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

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.

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Journal
Communications Biology
Published
2025-11-25
DOI
https://doi.org/10.1038/s42003-025-09053-0
Primary Topic
Metalloenzymes and iron-sulfur proteins
Type
article
Field-Weighted Citation Impact
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article

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

William B. Whitman, Pierre Garcia, Béatrice Golinelli‐Pimpaneau, Paolo Zecchin et al.
Communications Biology
Metalloenzymes and iron-sulfur proteins
article

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

William B. Whitman, Pierre Garcia, Béatrice Golinelli‐Pimpaneau, Paolo Zecchin, Emma Shelton, Nadia Touati, Nisha He, Ornella Bimaï, Sylvain Gervason, Marc Fontecave, Christophe Velours, Bruno Faivre, Ludovic Pecqueur, Taiwo S. Akinyemi, Jean‐Luc Ravanat
article en

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.

Communications BiologyVol. 8(1)
Centre National de la Recherche Scientifique (FR), Chimie ParisTech - PSL (FR), Université de Bordeaux (FR), Institut Pasteur (FR), University of Georgia (US), Collège de France (FR), Université Paris Cité (FR), Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR), Université Paris-Saclay (FR), CEA Grenoble (FR), Sorbonne Université (FR), Institut de Recherche Interdisciplinaire de Grenoble (FR), Institut de Microbiologie de la Méditerranée (FR), Institut de Biologie Intégrative de la Cellule (FR), Laboratoire de chimie des processus biologiques (FR), Institut de Recherche de Chimie Paris (FR), CEA Paris-Saclay (FR), Laboratoire de Chimie des Polymères Organiques (FR), Université Grenoble Alpes (FR)
U.S. Department of Energy, European Commission, Agence Nationale de la Recherche, Centre National de la Recherche Scientifique, Basic Energy Sciences
Openalex Percentile: Top 74%
Metalloenzymes and iron-sulfur proteins
DOIOpen Access PDFOpenAlex
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