Chemogenetic Manipulation of H <sub>2</sub> S with Spatiotemporal Precision

Hydrogen sulfide (H<sub>2</sub>S) is a signaling molecule with a plethora of biological functions, yet precision tools for modulating its intracellular flux remain scarce. Conventional small-molecule donors and enzymatic systems often suffer from off-target reactivity, uncontrolled release kinetics, and redox crosstalk, confounding mechanistic studies. Here, we establish a <i>Salmonella typhimurium</i> d-cysteine desulfhydrase (stDCyD)-derived chemogenetic tool for controlled H<sub>2</sub>S manipulation in living cells. stDCyD catalyzes the α,β-elimination of d-cysteine to selectively yield bioavailable H<sub>2</sub>S. We term this tool H<sub>2</sub>SWITCH. Our approach exhibits pronounced enantioselectivity for d-cysteine, robust catalytic efficiency at physiological temperatures, and temporal tunability through substrate dosing. This chemogenetic tool provides a chemically defined and interference-free method to unravel the physiological and pathological roles of H<sub>2</sub>S with unprecedented precision in complex biological systems.

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Publication Details

Journal
Precision Chemistry
Published
2025-12-31
DOI
https://doi.org/10.1021/prechem.5c00189
Primary Topic
Sulfur Compounds in Biology
Type
article
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article

Chemogenetic Manipulation of H 2 S with Spatiotemporal Precision

Emre Vatandaşlar, Toghrul Almammadov, Sven Vilain, Asel Aydeğer et al.
Precision Chemistry
Sulfur Compounds in Biology
article

Chemogenetic Manipulation of H 2 S with Spatiotemporal Precision

Emre Vatandaşlar, Toghrul Almammadov, Sven Vilain, Asel Aydeğer, Asal Ghaffari Zaki, Emrah Eroğlu, Esra Nur Yi̇ği̇t, Seyed Mohammad Miri, Tuba Akgül Çağlar, Muhammed İkbal, Omar Aljundi, Mehmet Şerif Aydın, Joudi Armouch, Sena Yildirim, Şeyma Çimen, Hamzah Issa, Refia Zeynep Mete
article en

Abstract

Hydrogen sulfide (H<sub>2</sub>S) is a signaling molecule with a plethora of biological functions, yet precision tools for modulating its intracellular flux remain scarce. Conventional small-molecule donors and enzymatic systems often suffer from off-target reactivity, uncontrolled release kinetics, and redox crosstalk, confounding mechanistic studies. Here, we establish a <i>Salmonella typhimurium</i> d-cysteine desulfhydrase (stDCyD)-derived chemogenetic tool for controlled H<sub>2</sub>S manipulation in living cells. stDCyD catalyzes the α,β-elimination of d-cysteine to selectively yield bioavailable H<sub>2</sub>S. We term this tool H<sub>2</sub>SWITCH. Our approach exhibits pronounced enantioselectivity for d-cysteine, robust catalytic efficiency at physiological temperatures, and temporal tunability through substrate dosing. This chemogenetic tool provides a chemically defined and interference-free method to unravel the physiological and pathological roles of H<sub>2</sub>S with unprecedented precision in complex biological systems.

Precision ChemistryVol. 4(1)
Sabancı Üniversitesi (TR), Academy of Nutrition and Dietetics (US), Istanbul Medipol University (TR), Institut thématique Génétique, génomique et bioinformatique (FR), Bioengineering Center (RU), Czech Academy of Sciences, Institute of Physiology (CZ), International School of Management (FR), Bolu Abant İzzet Baysal University (TR), Graduate School USA (US)
Openalex Percentile: Top 32%
Sulfur Compounds in Biology
DOIOpen Access PDFOpenAlex
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