Oxidative metabolism of lipoamino acids and vanilloids by lipoxygenases and cyclooxygenases

Prusakiewicz, Jeffery J.; Turman, Melissa V.; Vila, Andrew; Ball, Heather L.; Al-Mestarihi, Ahmad; Marzo, Vincenzo Di; Marnett, Lawrence J.

doi:10.1016/j.abb.2007.04.007

Cited by 31 publications

(43 citation statements)

References 58 publications

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“…2, and K M and V m values for 8,9-EET and ARA can be found in Table 1. The K M s obtained from these experiments for ARA reacting with COX-1 and COX-2 were similar to literature values (independent t test, P > 0.05) (21). Likewise, K M values for 8,9-EET with COX-1 and COX-2 are not significantly different from the ARA K M s, indicating that both substrates have similar affinities for both enzymes.…”

Section: Resultssupporting

confidence: 72%

See 1 more Smart Citation

Cyclooxygenase-derived proangiogenic metabolites of epoxyeicosatrienoic acids

Rand

Barnych

Morisseau

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Arachidonic acid (ARA) is metabolized by cyclooxygenase (COX) and cytochrome P450 to produce proangiogenic metabolites. Specifically, epoxyeicosatrienoic acids (EETs) produced from the P450 pathway are angiogenic, inducing cancer tumor growth. A previous study showed that inhibiting soluble epoxide hydrolase (sEH) increased EET concentration and mildly promoted tumor growth. However, inhibiting both sEH and COX led to a dramatic decrease in tumor growth, suggesting that the contribution of EETs to angiogenesis and subsequent tumor growth may be attributed to downstream metabolites formed by COX. This study explores the fate of EETs with COX, the angiogenic activity of the primary metabolites formed, and their subsequent hydrolysis by sEH and microsomal EH. Three EET regioisomers were found to be substrates for COX, based on oxygen consumption and product formation. EET substrate preference for both COX-1 and COX-2 were estimated as 8,9-EET > 5,6-EET > 11,12-EET, whereas 14,15-EET was inactive. The structure of two major products formed from 8,9-EET in this COX pathway were confirmed by chemical synthesis: ct-8,9-epoxy-11-hydroxy-eicosatrienoic acid (ct-8,9-E-11-HET) and ct-8,9-epoxy-15-hydroxy-eicosatrienoic acid (ct-8,9-E-15-HET). ct-8,9-E-11-HET and ct-8,9-E-15-HET are further metabolized by sEH, with ct-8,9-E-11-HET being hydrolyzed much more slowly. Using an s.c. Matrigel assay, we showed that ct-8,9-E-11-HET is proangiogenic, whereas ct-8,9-E-15-HET is not active. This study identifies a functional link between EETs and COX and identifies ct-8,9-E-11-HET as an angiogenic lipid, suggesting a physiological role for COX metabolites of EETs.omega-6 fatty acids | epoxyeicosatrienoic acids | metabolism | cyclooxygenase | angiogenesis A rachidonic acid (ARA) is an omega-6 fatty acid that is metabolized by three major classes of enzymes, cyclooxygenases (COXs), lipoxygenases, and cytochrome P450s (CYPs), to produce an array of biologically active metabolites (1-3). The CYP pathway transforms ARA into four epoxyeicosatrienoic acids (EETs) in addition to hydroxylated metabolites (1). EETs have several biological actions, and are considered antihypertensive, antiinflammatory, neuroprotective, cardioprotective, and analgesic (4). EETs also play a role in angiogenesis (5-10), the formation of new blood vessels from preexisting vessels that is important for many physiological and pathological processes, including cancer (11).EETs can enhance tumor growth and metastasis through their angiogenic activity (12); however, this activity is transient due to their metabolic instability. EETs are further metabolized by epoxide hydrolases (EHs), primarily soluble epoxide hydrolase (sEH), to their corresponding diols (4, 13), which are generally not biologically active (14) (Fig. 1A). Inhibition of sEH prolongs EET biological activity, potentiating their angiogenic activity, leading to increased tumor growth and metastasis in some systems (12, 15) (Fig. 1B).ARA can also be metabolized by COX to form proangiogenic and proinflammator...

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Section: Resultssupporting

confidence: 72%

“…Results are average ± SEM (n = 3 or 4). ARA kinetic values taken from the literature are in parentheses (21). The relatively high rate of 8,9-EET metabolism by COX-1 and COX-2 determined by oxygen consumption (cons.)…”

Section: Resultsmentioning

confidence: 99%

Cyclooxygenase-derived proangiogenic metabolites of epoxyeicosatrienoic acids

Rand

Barnych

Morisseau

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…NAGly is subject to cyclooxygenase and lipooxygenase metabolism, producing metabolites with unknown functions (Prusakiewicz et al, 2007). However, these metabolites are probably not involved in the T-channel inhibition since similar inhibition was obtained in cell-free outside-out patches.…”

Section: Discussionmentioning

confidence: 99%

T-Type Calcium Channel Inhibition Underlies the Analgesic Effects of the Endogenous Lipoamino Acids

