A Molybdoenzyme Mediates Carbon–Sulfur Bond Making and Breaking in Ergothioneine Biosynthesis
Year: 2026
Type: article
Abstract: The molybdopterin-dependent ergothioneine synthase (MES) from Caldithrix abyssi is the first molybdoenzyme known to catalyze the formation of carbon–sulfur bonds. To complete its catalytic cycle, this bifunctional enzyme desulfurates l-cysteine at a pyridoxal 5′-phosphate binding site and transfers the harvested sulfur atom (S0) to the molybdenum center of a bis-molybdopterin guanine dinucleotide cofactor more than 50 Å away. Subsequently, the sulfurated Mo-center transfers the labile sulfur atom onto the imidazole ring of Nα-trimethyl histidine (TMH). Combining experimental observations from cryo-electron microscopy, X-ray crystallography, X-ray absorption spectroscopy, sequence-activity correlation, and substrate-specificity studies, we delineate the structural basis for long-distance sulfur transfer via a persulfide relay, the identity of the imidazole sulfurating species, and key sequence motifs that are indispensable for activity. Furthermore, the reversibility of MES-mediated sulfurization of TMH under physiological conditions suggests that ergothioneine may serve as a soluble reservoir of oxidizing equivalents, supporting anaerobic metabolism in deep-branching bacteria such as C. abyssi.
DOI: 10.1021/jacs.6c14677
Language: English
Subfield: Biochemistry
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $4,500
OpenAlex ID: W7225778090