SULT1B1 Human

What is the primary physiological function of human SULT1B1?

Human SULT1B1 is the sole member of the SULT1B subfamily, with its main physiological function being the sulfation of thyroid hormones . This sulfation process is proposed to regulate iodothyronine metabolism through iodothyronine deiodinase, as sulfated metabolites of thyroxine (T4) and triiodothyronine (T3) undergo deiodination more rapidly than their unsulfated counterparts . Additionally, SULT1B1 is involved in the metabolism of xenobiotics, constituting a significant portion of the hepatic sulfotransferase activity in humans . The enzyme primarily catalyzes the transfer of a sulfonate group to various substrates, playing a crucial role in phase II metabolism reactions that generally inactivate biological compounds or prepare them for elimination.

How does SULT1B1 compare to other members of the SULT family in terms of tissue distribution and substrate specificity?

SULT1B1 is categorized within the SULT1 family, which includes several sulfotransferases that catalyze the sulfonation of catecholamines and many other compounds . While SULT1A1 is considered the major SULT isoform in human tissues due to its high expression in the liver and gastrointestinal tract, SULT1B1 also makes a significant contribution, with both enzymes accounting for approximately 70% of hepatic sulfotransferases .

In terms of substrate specificity, SULT1B1 has a particular affinity for thyroid hormones . In comparison, other SULT family members have different substrate preferences: SULT1A1 conjugates small phenolic compounds such as estrogens and phytoestrogens; SULT2 enzymes are selective for steroids like cholesterol and bile acids; while the physiological functions of SULT4 and SULT6 remain poorly understood . This diversity in substrate specificity enables the SULT enzyme family to metabolize a wide range of endogenous hormones and xenobiotics despite their structural similarities.

What is the genetic organization of the human SULT gene family, and where does SULT1B1 fit within this classification?

The human cytosolic sulfotransferase (hSULT) genes are organized into four distinct families: SULT1, SULT2, SULT4, and SULT6 . SULT1B1 belongs to the SULT1 family, which comprises nine members divided into four subfamilies (1A1-4, 1C1-3, 1B1, and 1E1) . SULT1B1 is the sole member of its subfamily, unlike other subfamilies that contain multiple isoforms.

The entire SULT family consists of 13 identified human cytosolic sulfotransferase genes . Despite considerable sequence and structural similarities among family members, they appear to have different biological functions. While SULT1 family members (including SULT1B1) generally sulfonate simple phenols, estradiol, thyroid hormones, and environmental xenobiotics, the SULT2 family catalyzes sulfonation of steroid hydroxyl groups, and SULT4A1 is primarily expressed in the brain with no identified activity or function yet .

How do structural characteristics of SULT1B1 influence its substrate binding and catalytic efficiency?

The active site of SULT1B1 contains specific amino acid residues that determine its substrate binding properties and catalytic function. In-silico docking studies have revealed that when binding to substrates like phthalate monoesters (MHP and MOP), SULT1B1's active site involves multiple amino acid residues including ARG-131, SER-49, TRP-53, GLY-50, THR-52, THR-51, PHE-256, LYS-48, PRO-255, SER-139, ARG-258, HIS-142, and PHE-143 .

The binding interactions typically involve both hydrogen bonds and hydrophobic contacts. For example, MHP forms eight hydrogen bonds with residues SER-139, ARG-131, LYS-48, SER-49, GLY-50, and THR-51, plus four hydrophobic contacts within the active cavity . The binding free energy values for various phthalate monoesters (MBP, MHP, MOP, MCHP, and MEHP) range from -7.66 to -8.92 kcal/mol, indicating strong binding affinities that contribute to effective enzyme-substrate interactions .

These structural characteristics are critical for understanding how SULT1B1 recognizes specific substrates and how genetic polymorphisms might alter its function. The enzyme's structure forms a "floor" for both substrate and PAPS (3′-phosphoadenosine-5′-phosphosulfate, the sulfate donor) binding domains, and any alterations to this structure can significantly impact catalytic properties .

What are the kinetic implications of the L145V SULT1B1 variant, and how might these impact metabolism in affected populations?

