NeuralCipher Research overview
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Reactive α-oxoaldehydes, such as glyoxal (GO) and methylglyoxal (MGO), are cytotoxic glycolysis byproducts that induce cellular dysfunction by nonenzymatically modifying diverse macromolecules. Although DJ-1 (PARK7), a protein linked to Parkinson's disease, acts as a type-III glyoxalase/methylglyoxalase, the physiological function(s) of its prokaryotic homologs remain poorly understood. Here, we investigated the enzymatic and physiological properties of YhbO, one of four DJ-1 homologs in Escherichia coli. We demonstrate that YhbO has higher catalytic efficiency than DJ-1 and exhibits broad-spectrum α-oxoaldehyde hydratase activity against GO, MGO, and phenylglyoxal. Structural modeling and mutational analyses revealed that residues E17, G73, G74, C104, and H105 are important for catalysis, whereas D78, previously thought to comprise a Cys-His-Asp triad, is dispensable. Notably, H105 is strictly required, distinguishing the YhbO catalytic mechanism from that of DJ-1 and HchA. Further underscoring mechanistic divergence within the DJ-1 family, YhbO converted MGO into both L- and D-lactate, whereas DJ-1 generates only L-lactate. In cell-based assays, overexpression of wild-type YhbO conferred resistance to GO- and MGO-induced stress and suppressed the formation of GO- and MGO-derived adducts such as carboxymethyl-lysine and methylglyoxal-hydroimidazolone. In contrast, catalytically impaired YhbO mutants were unable to suppress adduct formation. Further, comparable levels of endogenous GO- or MGO-derived adducts in cells with YhbO knocked out, or a YhbO/HchA double knockout, suggest redundancy within the canonical glyoxalase I pathway. Taken together, these findings establish YhbO as a unique α-oxoaldehyde hydratase with distinct catalytic requirements and provide insights into the mechanistic diversity within the DJ-1 protein family.
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