Discovery and Characterization of the Metallopterin-Dependent Ergothioneine Synthase from Caldithrix abyssi.

Abstract

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 O2-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.