SULT1E1 Human
Description
Introduction to SULT1E1
SULT1E1 (sulfotransferase family 1E member 1) is a cytosolic sulfotransferase enzyme encoded by the SULT1E1 gene located on chromosome 4q13 . It catalyzes the sulfation of estrogens, thyroid hormones, and xenobiotics using 3′-phosphoadenosine 5′-phosphosulfate (PAPS) as a sulfate donor, playing a critical role in hormone metabolism and detoxification . SULT1E1 is distinguished by its high affinity for estradiol (E2) and ethinylestradiol (EE2), with K<sub>m</sub> values in the nanomolar range, enabling efficient sulfation of physiological estrogen concentrations .
Gene and Protein Structure
-
Protein: ~35 kDa cytosolic enzyme with conserved active-site residues (e.g., His107, Lys105) critical for PAPS and substrate binding .
Substrate Specificity
SULT1E1 sulfates diverse compounds, including:
Genetic Polymorphisms and Functional Variants
SULT1E1 exhibits genetic polymorphisms that influence enzyme activity and disease susceptibility. Key variants include:
Functional SNPs
Population-Specific Haplotypes
Resequencing studies identified 23 polymorphisms, including 12 haplotypes. For example:
-
rs3775777 (intron variant): Linked to abiraterone acetate treatment failure in metastatic castration-resistant prostate cancer .
-
rs10019305: Associated with decreased survival in breast cancer .
Breast and Endometrial Cancers
-
SULT1E1 Expression: Reduced in breast cancer tissues compared to normal breast cells, correlating with tumor aggressiveness .
-
Mechanisms:
Thyroid Hormone Regulation
SULT1E1 sulfates reverse triiodothyronine (rT3) and thyroxine (T4), influencing thyroid hormone metabolism .
Biomarker Applications
-
LUAD Diagnosis: SULT1E1 expression levels distinguish LUAD from normal lung tissues, with potential for prognosis assessment .
-
Drug Metabolism: Variants like rs11569705 may predict responses to hormone therapies (e.g., abiraterone acetate) .
Targeted Interventions
-
PPARγ Activation: SULT1E1 overexpression enhances PPARγ signaling, offering a pathway for anti-cancer therapies .
-
Sulfation Modulation: Inhibiting SULT1E1 may prolong estrogen activity in hormone-dependent cancers, though clinical trials are needed .
Future Research Directions
-
Functional Genomics: Characterize novel missense variants (e.g., rs746067466, Phe254Cys) altering substrate binding .
-
Precision Medicine: Integrate SULT1E1 polymorphisms into therapeutic algorithms for hormone-sensitive cancers .
-
Immunological Interactions: Investigate correlations between SULT1E1 expression and immune cell infiltration (e.g., M2 macrophages) .
Product Specs
Q&A
What is the primary function of human SULT1E1 in estrogen metabolism?
SULT1E1 is a cytosolic sulfotransferase that catalyzes the transfer of a sulfuryl group from 3′-phosphoadenosine 5′-phosphosulfate (PAPS) to estrogens and structurally similar compounds. It plays a crucial role in estrogen inactivation and homeostasis regulation by catalyzing sulfate conjugation of estrone (E1), 17β-estradiol (E2), catecholestrogens, and 2-methoxyestradiol with remarkably low Km values in the nanomolar range . This high affinity makes SULT1E1 uniquely positioned to catalyze the sulfation of physiological concentrations of estrogens, enhancing their water solubility and facilitating renal excretion .
In which human tissues is SULT1E1 predominantly expressed?
SULT1E1 expression has been documented across multiple human tissues with significant physiological relevance:
Research has revealed considerable individual variations in SULT1E1 expression levels in both the small intestine and liver samples, suggesting potential heterogeneity in estrogen metabolism capacity across the population .
What approaches are used to identify and analyze SULT1E1 genetic polymorphisms?
Identification and analysis of SULT1E1 polymorphisms typically involve:
-
Comprehensive resequencing of the eight SULT1E1 exons, exon-intron splice junctions, and portions of the 5′-flanking region using DNA from diverse populations (e.g., 60 African-American and 60 Caucasian-American subjects)
-
Systematic database mining from repositories such as NCBI, PharmGKB, and UniProt to identify nonsynonymous coding SNPs (cSNPs)
-
Selection of missense SNPs based on critical criteria including proximity to substrate-binding sites, PAPS-binding regions, and significant changes in physicochemical properties of altered amino acid residues
-
PCR-based site-directed mutagenesis to generate cDNAs encoding different SULT1E1 allozymes
How do genetic variations in SULT1E1 affect its enzymatic function?
Studies have demonstrated that SULT1E1 genetic variants can significantly impact enzyme function:
-
Certain variant allozymes show decreased basal activity levels and reduced immunoreactive protein compared to wild-type enzyme
-
Substrate kinetic studies reveal distinctive differences in apparent Km and Vmax/Km ratios for variant allozymes
-
Purified SULT1E1 allozymes display differential sulfating activities toward various substrates including E2, 4-hydroxytamoxifen, and diethylstilbestrol
-
These variations may influence the metabolism of estrogens and related compounds in individuals with different SULT1E1 genotypes, potentially affecting drug responses and disease susceptibility
How can recombinant SULT1E1 allozymes be expressed and characterized for functional studies?
