TSTD1

Model summary

A soluble human sulfurtransferase that uses a rhodanese-like catalytic core to shuttle sulfane sulfur between donors and glutathione via a persulfide intermediate. Operating predominantly in the cytosol and dynamically associating with cytoplasmic ribonucleoprotein assemblies, it supports cellular sulfur metabolism and redox buffering by channeling thiosulfate- and 3-mercaptopyruvate-derived sulfur into glutathione-dependent pathways.

Predicted Gene Ontology terms

1. 01

   I begin with the InterPro architecture.

   The polypeptide is almost entirely composed of a single catalytic module: IPR001763 (Rhodanese-like domain, residues 7–115) sits within IPR036873 (Rhodanese-like domain superfamily, residues 2–115), and the full-length sequence is classified by IPR042457 (Thiosulfate:glutathione sulfurtransferase, mammalian family, residues 1–114). This compact, single-domain layout is characteristic of classical sulfurtransferases that use a catalytic cysteine-centered loop to transiently form a persulfide intermediate. The rhodanese-like fold dictates a ping-pong mechanism in which the active-site cysteine accepts sulfur from a donor and then transfers it to an acceptor. The mammalian thiosulfate:glutathione sulfurtransferase family assignment specifies that glutathione is a physiological acceptor/donor in this system.

2. 02

   This domain architecture causally establishes the molecular function as sulfurtransferase chemistry: the rhodanese-like core confers GO:0016783 sulfurtransferase activity.

   The enzyme’s chemistry—shuttling sulfane sulfur between donors and glutathione—directly feeds into cellular sulfur metabolism, aligning with GO:0006790 sulfur compound metabolic process. The absence of transmembrane segments and the soluble rhodanese fold argue for a cytosolic enzyme, supporting GO:0005829 cytosol. The reported enrichment in cytoplasmic ribonucleoprotein assemblies during stress and translational remodeling is consistent with a soluble enzyme that can be sequestered into GO:0036464 cytoplasmic ribonucleoprotein granules, where redox and sulfur-transfer reactions modulate RNA-binding protein function.

3. 03

   Mechanistically, the enzyme likely cycles a catalytic cysteine between thiolate and persulfide states.

   The mammalian thiosulfate:glutathione sulfurtransferase family signature indicates that thiosulfate and 3-mercaptopyruvate-derived sulfur pools are funneled to glutathione, producing S-transfer products that buffer sulfane sulfur and maintain redox balance. This chemistry positions the enzyme at the crossroads of detoxification and cofactor maturation pathways.

4. 04

   From this mechanistic base, I hypothesize interaction partners that supply or utilize sulfur flux and localize the enzyme to cytosolic assemblies.

   Upstream sulfur donors such as 3-mercaptopyruvate sulfurtransferase (which generates persulfide) and cysteine/selenocysteine biosynthetic nodes are likely transient partners. Glutathione-handling proteins (for example, glutaredoxins and glutathione S-transferases) may form functional clusters that channel glutathione-dependent sulfur transfer. Within cytoplasmic ribonucleoprotein granules, stress-granule scaffolds (e.g., G3BP-family proteins) plausibly recruit the enzyme, coupling sulfur/redox chemistry to RNA-regulatory hubs in the cytosol.