Metal-dependent inhibition of glyoxalase II: A possible mechanism to regulate the enzyme activity

Abstract

Glyoxalase II (GLX2, EC 3.1.2.6., hydroxyacylglutathione hydrolase) is a metalloenzyme involved in crucial detoxification pathways. Different studies have failed in identifying the native metal ion of this enzyme, which is expressed with iron, zinc and/or manganese. Here we report that GloB, the GLX2 from Salmonella typhimurium, is differentially inhibited by glutathione (a reaction product) depending on the bound metal ion, and we provide a structural model for this inhibition mode. This metal-dependent inhibition was shown to occur in metal-enriched forms of the enzyme, complementing the spectroscopic data. Based on the high levels of free glutathione in the cell, we suggest that the expression of the different metal forms of GLX2 during Salmonella infection could be exploited as a mechanism to regulate the enzyme activity.

A possible S‐glutathionylation of specific proteins by glyoxalase II: An in vitro and in silico study

“…To this purpose, we simulated an extended full atom molecular dynamics/docking simulation monitoring substrate position over time. In both cases, we could observe a peculiar stability of the formed Glo2‐GSH/GS − complexes, perfectly in agreement with the behavior observed by Campos‐Bermudez et al in Salmonella typhimurium Glo2. In particular, analyzing the MD trajectories of Glo2‐GSH (Figure A), we discovered that the ligand assumes a different orientation compared with the initial one.…”

“…Even if it is presumed that GS − is protonated by water molecules present in the active site, it is still unclear how GSH can be released from it. Besides, there is also experimental evidence that the addition of either substrate (SLG) or product (GSH) in Glo2 results in the formation of a stable enzyme‐product (Glo2‐GSH) complex . Starting from this evidence, we investigated the same ability to form highly stable complexes involving human Glo2 and GSH/GS − product.…”

Active Site Metal Ion in UDP-3-O-((R)-3-Hydroxymyristoyl)-N-acetylglucosamine Deacetylase (LpxC) Switches between Fe(II) and Zn(II) Depending on Cellular Conditions*

“…The absorbance spectrum of Fe(II)-bound LpxC has a broad peak with a maximum at 420 nM (⑀ 420 ϭ 1080 M Ϫ1 cm Ϫ1 ) (supplemental Fig. S1), similar to the spectra of other low spin non-heme Fe(II) complexes (41,42) and consistent with the extended x-ray absorption fine structure data suggesting pentacoordinate metal geometry (18).…”

Protein Tyrosine Phosphatase Inhibition by Metals and Metal Complexes

“…With the development of proteomics in the last two decades, the interactions between metal complexes and proteins have attracted more and more interest. Metal complexes have been shown to potently inhibit many enzymes, such as protein kinases, matrix metalloproteinases, telomerases, topoisomerase II, glutathione-S-transferases, histone deacetylases, and the chymotrypsin-like activity of the proteasome and so on (11,14,24,49,54,71,83). These enzymes have become possible targets for a novel metal-based drug design.…”