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Updated: Feb 28, 2026
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Enzymatic Synthesis of Epoxidized Metabolites of Docosahexaenoic, Eicosapentaenoic, and Arachidonic Acids
Published on: June 28, 2019
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Oxetane Substrates of Human Microsomal Epoxide Hydrolase
Francesca Toselli1, Marlene Fredenwall1, Peder Svensson1
1Cardiovascular and Metabolic Diseases, Innovative Medicines and Early Development, AstraZeneca, Mölndal, Sweden (F.T., M.F., X.-Q.L., A.J., L.W., M.A.H.); and Integrative Research Laboratories, Arvid Wallgrens Backe 20, Gothenburg, Sweden (P.S.).
Summary
Oxetane hydrolysis by human microsomal epoxide hydrolase (mEH) is a key metabolic pathway in drug development. Structural modifications near the oxetane ring significantly influence its breakdown rate, offering insights for designing new drugs.
Area of Science:
- Medicinal Chemistry
- Drug Metabolism
- Biocatalysis
Background:
- Oxetanyl building blocks enhance drug-like properties in drug candidates.
- Limited knowledge exists regarding the biotransformation of oxetanes.
Purpose of the Study:
- To investigate the biotransformation of oxetane-containing compounds.
- To identify the enzymes responsible for oxetane ring opening.
- To characterize the kinetics and structural determinants of oxetane hydrolysis.
Main Methods:
- Incubations with human liver fractions and hepatocytes.
- Use of inhibitors for cytochrome P450 (P450), microsomal epoxide hydrolase (mEH), and soluble epoxide hydrolase (sEH).
- Investigation of NADPH dependence in subcellular fractions.
- Kinetic characterization of oxetane hydrolysis in human liver microsomes and recombinant mEH.
Main Results:
- Direct evidence of oxetane hydrolysis by human recombinant microsomal epoxide hydrolase (mEH).
- mEH-mediated hydrolysis is the sole oxetane ring-opening metabolic route in human liver fractions and hepatocytes.
- No contribution from sEH or P450-catalyzed oxidation.
- Hydrolysis efficiency is modulated by structural elements near the oxetane, such as pKa, distance from benzylic nitrogen, and methyl group presence.
Conclusions:
- Oxetanes are identified as the first non-epoxide substrates for human mEH.
- Findings are valuable for developing biologically active oxetanes.
- Potential for biocatalytic generation of enantiomerically pure oxetanes and diols.
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