) formation, which are implicated in the pathogenesis of diabetic vascular complications.However, a systematic comparative analysis of their differential effects on the structural integrity of major vascular target proteins has been lacking.In the present study, we investigated the conformational and thermal stability changes induced by GO, MGO, GA, and GC in three proteins critical to the vascular microenvironment -human serum albumin (HSA), type I collagen, and fibrinogen -using circular dichroism (CD) spectroscopy and thermal denaturation analysis over an incubation period of up to 9 weeks at 37°C.All four compounds induced progressive secondary structural perturbations in all three proteins, as evidenced by attenuation of characteristic CD signals, loss of thermal stability, and promotion of intermolecular aggregation.Among the compounds tested, GC consistently induced the most pronounced and earliest conformational disruption across all three proteins, while GO exerted the weakest effects and MGO and GA demonstrated intermediate behavior.Size exclusion chromatography independently confirmed GC-induced high-molecular-weight aggregate formation in both HSA and fibrinogen.These differential reactivities are discussed in terms of the intrinsic chemical properties of each compound, including molecular size, electrophilicity, and hydration state, with particular emphasis on the unique capacity of GC -the smallest of the compounds retaining an appreciable free-aldehyde population -to access buried protein regions and destabilize hydrophobic cores.These findings provide new mechanistic insights into the chemical basis of differential protein glycation and its relevance to diabetic vascular pathology.