Ergothioneine is a histidine derivative with a 2-mercaptoimidazole
side chain and a trimethylated α-amino group. Although the physiological
function of this natural product is not yet understood, the facts
that many bacteria, some archaea, and most fungi produce ergothioneine
and that plants and animals have specific mechanisms to absorb and
distribute ergothioneine in specific tissues suggest a fundamental
role in cellular life. The observation that ergothioneine biosynthesis
has emerged multiple times in molecular evolution points to the same
conclusion. Aerobic bacteria and fungi attach sulfur to the imidazole
ring of trimethylhistidine
via
an O
2
-dependent
reaction that is catalyzed by a mononuclear non-heme iron enzyme.
Green sulfur bacteria and archaea use a rhodanese-like sulfur transferase
to attach sulfur
via
oxidative polar substitution.
In this report, we describe a third unrelated class of enzymes that
catalyze sulfur transfer in ergothioneine production. The metallopterin-dependent
ergothioneine synthase from
Caldithrix abyssi
contains an N-terminal module that is related to the tungsten-dependent
acetylene hydratase and a C-terminal domain that is a functional cysteine
desulfurase. The two modules cooperate to transfer sulfur from cysteine
onto trimethylhistidine. Inactivation of the C-terminal desulfurase
blocks ergothioneine production but maintains the ability of the metallopterin
to exchange sulfur between ergothioneine and trimethylhistidine. Homologous
bifunctional enzymes are encoded exclusively in anaerobic bacterial
and archaeal species.