Chemogenetic Manipulation of H₂S with Spatiotemporal Precision

Area of Science:

• Biochemistry
• Molecular Biology
• Cellular Signaling

Background:

• Hydrogen sulfide (H2S) is a crucial signaling molecule with diverse biological roles.
• Existing tools for H2S manipulation lack precision, exhibiting off-target effects and uncontrolled release.
• Mechanistic studies of H2S are hindered by the limitations of current methods.

Purpose of the Study:

• To develop a novel chemogenetic tool for precise and controlled manipulation of intracellular hydrogen sulfide (H2S) flux.
• To overcome the limitations of conventional H2S donors and enzymatic systems.
• To enable interference-free investigation of H2S physiological and pathological functions.

Main Methods:

• Engineered a tool, H2SWITCH, derived from *Salmonella typhimurium* d-cysteine desulfhydrase (stDCyD).
• stDCyD catalyzes the enantioselective α,β-elimination of d-cysteine to produce bioavailable H2S.
• Demonstrated temporal control via substrate dosing for tunable H2S release.

Main Results:

• H2SWITCH exhibits high enantioselectivity for d-cysteine.
• The system demonstrates robust catalytic efficiency at physiological temperatures.
• Achieved temporally controlled and selective H2S generation in living cells.

Conclusions:

• H2SWITCH provides a chemically defined and interference-free method for H2S manipulation.
• This chemogenetic tool allows for unprecedented precision in studying H2S roles.
• Facilitates deeper understanding of H2S in complex biological systems and disease.