Detoxification of methylglyoxal by the nucleophilic bidentate, phenylacylthiazolium bromide

G P Ferguson, S VanPatten, R Bucala, Y Al-Abed

Research output: Contribution to journalArticle

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Abstract

Dicarbonyl-containing compounds such as methylglyoxal (MG) are toxic to cells since they can interact with the nucleophilic centers of macromolecules. MG has been found to accumulate during hyperglycemia, and it has been suggested that this reactive dicarbonyl may contribute to the tissue damage and long-term complications of diabetes. A sensitive bacterial assay for investigating the ability of nucleophilic agents to interact with and detoxify MG has been developed. This assay utilizes the sensitivity of exponential phase cells of an Escherichia coli double mutant lacking the KefB and KefC potassium channels toward MG. The bidentate nucleophile, phenylacylthiazolium bromide (PTB), was found to protect and allow the growth of E. coli cells in the presence of either externally added or endogenously produced MG. In the absence of PTB, growth was completely inhibited and rapid cell death occurred under these conditions. PTB protected E. coli against MG almost as well as aminoguanidine, a compound shown previously to be involved in detoxification. The level of protection by PTB against MG was much greater than for the endogenous nucleophile, glutathione. These data suggested that PTB could interact with and detoxify MG. The mechanism of this interaction was characterized by NMR and mass spectroscopy.

Original languageEnglish
Pages (from-to)617-622
Number of pages6
JournalChemical Research in Toxicology
Volume12
Publication statusPublished - 1999

Keywords

  • ESCHERICHIA-COLI K-12
  • ADVANCED GLYCOSYLATION
  • POTASSIUM CHANNELS
  • N-ETHYLMALEIMIDE
  • IN-VITRO
  • GLUTATHIONE
  • ACTIVATION
  • SURVIVAL
  • SYSTEM
  • CELLS

Cite this

Ferguson, G. P., VanPatten, S., Bucala, R., & Al-Abed, Y. (1999). Detoxification of methylglyoxal by the nucleophilic bidentate, phenylacylthiazolium bromide. Chemical Research in Toxicology, 12, 617-622.

Detoxification of methylglyoxal by the nucleophilic bidentate, phenylacylthiazolium bromide. / Ferguson, G P ; VanPatten, S ; Bucala, R ; Al-Abed, Y .

In: Chemical Research in Toxicology, Vol. 12, 1999, p. 617-622.

Research output: Contribution to journalArticle

Ferguson, GP, VanPatten, S, Bucala, R & Al-Abed, Y 1999, 'Detoxification of methylglyoxal by the nucleophilic bidentate, phenylacylthiazolium bromide', Chemical Research in Toxicology, vol. 12, pp. 617-622.
Ferguson, G P ; VanPatten, S ; Bucala, R ; Al-Abed, Y . / Detoxification of methylglyoxal by the nucleophilic bidentate, phenylacylthiazolium bromide. In: Chemical Research in Toxicology. 1999 ; Vol. 12. pp. 617-622.
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N2 - Dicarbonyl-containing compounds such as methylglyoxal (MG) are toxic to cells since they can interact with the nucleophilic centers of macromolecules. MG has been found to accumulate during hyperglycemia, and it has been suggested that this reactive dicarbonyl may contribute to the tissue damage and long-term complications of diabetes. A sensitive bacterial assay for investigating the ability of nucleophilic agents to interact with and detoxify MG has been developed. This assay utilizes the sensitivity of exponential phase cells of an Escherichia coli double mutant lacking the KefB and KefC potassium channels toward MG. The bidentate nucleophile, phenylacylthiazolium bromide (PTB), was found to protect and allow the growth of E. coli cells in the presence of either externally added or endogenously produced MG. In the absence of PTB, growth was completely inhibited and rapid cell death occurred under these conditions. PTB protected E. coli against MG almost as well as aminoguanidine, a compound shown previously to be involved in detoxification. The level of protection by PTB against MG was much greater than for the endogenous nucleophile, glutathione. These data suggested that PTB could interact with and detoxify MG. The mechanism of this interaction was characterized by NMR and mass spectroscopy.

AB - Dicarbonyl-containing compounds such as methylglyoxal (MG) are toxic to cells since they can interact with the nucleophilic centers of macromolecules. MG has been found to accumulate during hyperglycemia, and it has been suggested that this reactive dicarbonyl may contribute to the tissue damage and long-term complications of diabetes. A sensitive bacterial assay for investigating the ability of nucleophilic agents to interact with and detoxify MG has been developed. This assay utilizes the sensitivity of exponential phase cells of an Escherichia coli double mutant lacking the KefB and KefC potassium channels toward MG. The bidentate nucleophile, phenylacylthiazolium bromide (PTB), was found to protect and allow the growth of E. coli cells in the presence of either externally added or endogenously produced MG. In the absence of PTB, growth was completely inhibited and rapid cell death occurred under these conditions. PTB protected E. coli against MG almost as well as aminoguanidine, a compound shown previously to be involved in detoxification. The level of protection by PTB against MG was much greater than for the endogenous nucleophile, glutathione. These data suggested that PTB could interact with and detoxify MG. The mechanism of this interaction was characterized by NMR and mass spectroscopy.

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