Methylglyoxal-Derived Hydroimidazolone Advanced Glycation End-Products of Human Lens Proteins

Abstract

Methylglyoxal hydroimidazolones are quantitatively major AGEs of human lens proteins. These substantial modifications of lens proteins may stimulate further glycation, oxidation, and protein aggregation leading to the formation of cataract.

Glucosepane Is a Major Protein Cross-link of the Senescent Human Extracellular Matrix

“…In contrast, although not measured directly, methylglyoxal levels in extracellular matrix would be expected to be relatively lower as assessed by the low levels of methylglyoxal found in blood versus lens in normal healthy human subjects, i.e. ϳ80 versus 2000 nM (34). In support, levels of the methylglyoxal-lysine dimer cross-link have also been found lower in nondiabetic human skin collagen versus lens, i.e.…”

“…ϳ2000 ( Fig. 2A) versus 250 pmol/mg of protein (11), is intriguing and may be due to the high concentration of methylglyoxal found in lens (34), which most likely competes with glucose for available modification sites. Indeed, the primary source of methylglyoxal is intracellular metabolism (35).…”

Increased expression of advanced glycation end-products and their receptor, and activation of nuclear factor kappa-B in lacrimal glands of diabetic rats

“…In addition, Il1b and Tnf mRNA are increased in lacrimal gland and salivary glands of animal models with exocrine gland inflammatory dysfunction and on the ocular surface of patients with dry eye syndrome [15,16]. AGE-related mechanisms have been found to play a role in the pathogenesis of ocular diseases such as diabetic vitreous-retinopathy [17][18][19], age-related macular degeneration [20,21] and cataract [22][23][24]. Taken together, these data suggest that the possible mechanisms by which hyperglycaemia and oxidative stress act in diabetes-related lacrimal gland dysfunction may involve the formation of AGE and activation of NFKB1 in the lacrimal gland, leading to the expression of pro-inflammatory cytokines such as IL1B and TNF in this tissue.…”

Evidence of Highly Conserved β-Crystallin Disulfidome that Can be Mimicked by In Vitro Oxidation in Age-related Human Cataract and Glutathione Depleted Mouse Lens*

“…In conclusion, the β-crystallin disulfidome is highly conserved in age-related nuclear cataract and LEGSKO mouse, and reproducible by in vitro oxidation, whereas some of the disulfide formation sites in γ-crystallins necessitate prior conformational changes. Overall, the LEGSKO mouse model is closely reminiscent of age- Aging lens crystallins accumulate post-synthetic modifications that can be broadly classified into three categories, namely (1) protein backbone changes, such as racemization and truncation (1-3), (2) conversion of one amino acid into another, such as deamidation of asparagine into aspartate or deguanidination of arginine into ornithine, deamination of lysine into allysine and 2-aminoadipic acid (4 -6), and (3) amino acid residue damage from reactive carbonyls and reactive oxygen species (7,8). Carbonyl damage results from the Maillard Reaction by glucose, methylglyoxal, or oxidation products of ascorbate, tryptophan or lipids which form adducts and crosslinks with nucleophilic group of lysine, arginine and cysteine.…”