Significant impact of redox regulation of estrogen-metabolizing proteins on cellular stress responses.

The ultimate driving force, stress, promotes adaptability/evolution in proliferating organisms, transforming tumorigenic growth. Estradiol (E2) regulates both phenomena. In this study, bioinformatics-tools, site-directed-mutagenesis (human estrogen-sulfotransferase/hSULT1E1), HepG2 cells tested with N-acetyl-cysteine (NAC/thiol-inducer) or buthionine-sulfoxamine (BSO/thiol-depletory) were evaluated for hSULT1E1 (estradiol-sulphating/inactivating) functions. Reciprocal redox regulation of steroid sulfatase (STS, E2-desulfating/activating) results in the Cys-formylglycine transition by the formylglycine-forming enzyme (FGE). The enzyme sequences and structures were examined across the phylogeny. Motif/domain and the catalytic conserve sequences and protein-surface-topography (CASTp) were investigated. The E2 binding to SULT1E1 suggests that the conserved-catalytic-domain in this enzyme has critical Cysteine 83 at position. This is strongly supported by site-directed mutagenesis/HepG2-cell research. Molecular-docking and superimposition studies of E2 with the SULT1E1 of representative species and to STS reinforce this hypothesis. SULT1E1-STS are reciprocally activated in response to the cellular-redox-environment by the critical Cys of these two enzymes. The importance of E2 in organism/species proliferation and tissue tumorigenesis is highlighted.