The L145V variant of SULT1B1 (leucine replaced by valine at position 145) demonstrates significant alterations in kinetic properties compared to the wild-type enzyme. This polymorphism results in:

• A four-fold decrease in affinity for PAP (3′, 5′-diphosphoadenosine)

• Similar Km values for PAPS (3′-phosphoadenosine-5′-phosphosulfate)

• Reduced maximal turnover rate of 0.86 pmol/(minμg) compared to 1.26 pmol/(minμg) for wild-type SULT1B1

• Altered kinetics toward small phenolic substrates, including a diminished p-nitrophenol Km

• Increased susceptibility to 1-naphthol substrate inhibition

This variant was found to have an allelic frequency of 25% in African Americans, while comprising 9% of a mixed-population study . The structural impact appears to involve destabilization of a conserved helix (α8) that forms the "floor" of both the substrate and PAPS binding domains .

While no significant correlation between this genotype and prostate or colorectal cancer was observed in the studied patients, the variant isoform could potentially underlie specific pathologies in sub-Saharan African carriers . The reduced catalytic efficiency might affect the metabolism of xenobiotics and endogenous compounds in carriers, potentially altering drug efficacy, toxicity profiles, or hormone regulation in these populations.

How does SULT1B1 expression and activity change during development and in various disease states?

While specific information about SULT1B1 developmental expression patterns is limited in the search results, studies indicate that SULTs generally are expressed at high levels during fetal development in humans, with some isoforms exclusively or primarily expressed during the prenatal period . This developmental regulation suggests important roles in fetal metabolism and protection.

Regarding disease states, studies have shown alterations in SULT activity in liver diseases. For instance, sulfation activity of various SULTs, including potentially SULT1B1, was substantially lower in livers from subjects with steatosis (23%), diabetic cirrhosis (16%), and cirrhosis (18%) relative to healthy livers (100%) . This reduced activity could result in higher exposure to xenobiotics like bisphenol A in patients with non-alcoholic fatty liver disease (NAFLD) .

What are the optimal methods for measuring SULT1B1 activity in tissue samples and recombinant systems?

When measuring SULT1B1 activity, researchers typically employ enzyme kinetics assays that monitor the transfer of sulfonate groups from PAPS to various substrates. Based on the experimental approaches described in the search results, the following methodological considerations are important:

For recombinant systems:

• Expression of human SULT1B1 in bacterial or mammalian expression systems to obtain purified enzyme

• Measurement of enzyme kinetics using spectrophotometric or radiochemical methods to track substrate conversion

• Determination of key parameters including Km values for both substrates and PAPS, as well as maximal turnover rates (as demonstrated in the L145V variant study where researchers quantified activity as pmol/(min*μg))

For tissue samples:

• Preparation of cytosolic fractions from liver or other relevant tissues

• Normalization of protein content across samples

• Use of specific substrates that preferentially react with SULT1B1 (such as thyroid hormones)

• Inclusion of appropriate controls to account for the activity of other SULT enzymes present in the sample

When comparing wild-type and variant forms, researchers should standardize experimental conditions and enzyme concentrations to ensure valid comparisons of kinetic parameters. Additionally, thermal stability assays may provide insights into structural integrity differences between variants, as altered protein stability may contribute to functional differences .

What techniques are most effective for studying SULT1B1-substrate interactions and inhibition mechanisms?

Several complementary techniques have proven effective for investigating SULT1B1-substrate interactions and inhibition mechanisms:

• In silico docking methods: These computational approaches have been successfully used to analyze binding mechanisms between SULT1B1 and inhibitors such as phthalate monoesters . The method involves docking chemical structures into the activity cavities of SULT1B1 and analyzing:

  • The specific amino acid residues involved in binding

  • The number and nature of hydrogen bonds formed

  • Hydrophobic contacts between the substrate/inhibitor and the enzyme cavity

  • Binding free energy calculations to quantify interaction strength

• Enzyme kinetics studies: Systematic evaluation of enzyme activity with varying substrate concentrations can reveal:

  • Competitive, non-competitive, or mixed inhibition patterns

  • IC50 values for inhibitors

  • Changes in Km and Vmax parameters in the presence of inhibitors

• Structural biology approaches: X-ray crystallography or cryo-electron microscopy of SULT1B1 in complex with substrates or inhibitors can provide direct visualization of binding interactions at atomic resolution.

• Site-directed mutagenesis: By strategically altering specific amino acid residues identified in structural studies, researchers can confirm their importance in substrate binding or catalysis.

