Elucidation of a Dual Control Mechanism for Detoxification and Excretion of Harmful Reactive Sulfur Species in the Body - How "Dual Control" by Methylation and Oxidation Protects Living Organisms

Chiba University Graduate School of Pharmaceutical Sciences Lecturer Yasunori Fukumoto and Professor Yasumitsu Ogura's research group, in collaboration with Gunma University and Toho University, has elucidated a mechanism by which reactive sulfur species (RSS) (Note 1) generated in vivo are detoxified by methylation and excreted from the body as urine. This study shows that RSS are controlled by two distinct pathways, methylation and oxidation, providing a fundamental basis for deepening the understanding of control mechanisms related to reductive stress in living organisms. In the future, it is expected to contribute to elucidating the relationship between dysregulation of RSS and physiological/pathological changes and diseases.

These research findings were published in the academic journal Redox Biology on April 1, 2026.

(Link to paper: 10.1016/j.redox.2026.104144)

Figure: Dual Control by Methylation and Oxidation of Reactive Sulfur Species

Background of Research

While RSS are indispensable for maintaining life, their excessive accumulation causes cytotoxicity, so their concentration is regulated in vivo. Until now, the elimination of RSS was thought to be primarily carried out by the oxidation pathway involving enzymes in the mitochondria. It has been hypothesized that a mechanism exists to detoxify and excrete RSS in a safe form under conditions where the oxidative system does not function normally, such as in cases of massive RSS accumulation or reductive stress, but its molecular mechanism remained unknown.

Key Points of Research Findings

1. Elucidation of the "three-stage methylation pathway" that detoxifies harmful RSS in the body and excretes them into urine

As a result of biochemical analysis focusing on methylating enzymes, it was identified for the first time that RSS are methylated by TPMT (Note 2). Starting from this reaction, it was revealed that a metabolic pathway exists where highly reactive RSS are converted into less volatile and less toxic TMS (Note 4) in three stages through the action of enzymes such as INMT (Note 3), and finally excreted from the body as urine. TMS was known as a sulfur metabolite detected in human urine, but its production mechanism has been elucidated by this study.

2. Discovery of "dual control" by "methylation" pathway and "oxidation" pathway

It was known that RSS are metabolized by mitochondrial "oxidation" enzymes, but this study showed that a different methylation pathway also exists in parallel. These two pathways are not merely redundant mechanisms but are suggested to be a "dual control mechanism" that acts as a safeguard depending on the situation.

3. Elucidation of the molecular mechanism of substrate selectivity in reactive sulfur methylation by computational science analysis

In silico (computational science) analysis and biochemical experiments elucidated the molecular mechanism by which TPMT preferentially methylates specific RSS. As a result, it was found that methylation efficiency strongly depends on the smallness of "steric hindrance" at the enzyme active site rather than the electrical properties of the molecule, indicating the mechanism by which certain RSS are selectively detoxified and excreted.

Future Outlook (Researcher Comments)

This research has revealed the previously unknown mechanism of detoxification and excretion of reactive sulfur. The dual control shown in this study represents a fundamental principle of reaction selectivity and metabolic control in vivo. These findings are not only of basic biological importance but are also expected to contribute to medicine. For example, personalized medicine could be considered, taking into account the health risks due to excessive RSS accumulation in people with low TPMT activity, which has high genetic individuality (polymorphism). Furthermore, by enhancing the effects of RSS-releasing drugs or reducing their side effects, safer and more appropriate treatments are expected to be realized. In the future, we aim to clarify what kind of physiological and pathological changes result from excessive RSS accumulation and dysregulation in TPMT-deficient models.

Glossary

Note 1) Reactive Sulfur Species (RSS): A general term for a group of highly reactive sulfur-containing molecules produced in living organisms. While involved in biological defense and intercellular signaling, their excessive accumulation causes cell damage.

Note 2) TPMT (Thiopurine S-methyltransferase): One of the enzymes responsible for methylation reactions in living organisms. In this study, it was newly identified as an enzyme involved in the detoxification and excretion of reactive sulfur.

Note 3) INMT (Indolethylamine N-methyltransferase): One of the enzymes responsible for methylation reactions in living organisms and involved in the metabolism of specific small molecular compounds.

Note 4) TMS (Trimethylsulfonium): A sulfur compound detected in urine. This study proved that it is the final product formed when reactive sulfur undergoes multi-stage methylation.