# Evolution, structure and function of L-cysteine desulfidase, an enzyme involved in sulfur metabolism in the methanogenic archeon Methanococcus maripaludis

## TL;DR

This study explores how the enzyme CyuA in the archaeon Methanococcus maripaludis helps manage sulfur metabolism by breaking down cysteine.

## Contribution

The paper reveals CyuA's role in sulfur metabolism and its evolutionary origin via horizontal gene transfer.

## Key findings

- CyuA was acquired by archaea through horizontal gene transfer from bacteria.
- CyuA uses a [4Fe-4S] cluster to catalyze cysteine desulfuration.
- A [4Fe-5S] intermediate may transfer sulfur to tRNA sulfuration enzymes.

## Abstract

The biosynthesis of sulfur-containing molecules, which play essential roles in cell metabolism, often relies on enzymes that mobilize sulfur from cysteine. The function of such enzyme, L-cysteine desulfidase CyuA, which catalyzes L-cysteine decomposition to pyruvate, ammonia, and hydrogen sulfide, remains incompletely understood. Here, we used phylogenetic, genetic, biochemical, spectroscopic, and structural approaches to connect molecular structure to cellular physiology and evolutionary history and elucidate CyuA’s role in sulfur metabolism. We found that Methanococcales and several other archaeal lineages acquired CyuA via horizontal gene transfer from bacteria. In Methanococcus maripaludis, CyuA (MmCyuA) stimulates growth in sulfide-rich conditions and enables slow growth with cysteine as the sole sulfur source. Crystallographic and biochemical data reveal that MmCyuA binds a [4Fe-4S] cluster coordinated by three conserved cysteines; the fourth ligand is a nonconserved cysteine in the wild-type enzyme but is replaced by glycerol or ethylene glycol in a variant. These results enabled modeling of the enzyme–substrate complex, allowing us to propose a detailed mechanism for L-cysteine desulfuration by CyuA, potentially involving a transient [4Fe-5S] species to transfer sulfur from cysteine to various [4Fe-4S]-dependent tRNA sulfuration enzymes. These findings advance understanding of sulfur activation and trafficking related to biosynthetic pathways leading to sulfur-containing compounds.

The L-cysteine desulfidase CyuA, acquired by Methanococcales and other archaea via horizontal gene transfer, employs a [4Fe-4S] cluster to catalyze cysteine desulfuration, and a [4Fe-5S] intermediate likely plays a role in sulfur transfer to tRNA sulfuration enzymes.