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Microsomal epoxide hydrolase is not a 2-arachidonyl glycerol hydrolase


Arand, Michael; Marowsky, Anne (2016). Microsomal epoxide hydrolase is not a 2-arachidonyl glycerol hydrolase. Matters:201605000008na.

Abstract

The endocannabinoid 2-arachidonyl glycerol (2-AG) is substantially hydrolysed by at least two enzymes, fatty acid amide hydrolase (FAAH) and monoarachidonyl glycerol lipase (MAGL), which thereby terminate its biological activity. In a recent report it has been claimed that microsomal epoxide hydrolase (mEH), hitherto known as a xenobiotic detoxifying enzyme, also rapidly catalyses the breakdown of 2-AG. However, the catalytic site architecture of mEH argues against an esterase activity. We therefore analyzed the capacity of recombinant purified human, mouse and rat mEH to hydrolyze 2-AG. In contrast to the previous finding, we find only marginal 2-AG esterase activity ( ≤ 50 nmol/mg protein/min) associated with the purified enzymes that was resistant to inhibition by the potent mechanism-based mEH inhibitor 1,1,1-trichloropropene 2,3-oxide (TCPO). Likewise, 2-AG hydrolysis in mouse liver microsomes was resistant to TCPO inhibition while being efficiently blocked by methyl arachidonyl fluorophosphonate (MAFP). MAFP, on the other hand, failed to inhibit epoxide hydrolase activity of both, purified mEH and mouse liver microsomes. We therefore conclude that mEH lacks any appreciable 2-AG hydrolase activity.

Abstract

The endocannabinoid 2-arachidonyl glycerol (2-AG) is substantially hydrolysed by at least two enzymes, fatty acid amide hydrolase (FAAH) and monoarachidonyl glycerol lipase (MAGL), which thereby terminate its biological activity. In a recent report it has been claimed that microsomal epoxide hydrolase (mEH), hitherto known as a xenobiotic detoxifying enzyme, also rapidly catalyses the breakdown of 2-AG. However, the catalytic site architecture of mEH argues against an esterase activity. We therefore analyzed the capacity of recombinant purified human, mouse and rat mEH to hydrolyze 2-AG. In contrast to the previous finding, we find only marginal 2-AG esterase activity ( ≤ 50 nmol/mg protein/min) associated with the purified enzymes that was resistant to inhibition by the potent mechanism-based mEH inhibitor 1,1,1-trichloropropene 2,3-oxide (TCPO). Likewise, 2-AG hydrolysis in mouse liver microsomes was resistant to TCPO inhibition while being efficiently blocked by methyl arachidonyl fluorophosphonate (MAFP). MAFP, on the other hand, failed to inhibit epoxide hydrolase activity of both, purified mEH and mouse liver microsomes. We therefore conclude that mEH lacks any appreciable 2-AG hydrolase activity.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Pharmacology and Toxicology
07 Faculty of Science > Institute of Pharmacology and Toxicology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:2016
Deposited On:06 Feb 2017 07:54
Last Modified:11 Feb 2017 04:08
Publisher:ScienceMatters AG
ISSN:2297-8240
Funders:SNF grant ° 31003A_146635
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.19185/matters.201605000008

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