One Hundred Years of Sulfido Ligand in the Molybdenum Cofactor: New Perspectives

The xanthine oxidase (XO) family of mononuclear molybdoenzymes consists of well-studied enzymes like XO, xanthine dehydrogenase (XDH), and aldehyde oxidase (AO) in eukaryotes. The characteristic of this family is a terminal sulfido ligand bound to the active site Mo or W ion. Historically, these enzymes were among the first to be investigated in a purified form. Since its discovery in 1902 in cow's milk, the XO enzyme is among the best-studied molybdoenzymes. Much pioneering work has been carried out including comprehensive spectroscopic and structural analyses to study the enzymes' molybdenum center. This led to the discovery that the enzyme produces superoxide and thereby inactivates itself by removal of the essential sulfido ligand at the active site. This sulfido ligand has been later discovered also in enzymes of the dimethyl sulfoxide (DMSO) reductase family. In this review, we describe historical aspects on the discovery and role of the sulfido ligand in the two enzyme families, contextualize new discoveries, and provide perspectives for future investigations into still elusive research questions urgently requiring determination, which may or may not span yet another 125 years.