Small Substrate or Large? Debate Over the Mechanism of Glycation Adduct Repair by DJ-1.

Glycation, the term for non-enzymatic covalent reactions between aldehyde metabolites and nucleophiles on biopolymers, results in deleterious cellular damage and diseases. Since Parkinsonism-associated protein DJ-1 was proposed as a novel deglycase that directly repairs glycated adducts, it has been considered a major contributor to glycation damage repair. Recently, an interesting debate over the mechanism of glycation repair by DJ-1 has emerged, focusing on whether the substrate of DJ-1 is glycated adducts or the free small aldehydes. The physiological significance of DJ-1 on glycation defense also remains in question. This debate is complicated by the fact that glycated biomolecular adducts are in rapid equilibrium with free aldehydes. Here, we summarize experimental evidence for the two possibilities, highlighting both consistencies and conflicts. We discuss the experimental complexities from a mechanistic perspective, and suggest classes of experiments that should help clarify this debate. Debate over repair of glycation by the enzyme DJ-1 has emerged, centering on whether the substrate is glycated biomacromolecules (deglycase activity) or free small-molecule aldehydes (glyoxalase activity). Jun and Kool summarize experimental evidence for each possibility, highlighting both consistencies and conflicts, and discuss the experimental complexities from a mechanistic perspective. [ABSTRACT FROM AUTHOR]