Journal
FEBS JOURNAL
Volume 289, Issue 3, Pages 787-807Publisher
WILEY
DOI: 10.1111/febs.16193
Keywords
flavin-dependent monooxygenase; flavin-N5-peroxide; oncometabolite; oxidoreductase; oxygenolytic bond cleavage
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Funding
- Deutsche Forschungsgemeinschaft (DFG) [TE 931/3-1, TE 931/4-1, 235777276/GRK1976]
- Hans-Fischer Gesellschaft
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The salvaging pathway encoded by the yxe operon in Bacillus subtilis has been identified for detoxification and utilization of S-(2-succino)-adducts. YxeK is characterized as an important enzyme in sulfur metabolism, potentially utilizing a noncanonical flavin-N5-peroxide mechanism for C-S bond oxygenolysis.
Thiol-containing nucleophiles such as cysteine react spontaneously with the citric acid cycle intermediate fumarate to form S-(2-succino)-adducts. In Bacillus subtilis, a salvaging pathway encoded by the yxe operon has recently been identified for the detoxification and exploitation of these compounds as sulfur sources. This route involves acetylation of S-(2-succino)cysteine to N-acetyl-2-succinocysteine, which is presumably converted to oxaloacetate and N-acetylcysteine, before a final deacetylation step affords cysteine. The critical oxidative cleavage of the C-S bond of N-acetyl-S-(2-succino)cysteine was proposed to depend on the predicted flavoprotein monooxygenase YxeK. Here, we characterize YxeK and verify its role in S-(2-succino)-adduct detoxification and sulfur metabolism. Detailed biochemical and mechanistic investigation of YxeK including O-18-isotope-labeling experiments, homology modeling, substrate specificity tests, site-directed mutagenesis, and (pre-)steady-state kinetics provides insight into the enzyme's mechanism of action, which may involve a noncanonical flavin-N5-peroxide species for C-S bond oxygenolysis.
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