# Enzymes that generate and regulate intracellular persulfides and polysulfides: mechanistic insights and inhibitors

## TL;DR

This review explores enzymes that produce and regulate persulfides and polysulfides, highlighting their roles in biological processes and potential therapeutic applications.

## Contribution

The paper provides a comprehensive overview of the mechanisms and inhibitors of enzymes involved in reactive sulfur species regulation.

## Key findings

- CBS, CSE, 3MST, and CARS2 are major sources of intracellular persulfides and polysulfides.
- Mitochondrial enzymes like SQOR, ETHE1, and TST help regulate persulfide levels.
- Selective enzyme inhibitors could aid in understanding RSS functions and offer therapeutic potential.

## Abstract

Reactive sulfur species (RSS), which include various persulfides and polysulfides, are generated by multiple enzymes in vivo and play critical roles in mammalian physiological processes such as redox signaling, metabolic regulation, radical scavenging and anti-inflammatory responses. Cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE) and 3-mercaptopyruvate sulfurtransferase (3MST) are well known to mediate endogenous production of hydrogen sulfide (H2S), and, together with the mitochondrial isoform of cysteinyl-tRNA synthetase (CARS2), are proposed to be major sources of intracellular persulfides and polysulfides. In mitochondria, enzymes involved in the sulfide oxidation pathway, including sulfide:quinone oxidoreductase (SQOR), persulfide dioxygenase (ETHE1) and thiosulfate sulfurtransferase (TST), also contribute to maintaining and regulating intracellular persulfide levels. Selective inhibitors targeting these enzymes are expected to be powerful tools for elucidating the functions of RSS, as well as having therapeutic potential. In this review, we present a comprehensive overview of these enzymes, focusing on their reaction mechanisms and inhibitors.