Journal
ANTIOXIDANTS & REDOX SIGNALING
Volume 18, Issue 7, Pages 743-755Publisher
MARY ANN LIEBERT, INC
DOI: 10.1089/ars.2012.4749
Keywords
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Funding
- Australian Research Council (ARC) [DP0986578]
- National Health & Medical Research Council (NHMRC) [565526]
- Australian Postgraduate Award
- Australian Research Council [DP0986578] Funding Source: Australian Research Council
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Aim: The glutathione-dependent AdhC-EstD formaldehyde detoxification system is found in eukaryotes and prokaryotes. It is established that it confers protection against formaldehyde that is produced from environmental sources or methanol metabolism. Thus, its presence in the human host-adapted bacterial pathogen Neisseria meningitidis is intriguing. This work defined the biological function of this system in the meningococcus using phenotypic analyses of mutants linked to biochemical and structural characterization of purified enzymes. Results: We demonstrated that mutants in the adhC and/or estD were sensitive to killing by formaldehyde. Inactivation of adhC and/or estD also led to a loss of viability in biofilm communities, even in the absence of exogenous formaldehyde. Detailed biochemical and structural analyses of the esterase component demonstrated that S-formylglutathione was the only biologically relevant substrate for EstD. We further showed that an absolutely conserved cysteine residue was covalently modified by S-glutathionylation. This leads to inactivation of EstD. Innovation: The results provide several conceptual innovations. They provide a new insight into formaldehyde detoxification in bacteria that do not generate formaldehyde during the catabolism of methanol. Our results also indicate that the conserved cysteine, found in all EstD enzymes from humans to microbes, is a site of enzyme regulation, probably via S-glutathionylation. Conclusion: The adhc-estD system protects against formaldehyde produced during endogenous metabolism. Antioxid. Redox Signal. 18, 743-755.
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