An international research team led by Dr. Daniel Ken Inaoka at Nagasaki University has uncovered a unique biochemical mechanism that enables the parasitic worm Schistosoma mansoni to survive in sulfide-rich environments within the human body. The findings have been accepted for publication in the international journal Free Radical Biology and Medicine.
Schistosoma mansoni is the causative agent of intestinal schistosomiasis (Figure 1), a neglected tropical disease affecting millions of people worldwide. Adult worms inhabit the mesenteric veins, where they are constantly exposed to high concentrations of hydrogen sulfide produced by gut microbiota. Hydrogen sulfide is toxic to most aerobic organisms, yet the parasite thrives in this environment.
The researchers focused on sulfide:quinone oxidoreductase (SQOR), a mitochondrial enzyme responsible for the first step of sulfide metabolism. While SQOR has been well studied in humans and bacteria, its function in parasitic worms had remained largely unknown.
In this study, the team demonstrated that S. mansoni expresses a functional SQOR (SmSQOR) throughout its life cycle, including eggs, larvae (cercariae), and adult worms. Biochemical and spectroscopic analyses revealed that SmSQOR operates via a distinct quaternary reaction mechanism, requiring the simultaneous presence of sulfide, quinone, and a sulfur acceptor—unlike the human enzyme (Figure 1).
A key discovery was that SmSQOR forms an unusually stable charge-transfer complex, an electronic interaction between the enzyme and sulfur-containing substrates. This complex can persist for extended periods and is associated with reduced enzyme activity, a feature not observed in human SQOR. The researchers also identified specific amino acid residues essential for enzyme activity and charge-transfer complex formation.
“This parasite enzyme shows biochemical properties that are clearly different from those of the human counterpart,” said Dr. Inaoka. “These differences likely reflect an evolutionary adaptation to the sulfide-rich intestinal environment.”
The study further revealed that SmSQOR is localized in parasite mitochondria and is strongly expressed in adult worms, particularly in the tegument—the interface between parasite and host. Because sulfide metabolism appears essential for parasite survival and differs from that of humans, SmSQOR may represent a promising new target for antiparasitic drug development.
Abstract
Adults of Schistosoma mansoni reside in the mesenteric veins, where they are naturally exposed to high levels of hydrogen sulfide (H2S). S. mansoni and other intestinal parasites have adapted to this sulfide-rich environment, but the evolved mechanisms to metabolize sulfide remain unelucidated. Here we reveal that the putative sulfide:quinone oxidoreductase (SQOR) encoded by S. mansoni is indeed an SQOR, catalyzing the first step of sulfide metabolism. We demonstrated that S. mansoni SQOR (SmSQOR) is expressed in eggs, cercaria and adult stages and localized in the mitochondria. The reaction catalyzed by SmSQOR was investigated using sulfane sulfur probe 4 (SSP4) and shown to require the co-presence of sulfide, quinone, and a sulfur acceptor, indicating a quaternary complex-mediated mechanism. Unlike human and bacterial SQORs, purified SmSQOR could not reduce quinones in the presence of sulfide alone unless sulfite, cyanide, or L-cysteine (but not coenzyme A or glutathione) was provided as the sulfur acceptor. In the presence of these sulfur acceptors, SmSQOR formed a long-lived charge-transfer (CT) complex, a transient electronically coupled association between electron donor and acceptor, as indicated by a broad band around 637–755 nm in the spectrum, which was associated with a partial loss of enzyme activity. Moreover, residues critical for CT complex formation and SQOR catalysis were identified. Using SSP4, we also demonstrated that SQOR was active in S. mansoni adult, egg, and cercaria stages. Taken together, these features suggest that metabolism of sulfide proceeds differently in S. mansoni than in humans.
Journal Information
Journal: Free Radical Biology and Medicine
Title: Distinct quaternary reaction behavior and stable charge-transfer complex formation in Schistosoma mansoni sulfide:quinone oxidoreductase
Authors: Augustin Tshibaka Kabongo, Talaam Keith Kiplangat, Yuki Tayama, Acharjee Rajib, Yuichi Matsuo, Linh Manh Ha, Samandram Sushilkumar Singh, Tetsuo Yamashita, Euki Yazaki, Endah Dwi Hartuti, Tetsuro Matsunaga, Tomoaki Ida, Tomoyoshi Nozaki, Takaaki Akaike, Tomoo Shiba, Jun-ichi Kishikawa, Shinjiro Hamano, Kiyoshi Kita, and Daniel Ken Inaoka
DOI: https://doi.org/10.1016/j.freeradbiomed.2026.01.063
For more details, please refer to the full article published in Free Radical Biology and Medicine.