AGEs improving chaperone function in the optic lens?

Nonenzymatic carbohydrate modification of proteins results in the formation advanced glycation endproducts (AGEs), which can interfere with protein function. These molecules accumulate over the course of aging, in part because their unusual chemistry makes them difficult to clear. In the retina, accumulation of AGE and concomitant activation of the AGE receptor (RAGE) have been implicated in retinal aging and age-related macular degeneration (AMD), the primary cause of industrial blindness in the industrialized world.

In the lens of the eye, however, the story is more complex. A specific type of AGE, resulting from reaction with the abundant small carbohydrate methylglyoxal (MGO), can actually improve the function of a major lens chaperone that prevents cataracts. From Nagaraj et al.:

The Other Side of the Maillard Reaction

The Maillard reaction plays an important role in eye lens aging and cataract formation. Methylglyoxal (MGO) is a metabolic dicarbonyl compound present in the lens. It reacts with arginine residues in lens proteins to form advanced glycation end products (AGEs), such as hydroimidazolones and argpyrimidine. -Crystallin, comprising A- and B-crystallin, is a major protein of the lens and it functions as a chaperone protein. We have found that upon reaction with MGO, human A-crystallin becomes a more effective chaperone. Modification of specific arginine residues to AGEs appears to be the reason. Mutation of these arginine residues to alanine mirrors the effect of MGO, suggesting neutralization of the positive charge on arginine residues as a cause for improved chaperone function. Reaction with MGO also blocks the loss of the chaperone function of A-crystallin caused by nonenzymatic glycation by ascorbate and ribose. These findings suggest that low levels of MGO might help the lens remain transparent during aging.

Not all AGE-ylation of crystallins improve function, so there’s something special about the MGO modification — among other things, it prevents more deleterious modifications by other carbs.

One wonders whether instead of coming up with ways to break AGEs, we should be looking for ways to “pre-AGE” all vulnerable proteins with small carbohydrates whose adducts preserve (or, as is the case here, even improve) protein function.

Another thought: If we do identify good AGE-breakers, we’d better make sure they either target all AGEs equally, or hit deleterious AGEs harder. Otherwise, we could end up in a situation where we’re removing smaller, relatively innocuous modifications (e.g., by MGO) and making proteins more vulnerable to larger, more insidious ones (e.g., by ribose and ascorbate).


One comment

Comments are closed.