Recombinant Rabbit UDP-glucuronosyltransferase 1-6 (UGT1)
Description
Introduction to Recombinant Rabbit UDP-glucuronosyltransferase 1-6 (UGT1)
Recombinant Rabbit UDP-glucuronosyltransferase 1-6 (UGT1) refers to a genetically engineered version of the UDP-glucuronosyltransferase enzyme, specifically designed for research purposes. This enzyme is part of a larger family of glycosyltransferases that play a crucial role in the metabolism of various substances, including drugs and endogenous compounds, by conjugating them with glucuronic acid, thereby enhancing their solubility and facilitating their excretion from the body.
Functionality and Role of UGT1 Enzymes
UDP-glucuronosyltransferases (UGTs) are phase II drug-metabolizing enzymes that are essential for the biotransformation of lipophilic compounds into more water-soluble forms. This process is critical for the elimination of drugs and toxins from the body. The UGT1 family, which includes UGT1A1 to UGT1A10, is involved in the glucuronidation of a wide range of substrates, including bilirubin, hormones, and numerous drugs such as opioids and antiepileptics .
Key Substrates for UGT1 Isoforms
| UGT Isoform | Substrates |
|---|---|
| UGT1A1 | Bilirubin, R-carvedilol, etoposide, B-estradiol, ezetimibe, SN-38 (irinotecan metabolite) |
| UGT1A3 | Ezetimibe, telmisartan, bile acids, vitamin D metabolites |
| UGT1A4 | Amitriptyline, lamotrigine, midazolam, olanzapine, trifluoperazine |
| UGT1A6 | Deferiprone, paracetamol, serotonin, 5-hydroxytryptamine |
| UGT1A9 | Propofol, entacapone, indomethacin, mycophenolic acid, oxazepam |
Genetic Variants and Their Clinical Impact
The UGT1A and 2B genes are highly polymorphic, with genetic variants that can significantly affect drug metabolism and response. For example, the UGT1A128 allele is associated with increased risk of hyperbilirubinemia in patients treated with certain drugs like atazanavir . Similarly, the UGT1A16 allele can increase the risk of neutropenia in patients treated with irinotecan .
Recombinant UGT1 Enzymes in Research
Recombinant UGT enzymes, such as Recombinant Rabbit UDP-glucuronosyltransferase 1-6, are used extensively in research to study drug metabolism and to predict potential drug interactions. These enzymes are produced through genetic engineering techniques, allowing for controlled expression and purification. This enables researchers to conduct in vitro studies that mimic in vivo conditions, providing valuable insights into how drugs are metabolized and how genetic variations might affect this process.
Table: Key Features of Recombinant Rabbit UGT1 Enzymes
| Feature | Description |
|---|---|
| Source | Genetically engineered from rabbit UGT1 genes |
| Function | Catalyzes glucuronidation of lipophilic compounds |
| Substrates | Drugs, bilirubin, hormones, and other endogenous compounds |
| Applications | In vitro drug metabolism studies, pharmacogenomics research |
| Advantages | Controlled expression, high purity, consistent activity |
| Limitations | May not fully replicate in vivo conditions, requires specialized equipment |
Product Specs
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Target Background
UDP-glucuronosyltransferase 1-6 (UGT1) plays a crucial role in conjugating and eliminating potentially toxic xenobiotics and endogenous compounds. It conjugates small planar phenolic molecules such as 4-nitrophenol, 1-naphthol, and 4-methylumbelliferone. However, it does not readily conjugate larger phenolic molecules like 4-hydroxybiphenyl, androgens, or estrogens. 2-hydroxybiphenyl is an excellent substrate.
KEGG: ocu:100037718
UniGene: Ocu.6910
Q&A
Recombinant Rabbit UDP-glucuronosyltransferase 1-6 (UGT1A6) plays a critical role in phase II drug metabolism, particularly in glucuronidation reactions that enhance the excretion of xenobiotics and endogenous compounds. Below are structured FAQs addressing key research considerations, supported by experimental methodologies and data from peer-reviewed studies.
What is the physiological role of UGT1A6 in detoxification pathways?
UGT1A6 conjugates glucuronic acid to phenolic compounds and planar molecules, facilitating their elimination. It operates in tandem with cytochrome P450 enzymes, which oxidize substrates to produce intermediates for UGT1A6-mediated glucuronidation .
Methodological approach:
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Use liver or intestinal microsomes to assess glucuronidation activity.
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Validate specificity via inhibition assays (e.g., with β-glucuronidase) .
Which expression systems are optimal for recombinant UGT1A6 production?
HEK293 and CHO cells are widely used due to their ability to perform post-translational modifications and generate active enzyme .
Key considerations:
How to verify UGT1A6 expression and purity in recombinant systems?
Workflow:
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Western blot: Use anti-UGT1A6 antibodies (e.g., ab157476 or ab97646) at 1:1,000 dilution .
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Catalytic activity: Measure UDP-glucuronic acid (UDP-GA) consumption via HPLC or LC-MS .
How to resolve contradictory kinetic data (e.g., K<sub>M</sub> and V<sub>max</sub>) across studies?
Strategies:
How do genetic polymorphisms affect UGT1A6 function in drug metabolism?
Key variants and impacts:
| Variant | Substrate Affected | Functional Change | Clinical Relevance |
|---|---|---|---|
| UGT1A1*28 | Irinotecan | Reduced clearance | Neutropenia risk in Asians |
| UGT1A6 S432G | Bilirubin | Altered pH activity profile | Hyperbilirubinemia models |
Methodology:
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Use site-directed mutagenesis to introduce variants.
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Compare catalytic efficiency (k<sub>cat</sub>/K<sub>M</sub>) across isoforms .
How to optimize UGT1A6 catalytic efficiency for novel substrates?
Approaches:
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pH optimization: Test activity at pH 6.5–8.5 (optimal for phenolic substrates) .
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Cofactor stability: Stabilize UDP-GA with 5 mM Mg<sup>2+</sup> and saccharolactone .
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Phosphorylation modulation: Inhibit kinases with curcumin to assess activity changes .
