Ligand binding remodels the oligomeric state and active site of Klebsiella pneumoniae azoreductase
Hitchings, R.; Ghosh, A.; Arcinas, A. J.; Almo, S. C.; Kelly, L.; Ryan, A.
Show abstract
Azo dyes are widespread in the environment, and humans ingest a range of these dyes present in food and drugs. The human gut microbiome significantly impacts the fate of ingested azo dyes primarily through the reduction of the azo bond (R-N=N-R'). Flavin-dependent azoreductases have been considered the key enzymatic drivers of this process. To challenge this paradigm, we constructed a sequence similarity network of known azoreductases and focused on AzoA of Klebsiella pneumoniae, a central representative within the gut microbiome cluster. Unexpectedly, K. pneumoniae AzoA displayed relatively low in vitro activity against a range of azo compounds. While the physiological implications remain unclear, these findings are consistent with the possibility that non-enzymatic mechanisms contribute substantially to azo compound reduction in the gut. Furthermore, structural characterization of AzoA, as a holoenzyme and in its substrate-bound state, revealed a previously unrecognized ligand-coupled mechanism involving remodeling of the active site and oligomeric state.
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