Selective Deamination of Mutagens by a Mycobacterial Enzyme.

Structure-based methods are powerful tools that are being exploited to unravel new functions with therapeutic advantage. Here, we report the discovery of a new class of deaminases, predominantly found in mycobacterial species that act on the commercially important s-triazine class of compounds. The enzyme Msd from Mycobacterium smegmatis was taken as a representative candidate from an evolutionarily conserved subgroup that possesses high density of Mycobacterium deaminases. Biochemical investigation reveals that Msd specifically acts on mutagenic nucleobases such as 5-azacytosine and isoguanine and does not accept natural bases as substrates. Determination of the X-ray structure of Msd to a resolution of 1.9 Å shows that Msd has fine-tuned its active site such that it is a hybrid of a cytosine as well as a guanine deaminase, thereby conferring Msd the ability to expand its repertoire to both purine and pyrimidine-like mutagens. Mapping of active site residues along with X-ray structures with a series of triazine analogues aids in deciphering the mechanism by which Msd proofreads the base milieu for mutagens. The genome location of the enzyme reveals that Msd is part of a conserved cluster that confers the organism with innate resistance toward select xenobiotics by triggering their efflux.