Sulfotransferase 4A1 activity facilitates sulfate-dependent cellular protection to oxidative stress

Evan J Brettrager,Arthur W Meehan,Robert C A M Van Waardenburg,Charles N Falany

doi:10.1038/s41598-022-05582-4

Evan J Brettrager, Arthur W Meehan + Show 2 more

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https://doi.org/10.1038/s41598-022-05582-4

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Journal: Scientific Reports	Publication Date: Jan 31, 2022
Citations: 8	License type: open-access

Affiliation: University of Alabama at Birmingham

Abstract

Sulfotransferase 4A1 (SULT4A1) is an orphan member of the cytosolic SULT superfamily that contains enzymes that catalyze the sulfonation of hydrophobic drugs and hormones. SULT4A1 has been assessed through all classical SULT approaches yet no SULT activity has been reported. To ascertain SULT4A1 function and activity, we utilized Saccharomyces cerevisiae as a model system, which exhibits no endogenous SULT activity nor possesses SULT-related genes. We observed that ectopic SULT4A1 expression in yeast displays similar subcellular localization as reported in mouse neurons and observed that SULT4A1 is associated with the outer mitochondria membrane. SULT4A1 expression stimulates colony formation and protects these cells from hydrogen peroxide and metabolism-associated oxidative stress. These SULT4A1-mediated phenotypes are dependent on extracellular sulfate that is converted in yeast to PAPS, the universal sulfonate donor for SULT activity. Thus, heterologous SULT4A1 expression in yeast is correctly distributed and functional, and SULT4A1 antioxidant activity is sulfate dependent supporting the concept that SULT4A1 has sulfate-associated activity.

Highlights

Sulfotransferase 4A1 (SULT4A1) is an orphan member of the cytosolic SULT superfamily that contains enzymes that catalyze the sulfonation of hydrophobic drugs and hormones
A recent report suggested that SULT4A1 is able to sulfonate 1-napthol using the S. pombe ‘enzyme’ bag assay, yet this observation has not been reproduced by other laboratories[32]
SULT4A1 gene deletion has been linked to Phelan-McDermid Syndrome (PMS), a generalized cognitive and developmental autism spectrum s yndrome[13,14]

Summary

Introduction

Sulfotransferase 4A1 (SULT4A1) is an orphan member of the cytosolic SULT superfamily that contains enzymes that catalyze the sulfonation of hydrophobic drugs and hormones. SULT4A1 expression stimulates colony formation and protects these cells from hydrogen peroxide and metabolismassociated oxidative stress These SULT4A1-mediated phenotypes are dependent on extracellular sulfate that is converted in yeast to PAPS, the universal sulfonate donor for SULT activity. Hossain et al reported that ectopic expressed SULT4A1 has a direct regulatory role in mitochondria function and redox-homeostasis[9] These observations could explain the critical regulatory role of SULT4A1 in neuronal cell populations that exhibit a remarkably high-energy demand and generate increased levels of oxidative stress in the form of reactive oxygen species. We report that ectopic SULT4A1 expression in yeast displays a similar subcellular cytosolic and mitochondrial distribution as mouse neurons and cultured neuronal cell m odels[7,9]. The SULT4A1 mediated protective and growth stimulating phenotypes are sulfate dependent, suggesting that SULT4A1 exhibits functional sulfate-activity

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