1 research outputs found
Inhibition and Regulation of the Ergothioneine Biosynthetic Methyltransferase EgtD
Ergothioneine is
an emerging factor in cellular redox homeostasis
in bacteria, fungi, plants, and animals. Reports that ergothioneine
biosynthesis may be important for the pathogenicity of bacteria and
fungi raise the question as to how this pathway is regulated and whether
the corresponding enzymes may be therapeutic targets. The first step
in ergothioneine biosynthesis is catalyzed by the methyltransferase
EgtD that converts histidine into N-α-trimethylhistidine. This
report examines the kinetic, thermodynamic and structural basis for
substrate, product, and inhibitor binding by EgtD from <i>Mycobacterium
smegmatis</i>. This study reveals an unprecedented substrate
binding mechanism and a fine-tuned affinity landscape as determinants
for product specificity and product inhibition. Both properties are
evolved features that optimize the function of EgtD in the context
of cellular ergothioneine production. On the basis of these findings,
we developed a series of simple histidine derivatives that inhibit
methyltransferase activity at low micromolar concentrations. Crystal
structures of inhibited complexes validate this structure- and mechanism-based
design strategy