Biosynthesis of D/L-lactate from methylglyoxal

Parkinsonism-Associated Protein DJ-1 Is an Antagonist, Not an Eraser, for Protein Glycation

“…Only one other report has described a subsequent DJ-1 treatment protocol similar to ours, which produced results consistent with our findings. 32 Two other reports used buffer exchange via spin concentration to remove excess MGO, but subsequently evaluated only lactate formation 33 or MGO consumption 21 —not protein or peptide glycation—in the presence of DJ-1. Based on the experimental details provided, which involved very high initial concentrations of MGO (5 mM 33 or 100 mM 21 ), it is likely that the observed lactate formation (measured by HPLC) 33 or MGO consumption (measured by DNPH absorbance), 21 was due to carryover free MGO and/or a spontaneous AGE reversal process that released free MGO (see Figure S6 ) and reproduced conditions more similar to our concurrent protocol.…”

“…While our conclusions differ from most studies that have evaluated DJ-1 as a potential deglycase, our findings are straightforward to reconcile with this prior work. Most prior studies have used conditions that match closely with our concurrent protocol. ,,− ,,− ,− These include examples where the glycation reaction is started at an earlier time than the DJ-1 incubation, but free MGO remains unquenched when DJ-1 is added. ,,,− , Because MGO is a substrate for DJ-1, any attempt to measure “deglycase” activity without quenching free MGO will result in less glycation simply because there is less MGO available to react. In contrast, our work carefully included steps to remove excess, unbound MGO and quench glycation reactions prior to adding DJ-1.…”

“…Indeed, that is what we observed in the presence of glutathione, which we demonstrated to be an allosteric activator of DJ-1. Many prior studies have evaluated DJ-1 activity in the presence of glutathione; 20,25,[27][28][29]33 our results herein suggest that these may need to be reinterpreted in light of the finding that GSH augments DJ-1 activity. In particular, past kinetic studies may need to be revisited as allosteric enzymes do not obey traditional Michaelis−Menten kinetics and past work has typically co-varied equimolar concentrations of MGO and GSH.…”

The Tale of DJ-1 (PARK7): A Swiss Army Knife in Biomedical and Psychological Research

“…In this enzymatic reaction, GSH is believed to serve as a cofactor of DJ-1 and activate the aldehyde substrates ( Figure 2 ) [ 30 ]. Distinct from the glyoxalase activity of the GLO1–GLO2 system, the product of DJ-1 in the presence of GSH is L-lactate rather than D-lactate [ 19 , 30 ], which is attributed to the different enzyme microenvironments for catalytic stereoselectivity. Based on the same biochemical mechanism and esterase activity of DJ-1, other small molecule thiols (e.g., coenzyme A) can also act as the cofactor in this enzymatic process [ 30 ].…”

“…The redox activity of DJ-1 enables it to act as an important regulator in cells, against oxidative stress [ 1 ]. Recent research advances from our own lab [ 13 , 14 , 15 , 16 , 17 , 18 , 19 ] and other groups [ 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 ] have indicated that DJ-1 is a scavenger enzyme, not only for quenching reactive oxygen species (ROS) [ 12 ], but also for reactive carbonyl species (RCS), which include methylglyoxal (MGO) and glyoxal (GO). Moreover, DJ-1 exhibits other enzymatic activities, such as glyoxalase [ 29 , 30 ], deglycase [ 20 , 25 ], peptidase/protease [ 31 , 32 , 33 ], and esterase [ 30 , 34 ] functions, which are important in maintaining cellular protein homeostasis [ 1 ].…”