The combination of these approaches provides comprehensive insights into how SULT1B1 recognizes different substrates and how inhibitors may interfere with its function. For example, the docking studies with phthalate monoesters revealed not only the specific residues involved in binding but also quantified binding energies ranging from -7.66 to -8.92 kcal/mol for different compounds .

What is the distribution of known SULT1B1 genetic variants across different populations, and what are their functional consequences?

The most well-characterized SULT1B1 genetic variant is the L145V polymorphism (leucine to valine substitution at position 145). This variant has a distinct population distribution pattern:

The functional consequences of this polymorphism include:

• Destabilization of a conserved helix (α8) that forms the "floor" of both substrate and PAPS binding domains

• Four-fold decrease in affinity for PAP (3′, 5′-diphosphoadenosine)

• Similar Km values for PAPS compared to wild-type

• Slower maximal turnover rate (0.86 pmol/(minμg) vs. 1.26 pmol/(minμg) for wild-type)

• Altered kinetics toward small phenolic substrates, including diminished p-nitrophenol Km

• Increased susceptibility to 1-naphthol substrate inhibition

While other SULT enzymes like SULT1A1, SULT1E1, and SULT2B1 have multiple well-documented polymorphisms associated with various diseases (as shown in Table 3 from source ), the L145V variant is the first well-characterized SULT1B1 allelic variant . This underscores the need for further research into additional SULT1B1 polymorphisms and their potential functional significance.

How might alterations in SULT1B1 activity affect drug metabolism, efficacy, and toxicity in clinical settings?

Alterations in SULT1B1 activity, whether due to genetic polymorphisms, disease states, or drug interactions, could significantly impact drug metabolism with several clinical implications:

While no direct associations between SULT1B1 variants and disease risk have been established, the potential impact on drug metabolism warrants consideration in personalized medicine approaches, particularly for African American patients who have a higher frequency of the L145V variant .

What is the relationship between SULT1B1 and thyroid hormone metabolism, and how might this impact thyroid-related disorders?

SULT1B1's main physiological function has been proposed to be in the sulfation of thyroid hormones (T4 and T3) . This sulfation process plays a regulatory role in iodothyronine metabolism through its effects on iodothyronine deiodinase activity. Specifically, sulfated metabolites of thyroxine (T4) and triiodothyronine (T3) undergo deiodination more rapidly than their unsulfated counterparts .

The potential implications for thyroid-related disorders include:

• Altered thyroid hormone bioavailability: Since sulfation generally inactivates hormones , changes in SULT1B1 activity could affect the availability of active thyroid hormones in tissues, potentially contributing to hypo- or hyperthyroid states.

• Impact of genetic variants: The L145V variant of SULT1B1, which shows altered kinetic properties , might affect thyroid hormone metabolism differently in African American populations where this variant is more prevalent.

• Developmental considerations: Given that SULTs are expressed at high levels during fetal development , SULT1B1's role in thyroid hormone metabolism could be particularly significant during this critical period when thyroid hormones are essential for proper development, especially of the central nervous system.

• Drug interactions affecting thyroid function: Medications or environmental compounds that inhibit SULT1B1 (such as the studied phthalate monoesters ) could potentially interfere with thyroid hormone metabolism, representing an indirect mechanism by which xenobiotics might affect thyroid function.

• Liver disease implications: The reduced sulfation capacity observed in liver diseases might contribute to altered thyroid hormone metabolism in these patients, potentially exacerbating thyroid dysfunction.

Despite these potential connections, the search results do not provide direct evidence linking SULT1B1 variants to specific thyroid disorders, suggesting this is an area requiring further research, particularly given the enzyme's proposed role in thyroid hormone metabolism.

How does SULT1B1 contribute to the bioactivation or detoxification of environmental carcinogens?

SULT1B1 plays a dual role in the metabolism of environmental compounds, contributing to both detoxification and bioactivation processes:

• Bioactivation of carcinogens: SULT1B1 has been specifically identified as capable of bioactivating polycyclic aromatic hydrocarbons (PAHs) . This bioactivation process can transform relatively harmless parent compounds into more reactive metabolites that may have increased carcinogenic potential. The sulfate conjugates formed can undergo further reactions, generating electrophilic species capable of forming DNA adducts and potentially initiating carcinogenesis.

• Detoxification of xenobiotics: Conversely, SULT1B1 also contributes to the detoxification of many xenobiotics by increasing their water solubility through sulfate conjugation, thereby facilitating their elimination from the body . This represents a protective function that helps reduce exposure to potentially harmful compounds.

