Evidence Against a Role for the Parkinsonism-associated Protein DJ-1 in Methylglyoxal Detoxification

Abstract

Edited by Gerald W. HartMethylglyoxal (MG) is a reactive metabolite that forms adducts on cysteine, lysine and arginine residues of proteins, thereby affecting their function. Methylglyoxal is detoxified by the Glyoxalase system, consisting of two enzymes, Glo1 and Glo2, that act sequentially to convert MG into D-lactate. Recently, the Parkinsonism-associated protein DJ-1 was described in vitro to have glyoxalase activity, thereby detoxifying the MG metabolite, or deglycase activity, thereby removing the adduct formed by MG on proteins. Since Drosophila is an established model system to study signaling, neurodegeneration, and metabolic regulation in vivo, we asked whether DJ-1 contributes to MG detoxification in vivo. Using both DJ-1 knockdown in Drosophila cells in culture, and DJ-1␤ knock-out flies, we could detect no contribution of DJ-1 to survival to MG challenge or to accumulation of MG protein adducts. Furthermore, we provide data suggesting that the previously reported deglycation activity of DJ-1 can be ascribed to a TRIS buffer artifact.

The Role of Advanced Glycation End Products in Aging and Metabolic Diseases: Bridging Association and Causality

“…The deglycase activity of DJ1 was not supported in a follow-up study due to a potential artifact arising from TRIS buffer (Pfaff et al, 2017). More recent studies using deglycase-depleted cells reinforce DJ1 as a bona fide deglycase (Richarme and Dairou, 2017).…”

Methylglyoxal and Advanced Glycation End Products in Patients with Diabetes – What We Know so Far and the Missing Links

“…Therefore MG is a precursor of advanced glycation end products (AGEs). MG is metabolized by glyoxalase 1 (GLO-1) and GLO-2 to the end product D-lactate [27], as well as by increased catalytic efficiency of aldose reductase towards hemithioacetal, most likely caused by S-nitrosylation of aldose reductase, but not by Parkinsonism-associated protein DJ-1 [23,[28][29][30][31][32]. There is mounting evidence that advanced glycation end products are playing a causative role in microvascular diabetic complications.…”

C Terminus of DJ-1 Determines Its Homodimerization, Deglycation Activity and Suppression of Ferroptosis

“…MGO produced by glucose oxidation, lipid peroxidation and DNA oxidation are reactive metabolites that form adducts on cysteine, lysine and arginine residues of protein [30]. MGO is converted into D-lactate by two enzymes Glyoxalase1 (Glo1) and Glyoxalase 2 (Glo 2) in the glyoxalase system via a mechanism requiring reduced glutathione (GSH) [31].…”

“…3b) [22]. The glyoxalase and deglycase activity could be summarized as the MGO detoxification ability of DJ-1 [30]. What we next wanted to investigate was that whether C terminus of DJ-1 has effects on the MGO detoxification ability of DJ-1.…”