The production and characterization of recombinant SULT1E1 allozymes typically follows this methodology:
-
Generation of cDNAs encoding different allozymes using PCR-based site-directed mutagenesis with mutagenic oligonucleotide primers and wild-type SULT1E1 cDNA as template
-
PCR amplification conditions: initial denaturation (30s at 94°C), followed by 12 cycles of template denaturation (30s at 95°C), primer annealing (1min at 55°C), and extension (15min at 72°C)
-
Bacterial expression of recombinant proteins using appropriate vectors (e.g., pGEX-2TK prokaryotic expression vector)
-
Enzymatic assays to determine sulfating activity toward various substrates
What techniques are employed to study substrate kinetics of SULT1E1?
Substrate kinetic analysis of SULT1E1 typically involves:
How does SULT1E1 expression correlate with cancer progression?
Recent research has established significant associations between SULT1E1 and various cancers:
-
In lung adenocarcinoma (LUAD), SULT1E1 expression is significantly reduced across multiple tissues and cell lines
-
Bioinformatics analyses suggest SULT1E1 may exert anticarcinogenic effects by modulating protein serine/threonine kinase activity pathways
-
KEGG and GSEA analyses indicate SULT1E1's involvement in drug metabolism, choline metabolism in cancer, and hormone synthesis
-
The suppressive role of SULT1E1 in LUAD suggests its potential as a biomarker for diagnosis and prognosis prediction
-
Genetic variants of SULT1E1 are associated with several diseases, particularly sex-hormone-related cancers
What experimental approaches are used to assess SULT1E1's role in cancer?
Multiple complementary techniques are employed to investigate SULT1E1's role in cancer:
-
Bioinformatics analysis using public databases to examine molecular characteristics, disease relevance, and expression levels in different cancers
-
Analysis tools like GEPIA 2 and Starbase to compare expression levels between cancerous and normal tissues
-
Prognostic analysis using KM database and tumor databases to correlate expression with clinical outcomes
-
Protein interaction network construction using STRING database
-
Western blot and immunohistochemical staining to detect expression levels in cancer cell lines and tissue samples
-
Cellular immunofluorescence to detect subcellular localization in cytoplasm and nucleus
-
Functional enrichment and immune infiltration analyses using cancer genomic datasets
How should researchers address substrate inhibition when designing SULT1E1 activity assays?
When designing SULT1E1 activity assays, researchers should:
-
Perform preliminary concentration dependence experiments to identify the threshold at which substrate inhibition occurs for each substrate
-
Select multiple concentration points both below and at the inhibition threshold (e.g., for E2, using 0.5μM, 2μM, and 4μM)
-
Consider substrate-specific inhibition patterns, as different substrates may exhibit different inhibition kinetics
-
Interpret results with awareness of the bell-shaped activity curves typical for SULT1E1
-
Include appropriate controls to account for potential variations in enzyme preparation quality and activity
What are the recommended approaches for studying SULT1E1 polymorphisms in diverse populations?
For comprehensive population studies of SULT1E1 polymorphisms:
-
Employ diverse subject pools representing different ethnic backgrounds (e.g., the study that used DNA from 60 African-American and 60 Caucasian-American subjects)
-
Ensure proper ethical protocols and informed consent (e.g., samples anonymized by NIH with written consent for experimental use)
-
Conduct comprehensive resequencing of all exons, exon-intron junctions, and regulatory regions
-
Categorize identified polymorphisms into coding (synonymous, non-synonymous, nonsense) and non-coding (introns, 3'UTR, 5'UTR) SNPs
-
Select functionally relevant polymorphisms based on location (proximity to functional sites) and amino acid property changes
-
Perform functional genomic studies using recombinant allozymes to assess biochemical impact
Product Science Overview
Estrogen sulfotransferase (SULT1E1) is a phase II enzyme that plays a crucial role in the metabolism of estrogens. It catalyzes the sulfation of estrogens, converting them into inactive estrogen sulfates, thereby regulating their homeostasis . This enzyme is also involved in the sulfation of thyroid hormones and several marketed medicines .
SULT1E1 belongs to the sulfotransferase (SULT) family, which is responsible for the sulfonation of various endogenous and exogenous compounds. Sulfonation is a biochemical process that involves the transfer of a sulfonate group (SO3−) from the donor molecule 3′-phosphoadenosine 5′-phosphosulfate (PAPS) to the hydroxyl or amino groups of acceptor substrates . This reaction increases the water solubility of the substrates and generally decreases their biological activity .
Genetic variants of the SULT1E1 gene have been associated with various diseases, particularly sex-hormone-related cancers such as breast and endometrial cancer . Understanding the role and polymorphisms of SULT1E1 is crucial for developing its clinical relevance. Research has shown that interindividual variation in sulfonation capacity may influence an individual’s response to xenobiotics and susceptibility to certain diseases .
The clinical significance of SULT1E1 extends beyond its role in estrogen metabolism. It is also involved in the metabolism of thyroid hormones and various drugs, making it a key player in pharmacogenomics . Understanding the molecular regulation and polymorphisms of SULT1E1 can aid in the development of personalized medicine approaches, particularly for hormone-related conditions and diseases.
