The ubiquitous sulfur metabolite ergothioneine is biosynthesized by oxidative
attachment of a sulfur atom to the imidazole ring of Nα-trimethylhistidine.
Most actinobacteria, including Mycobacterium tuberculosis, use γ-glutamyl
cysteine as a sulfur donor. In subsequent steps the carbon scaffold of
γ-glutamyl cysteine is removed by the glutamine amidohydrolase EgtC and the
β-lyase EgtE. We determined the crystal structure of EgtC from Mycobacterium
smegmatis in complex with its physiological substrate. The set of active site
residues that define substrate specificity in EgtC are highly conserved, even in
homologues that are not involved in ergothioneine production. This conservation
is compounded by the phylogenetic distribution of EgtC-like enzymes indicates
that their last common ancestor might have emerged for a purpose other than
ergothioneine production.
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