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

Abstract

AbstractThe 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.