# Molybdenum-independent [4Fe-4S]-Catalyzed Sulfate Assimilation Sustains Salmonella Virulence

## TL;DR

Salmonella uses a unique [4Fe-4S] enzyme to assimilate sulfur without molybdenum, supporting its survival and virulence in the host.

## Contribution

Discovery of molybdenum-independent periplasmic sulfate reductases in Salmonella with [4Fe-4S] catalysis.

## Key findings

- Three periplasmic sulfate reductases in Salmonella MopB family enable sulfur assimilation and virulence.
- These enzymes use [4Fe-4S] instead of molybdenum cofactor for catalysis, a novel mechanism in MopB enzymes.
- Orthologs suggest [4Fe-4S] catalysis may be widespread in the MopB superfamily.

## Abstract

Nontyphoidal Salmonella exploits the metabolic versatility of its 17 molybdenum cofactor (MOCO)-containing MopB family members to respire on substrates as chemically disparate as formate, nitrate, and methionine sulfoxide1–4. Here, we identify three hitherto unknown periplasmic sulfate reductases within the Salmonella MopB family. These enzymes have departed from the conventional energetics of canonical MopB molybdoenzymes to embrace roles in the biosynthetic assimilation of sulfur. The three periplasmic sulfate reductases facilitate the formation of hydrogen sulfide and [Fe-S] metalloproteins, thereby enabling Salmonella to grow in gut and viscera while defending against reactive species engendered by the phagocyte NADPH oxidase. In unprecedented fashion, the catalytic cycle of these periplasmic sulfate reductases is independent of the MOCO metal center used by archetypical MopB enzymes such as nitrate or dimethyl sulfoxide reductases, relying instead on the redox activity of the nearby [4Fe-4S] prosthetic group. The existence of orthologs of Salmonella periplasmic sulfate reductases in distant evolutionary branches suggests that [4Fe-4S]-dependent catalysis may occur across the ubiquitous MopB superfamily. Our research in Salmonella offers insights into the modular evolution of redox centers in the widespread MopB superfamily, which has significantly shaped the biogeochemistry of Earth for over 2.5 billion years.