Barbara¹,

Alloui²,

Nargeot³

et al. 2009

J. Neurosci.

101

109

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Lipoamino acids are anandamide-related endogenous molecules that induce analgesia via unresolved mechanisms. Here, we provide evidence that the T-type/Cav3 calcium channels are important pharmacological targets underlying their physiological effects. Various lipoamino acids, including N-arachidonoyl glycine (NAGly), reversibly inhibited Cav3.1, Cav3.2, and Cav3.3 currents, with potent effects on Cav3.2 [EC 50 ϳ200 nM for N-arachidonoyl 3-OH-␥-aminobutyric acid (NAGABA-OH)]. This inhibition involved a large shift in the Cav3.2 steady-state inactivation and persisted during fatty acid amide hydrolase (FAAH) inhibition as well as in cell-free outside-out patch. In contrast, lipoamino acids had weak effects on high-voltage-activated (HVA) Cav1.2 and Cav2.2 calcium currents, on Nav1.7 and Nav1.8 sodium currents, and on anandamide-sensitive TRPV1 and TASK1 currents. Accordingly, lipoamino acids strongly inhibited native Cav3.2 currents in sensory neurons with small effects on sodium and HVA calcium currents. In addition, we demonstrate here that lipoamino acids NAGly and NAGABA-OH produced a strong thermal analgesia and that these effects (but not those of morphine) were abolished in Cav3.2 knock-out mice. Collectively, our data revealed lipoamino acids as a family of endogenous T-type channel inhibitors, suggesting that these ligands can modulate multiple cell functions via this newly evidenced regulation.

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“…We have shown that N-acylglycines are biosynthetic precursors to the PFAMs using purified PAM [72] and in PAM-expressing neuroblastoma cells [93][73] [92][E1]. Marnett and co-workers have found that the N-arachidonoylamino acids are substrates for lipoxygenase and cyclooxygenase in vitro [94,95], pointing either to a mechanism for the inactivation of the N-arachidonoylamino acids or for the formation of other bioactive, oxidized amino acid conjugates. Clearly, there is much work remaining to better define the pathways of biosynthesis and degradation for the N-acylamino acids.…”

Section: N-acylamino Acidsmentioning

confidence: 99%

“…The most common N-terminal acyl group found in eukaryotes is myristic acid, but other fatty acids, including lauric acid, (cis-Δ 5 )-tetradecaenoic acid (physeteric acid), (cis,cis- The catabolic fates of the N-acylamino acids are not well-defined. FAAH will hydrolyze the N-acyltaurines and N-arachidonoylglycine to the corresponding fatty acid and amino acid [33,76] [94,95], pointing either to a mechanism for the inactivation of the N-arachidonoylamino acids or for the formation of other bioactive, oxidized amino acid conjugates. Clearly, there is much work remaining to better define the pathways of biosynthesis and degradation for the N-acylamino acids.…”

Section: N-acylamino Acidsmentioning

confidence: 99%

Biosynthesis, degradation and pharmacological importance of the fatty acid amides

Farrell

Merkler

2008

Drug Discovery Today

115

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The identification of two biologically active fatty acid amides, N-arachidonoylethanolamine (anandamide) and oleamide, has generated a great deal of excitement and stimulated considerable research. However, anandamide and oleamide are merely the best-known and best-understood members of a much larger family of biologically-occurring fatty acid amides. In this review, we will outline which fatty acid amides have been isolated from mammalian sources, detail what is known about how these molecules are made and degraded in vivo, and highlight their potential for the development of novel therapeutics. Keywords N-acylamino acid; N-acyldopamine; N-acylethanolamine; primary fatty acid amide; N-acylamideThe fatty acid amide bond has long been recognized in nature, being important in the structure of the ceramides [1] and the sphingolipids [2]. The first non-sphingosine based fatty acid amide isolated from a natural source was N-palmitoylethanolamine from egg yolk in 1957 [3]. Interest in the N-acylethanolamines (NAEs) dramatically increased upon the identification of Narachidonoylethanolamine (anandamide) as the endogenous ligand for the cannabinoid receptors in the mammalian brain [4]. It is now known that a family of NAEs is found in the brain and in other tissues [5,6].In addition to the NAEs, other classes of fatty acid amides have been characterized, namely the N-acylamino acids (NAAs) [7], the N-acyldopamines (NADAs) [8] and the primary fatty acid amides (PFAMs) [9,10] (Figure 1). Relative to NAEs, much less is currently known about the NAAs, the NADAs and the PFAMs, except that they are found in biological systems. The goal of this review is to summarize the current state of knowledge regarding the different classes of endogenous fatty acid amides and highlight their potential for drug discovery (see refs. [11-13] for earlier reviews) © 2008 Elsevier Ltd. All rights reserved.Corresponding author: Merkler, D.J (E-mail: merkler@cas.usf.edu) phone 813-974-3579; fax 813-974-1733. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.Teaser SentenceFatty acid amides are a family of mammalian bioactive compounds. These molecules and the enzymes involved in their metabolism provide an opportunity to develop new drugs to treat human disease. -palmitoyl-, N-stearoyl-and N-oleoylethanolamine [5,11], each compromising ≥25% of total brain NAEs. Other less abundant NAEs found in the brain are anandamide, N-linoleoyl-, N-linolenoyl-, N-dihomo-γ-linolenoyl-and N-docosatetraenoylethanolamine [11]. In addition to the brain, the NAEs are widespread in the peripheral tissues [5]. The mos...

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Oxidative metabolism of lipoamino acids and vanilloids by lipoxygenases and cyclooxygenases

Cited by 31 publications

References 58 publications

Cyclooxygenase-derived proangiogenic metabolites of epoxyeicosatrienoic acids

Cyclooxygenase-derived proangiogenic metabolites of epoxyeicosatrienoic acids

T-Type Calcium Channel Inhibition Underlies the Analgesic Effects of the Endogenous Lipoamino Acids

Biosynthesis, degradation and pharmacological importance of the fatty acid amides

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