• Population differences in metabolism: The L145V variant of SULT1B1, found predominantly in African Americans , shows altered kinetic properties that could potentially affect both the bioactivation and detoxification of environmental compounds differently in this population. This might contribute to population-specific differences in susceptibility to certain environmental carcinogens.

• Interaction with other metabolic pathways: SULT1B1's activity may complement or compete with other phase II enzymes, creating a complex metabolic network that determines the ultimate fate of environmental compounds. The balance between different metabolic pathways can influence whether a compound is predominantly detoxified or bioactivated.

While no direct correlations between SULT1B1 genotype and cancer risk were observed in the limited studies available , the enzyme's dual capacity for both bioactivation and detoxification suggests it could play a complex role in modulating risk from environmental exposures. More comprehensive epidemiological studies are needed to fully elucidate these relationships.

What are the most promising approaches for targeting or modulating SULT1B1 activity in therapeutic applications?

Based on our understanding of SULT1B1 structure, function, and role in metabolism, several approaches show promise for therapeutic applications:

• Structure-based inhibitor design: The detailed information available about SULT1B1's binding pocket and the specific amino acid residues involved in substrate interactions provides a foundation for rational drug design. Compounds could be designed to specifically inhibit SULT1B1 when selective modulation is desired, such as in cases where preventing bioactivation of certain compounds would be beneficial.

• Isoform-selective modulators: Developing compounds that selectively target SULT1B1 while sparing other SULT enzymes could help minimize off-target effects. The differences in substrate binding sites between SULT isoforms offer potential for achieving such selectivity.

• Allosteric modulators: Beyond targeting the active site, compounds that bind to allosteric sites could modulate SULT1B1 activity without competing directly with endogenous substrates, potentially offering more nuanced control of enzyme function.

• Genetic approaches: For conditions potentially linked to SULT1B1 variants, gene therapy approaches might eventually be considered to correct or compensate for functional deficiencies, particularly in populations with high frequencies of variants with reduced function, such as the L145V variant in African Americans .

• Personalized medicine strategies: Given the population-specific distribution of variants like L145V , therapeutic approaches could be tailored based on genotype. This might include adjusted dosing for drugs metabolized by SULT1B1 or alternative treatment strategies for patients with variants that significantly alter enzyme function.

While these approaches hold promise, their development would require further research characterizing SULT1B1's role in specific disease states and a more comprehensive understanding of its interactions with various drugs and endogenous compounds.

What experimental models are most appropriate for studying SULT1B1 function in complex physiological and pathological contexts?

Several experimental models offer different advantages for studying SULT1B1 function in complex biological contexts:

• Recombinant enzyme systems: Purified recombinant SULT1B1 provides a controlled environment for detailed enzyme kinetics, inhibition studies, and comparisons between wild-type and variant forms . While limited in physiological context, these systems are essential for mechanistic studies and initial drug screening.

• Cell-based models:

  • Human hepatocyte cultures maintain the cellular context of SULT1B1 function

  • Engineered cell lines expressing SULT1B1 variants allow comparative studies

  • Co-expression systems with other metabolic enzymes can model complex metabolic pathways

• Organoid models: Liver organoids derived from human tissue can recapitulate the complex cellular environment while maintaining genetic characteristics of the donor, potentially allowing studies of rare SULT1B1 variants in a physiologically relevant context.

• Humanized animal models: Mice genetically engineered to express human SULT1B1 (wild-type or variants) can provide insights into systemic effects of altered SULT1B1 function, particularly regarding thyroid hormone metabolism and xenobiotic detoxification.

• Human tissue samples: Studies using human liver samples from various disease states have revealed important insights into how pathological conditions affect sulfotransferase activity . Biobanked tissue collections that include demographic and genetic information can be particularly valuable for studying population-specific variants like L145V .

• Computational models: In silico approaches such as molecular docking and physiologically-based pharmacokinetic modeling can predict SULT1B1-substrate interactions and systemic impacts of altered enzyme function, guiding more focused experimental studies.

Each model has specific strengths and limitations, suggesting that comprehensive understanding of SULT1B1 function in complex contexts will likely require complementary approaches combining multiple model systems. The choice of model should be guided by the specific research question, with consideration of factors such as throughput requirements, physiological relevance, and available resources.