Parkinsonism-associated Protein DJ-1/Park7 Is a Major Protein Deglycase That Repairs Methylglyoxal- and Glyoxal-glycated Cysteine, Arginine, and Lysine Residues

Gilbert Richarme,Mouadh Mihoub,Julien Dairou,Linh Chi Bui,Thibaut Leger,Aazdine Lamouri

doi:10.1074/jbc.m114.597815

Abstract

Glycation is an inevitable nonenzymatic covalent reaction between proteins and endogenous reducing sugars or dicarbonyls (methylglyoxal, glyoxal) that results in protein inactivation. DJ-1 was reported to be a multifunctional oxidative stress response protein with poorly defined function. Here, we show that human DJ-1 is a protein deglycase that repairs methylglyoxal- and glyoxal-glycated amino acids and proteins by acting on early glycation intermediates and releases repaired proteins and lactate or glycolate, respectively. DJ-1 deglycates cysteines, arginines, and lysines (the three major glycated amino acids) of serum albumin, glyceraldehyde-3-phosphate dehydrogenase, aldolase, and aspartate aminotransferase and thus reactivates these proteins. DJ-1 prevented protein glycation in an Escherichia coli mutant deficient in the DJ-1 homolog YajL and restored cell viability in glucose-containing media. These results suggest that DJ-1-associated Parkinsonism results from excessive protein glycation and establishes DJ-1 as a major anti-glycation and anti-aging protein.

Highlights

Protein glycation is a nonenzymatic covalent reaction between proteins and carbonyl groups resulting in protein denaturation
DJ-1 prevented protein glycation in an Escherichia coli mutant deficient in the DJ-1 homolog YajL and restored cell viability in glucose-containing media. These results suggest that DJ-1-associated Parkinsonism results from excessive protein glycation and establishes DJ-1 as a major antiglycation and anti-aging protein
Mechanisms to protect the cells against carbonyl/electrophile stress involve aldoketoreductases, which reduce carbonyls into alcohols [23]; glyoxalases, which degrade glyoxals into acid-alcohols [24, 25]; detoxification systems that form and export electrophile-glutathione conjugates [26], and fructosamine-3-kinases (FN3Ks), which, by phosphorylating lysine-fructosamines formed after Amadori rearrangement of protein lysines glycated by glucose, increase their rate of deglycation by a factor of three and release repaired proteins and

Summary

Background

Protein glycation is a nonenzymatic covalent reaction between proteins and carbonyl groups resulting in protein denaturation. DJ-1 prevented protein glycation in an Escherichia coli mutant deficient in the DJ-1 homolog YajL and restored cell viability in glucose-containing media These results suggest that DJ-1-associated Parkinsonism results from excessive protein glycation and establishes DJ-1 as a major antiglycation and anti-aging protein. Mechanisms to protect the cells against carbonyl/electrophile stress involve aldoketoreductases, which reduce carbonyls into alcohols [23]; glyoxalases, which degrade glyoxals into acid-alcohols [24, 25]; detoxification systems that form and export electrophile-glutathione conjugates [26], and fructosamine-3-kinases (FN3Ks), which, by phosphorylating lysine-fructosamines formed after Amadori rearrangement of protein lysines glycated by glucose, increase their rate of deglycation by a factor of three and release repaired proteins and

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EXPERIMENTAL PROCEDURES

RESULTS

DISCUSSION