Emerging Chemical Diversity and Potential Applications of Enzymes in the DMSO Reductase Superfamily

Abstract

Molybdenum- and tungsten-dependent proteins catalyze essential processes in living organisms and biogeochemical cycles. Among these enzymes, members of the dimethyl sulfoxide (DMSO) reductase superfamily are considered the most diverse, facilitating a wide range of chemical transformations that can be categorized as oxygen atom installation, removal, and transfer. Importantly, DMSO reductase enzymes provide high efficiency and excellent selectivity while operating under mild conditions without conventional oxidants such as oxygen or peroxides. Despite the potential utility of these enzymes as biocatalysts, such applications have not been fully explored. In addition, the vast majority of DMSO reductase enzymes still remain uncharacterized. In this review, we describe the reactivities, proposed mechanisms, and potential synthetic applications of selected enzymes in the DMSO reductase superfamily. We also highlight emerging opportunities to discover new chemical activity and current challenges in studying and engineering proteins in the DMSO reductase superfamily. Expected final online publication date for the Annual Review of Biochemistry, Volume 91 is June 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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

“…A second explanation could be that oxidative sulfurization of heterocycles is or was a much more common microbial activity than is currently appreciated. Some of the many EanB-like enzymes, , and mononuclear molybdenum-containing enzymes that are encoded in bacterial genomes and have no known function, may attach sulfur to heterocycles. An abundance and diversity of such enzymes with promiscuous activity for TMH may have facilitated the emergence of new ergothioneine synthases …”

“…We consider this mechanism less likely. Irrespective of the mechanism, we anticipate that further examination of the structure and mechanism of MES will open new avenues for exploiting Mo-dependent enzymes in biocatalysis, not the least for applications in the fermentative production of ergothioneine in recombinant microorganisms. − …”

“…All members of the DMSO reductase (DMSOR) family bind similar cofactors with either terminal oxo or sulfido ligands and with Ser, Asp, or Cys as a single protein-derived metal ligand. 23,26 BL21 cells transformed with the CaMES encoding vector produced 10-fold less ergothioneine (entry 3, Table 1 and Figure S7). This observation is consistent with the known difficulties of BL21 cells to produce MPT-dependent enzymes.…”

“…Our observations suggest that the two modules cooperate to transfer a sulfur atom from l -cysteine to TMH. Among the diverse family of mononuclear molybdenum- and tungsten-dependent enzymes, − the metallopterin-dependent ergothioneine synthase (MES) is the first example that catalyzes carbon–sulfur bond formation. Homologous enzymes occur in a variety of strictly anaerobic organisms, including Caldithrix abyssi and other bacteria that were isolated from deep-ocean hydrothermal vents …”

“…Bottom: proposed structure of the bis-MGD cofactor of MES. All members of the DMSO reductase (DMSOR) family bind similar cofactors with either terminal oxo or sulfido ligands and with Ser, Asp, or Cys as a single protein-derived metal ligand 23,26.…”