Regulatory Effects of Antioxidants on Indoxyl Sulfate-Enhanced Intracellular Oxidation and Impaired Phagocytic Activity in Differentiated U937 Human Macrophage Cells.

Indoxyl sulfate (IS), a uremic toxin, is a physiologically active sulfated metabolite, specifically in kidney failure patients. Our previous studies have shown that IS downregulates phagocytic immune function in a differentiated HL-60 human macrophage cell model. However, it remains unclear whether IS exerts similar effects on macrophage function in other cell types or in lipopolysaccharide (LPS)-sensitive immune cell models. Therefore, this study aimed to investigate the effects of IS on intracellular oxidation levels and phagocytic activity in a differentiated U937 human macrophage cell model, both in the absence and presence of LPS. Our results demonstrated that IS significantly increases intracellular oxidation levels and decreases phagocytic activity, particularly in cells activated by LPS. Furthermore, we found that 2-acetylphenothiazine, an NADH oxidase inhibitor, attenuates the effects of IS in LPS-activated macrophage cells. Representative antioxidants, trolox, α-tocopherol, and ascorbic acid, significantly mitigated the effects of IS on the macrophages responding to LPS.

A new type of sulfation reaction: C-sulfonation for α,ß-unsaturated carbonyl groups by a novel sulfotransferase SULT7A1.

Cytosolic sulfotransferases (SULTs) are cytosolic enzymes that catalyze the transfer of sulfonate group to key endogenous compounds, altering the physiological functions of their substrates. SULT enzymes catalyze the O-sulfonation of hydroxy groups or N-sulfonation of amino groups of substrate compounds. In this study, we report the discovery of C-sulfonation of α,ß-unsaturated carbonyl groups mediated by a new SULT enzyme, SULT7A1, and human SULT1C4. Enzymatic assays revealed that SULT7A1 is capable of transferring the sulfonate group from 3'-phosphoadenosine 5'-phosphosulfate to the α-carbon of α,ß-unsaturated carbonyl-containing compounds, including cyclopentenone prostaglandins as representative endogenous substrates. Structural analyses of SULT7A1 suggest that the C-sulfonation reaction is catalyzed by a novel mechanism mediated by His and Cys residues in the active site. Ligand-activity assays demonstrated that sulfonated 15-deoxy prostaglandin J2 exhibits antagonist activity against the prostaglandin receptor EP2 and the prostacyclin receptor IP. Modification of α,ß-unsaturated carbonyl groups via the new prostaglandin-sulfonating enzyme, SULT7A1, may regulate the physiological function of prostaglandins in the gut. Discovery of C-sulfonation of α,ß-unsaturated carbonyl groups will broaden the spectrum of potential substrates and physiological functions of SULTs.

Evolution and multiple functions of sulfonation and cytosolic sulfotransferases across species.

Organisms have conversion systems for sulfate ion to take advantage of the chemical features. The use of biologically converted sulfonucleotides varies in an evolutionary manner, with the universal use being that of sulfonate donors. Sulfotransferases have the ability to transfer the sulfonate group of 3'-phosphoadenosine 5'-phosphosulfate to a variety of molecules. Cytosolic sulfotransferases (SULTs) play a role in the metabolism of low-molecular-weight compounds in response to the host organism's living environment. This review will address the diverse functions of the SULT in evolution, including recent findings. In addition to the diversity of vertebrate sulfotransferases, the molecular aspects and recent studies on bacterial and plant sulfotransferases are also addressed.