5-Lipoxygenase inhibition by acetyl-11-keto-β-boswellic acid (AKBA) by a novel mechanism

Safayhi, H.; Sailer, E.‐R.; Ammon, H. P. T.

doi:10.1016/s0944-7113(96)80013-4

Cited by 98 publications

(118 citation statements)

References 7 publications

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“…In contrast to many other natural compounds that block 5-LO activity by chelating and redox actions, the PTs are assumed to act by a distinct mode, apparently by interference with a (regulatory) fatty acid-binding site of 5-LO [154], [155]. The most-recognized PTs that act on 5-LO are BAs, and many studies addressed the respective molecular interactions (for detailed review see [153], [156]).…”

Section: Pentacyclic Triterpenesmentioning

confidence: 99%

“…The most-recognized PTs that act on 5-LO are BAs, and many studies addressed the respective molecular interactions (for detailed review see [153], [156]). BAs with an 11-keto moiety, preferably 3-O-acteyl-11-keto-b-BA (AKBA 89, Table 6) are of particular interest, and AKBA 89 is the most efficient derivative with IC 50 values 1.5 ± 15 mM in intact cells [74], [154], [157], [158], [159]. Studies using isolated 5-LO or other types of cell-free assays showed that AKBA 89 is a direct, non-redox-type 5-LO inhibitor (IC 50 values 8 ± 50 mM) [74], [154], [159].…”

Section: Pentacyclic Triterpenesmentioning

confidence: 99%

“…BAs with an 11-keto moiety, preferably 3-O-acteyl-11-keto-b-BA (AKBA 89, Table 6) are of particular interest, and AKBA 89 is the most efficient derivative with IC 50 values 1.5 ± 15 mM in intact cells [74], [154], [157], [158], [159]. Studies using isolated 5-LO or other types of cell-free assays showed that AKBA 89 is a direct, non-redox-type 5-LO inhibitor (IC 50 values 8 ± 50 mM) [74], [154], [159]. The discrepancies in the potency of AKBA 89 for 5-LO inhibition (1.5 ± 50 mM) reported from different studies may be due to different experimental settings such as cell type, species and enzyme source (purified 5-LO, crude homogenates).…”

Section: Pentacyclic Triterpenesmentioning

confidence: 99%

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Inhibition of 5-Lipoxygenase Product Synthesis by Natural Compounds of Plant Origin

Werz¹

2007

Planta Med

151

135

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The biosynthesis of leukotrienes (LTs) is initiated by the transformation of free arachidonic acid to LTA 4 by 5-lipoxygenase (5-LO). Subsequent enzymatic conversion of LTA 4 yields LTB 4 and the cysteinyl-LTs C 4 , D 4 and E 4 . LTs have prominent functions in pathophysiology and are connected to numerous disorders including bronchial asthma, allergic rhinitis, inflammatory bowel and skin diseases, rheumatoid arthritis, cancer, osteoporosis and cardiovascular diseases. Pharmacological and genetic interruption of the 5-LO pathway or blockade of LT receptors, serving as means for intervention with LTs, may be of therapeutic value for certain related disorders. Natural or plant-derived substances were among the first 5-LO inhibitors identified in the early 1980 s. To date, a huge number of diverse plant-derived compounds have been reported to interfere with 5-LO product synthesis. However, many investigations have addressed the efficacy of a given compound solely in cellular test systems and analysis of direct interference with 5-LO has been neglected. In the first part of this review, the biology and molecular pharmacology of the 5-LO pathway is summarized in order to understand its overall regulation and complexity as well as to comprehend the possible points of attack of compounds that eventually lead to inhibition of 5-LO product formation in intact cells. In the second part, natural compounds that interfere with 5-LO product formation are compiled and grouped into structural classes, and the underlying molecular mechanisms and structureactivity relationships are discussed.

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Section: Pentacyclic Triterpenesmentioning

confidence: 99%

Section: Pentacyclic Triterpenesmentioning

confidence: 99%

Section: Pentacyclic Triterpenesmentioning

confidence: 99%

See 1 more Smart Citation

Inhibition of 5-Lipoxygenase Product Synthesis by Natural Compounds of Plant Origin

Werz¹

2007

Planta Med

151

135

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“…We previously deduced from structure/activity-relationship data that the ring system of AKBA and analogues is crucial for the binding to an effector site, and two functional groups (i.e., a hydrophilic group on C4 and a ketofunction on C11) are essential for the inhibitory action [9]. The modification or elimination of these functional groups led to partial inhibitory (e.g., β-boswellic acid) and non-inhibitory (e.g., amyrin) compounds that competed with the AKBA-mediated inhibition of the 5-lipoxygenase activity [8,9]. An AKBA-containing drug was recently reported to decrease urinary leukotriene E 4 excretion in patients with malignant glioblastomas and in parallel to reduce peritumoral edema [10,11].…”

mentioning

confidence: 99%

Characterization of an acetyl‐11‐keto‐β‐boswellic acid and arachidonate‐binding regulatory site of 5‐lipoxygenase using photoaffinity labeling

Sailer

Schweizer

Boden

et al. 1998

European Journal of Biochemistry

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AKBA (acetyl-11-keto-β-boswellic acid), a natural pentacyclic triterpene, is an orally active leukotriene-synthesis inhibitor, which acts by a 5-lipoxygenaseϪdirected, non-redox, non-competitive mechanism. It is the only leukotriene-synthesis inhibitor so far identified that inhibits 5-lipoxygenase activity as an allosteric regulator and not by a reducing or competitive mechanism. To characterize AKBA's effector site we prepared azido 125 I-KBA (4-azido-5-125 iodo-salicyloyl-β-alanyl-11-keto-β-boswellic acid) as a photoaffinity analogue, which inhibited 5-lipoxygenase activity as efficiently as the lead compound and specifically labeled human 5-lipoxygenase protein. The labeling of 5-lipoxygenase by azido-125 I-KBA strictly depended on the presence of calcium ([Ca 2ϩ ] free Ͼ 500 nM) and was abolished by heat denaturation or by priorincubation with a series of pentacyclic triterpenes (e.g., amyrin, β-boswellic acid, AKBA and 18A-glycyrrhetinic acid). In contrast, 18-β-glycyrrhetinic acid and competitive 5-lipoxygenase inhibitors (e.g., ZM-230,487 and L-739,010) did not affect labeling. Arachidonic acid, in enzyme-activity-inhibiting concentrations, reduced photoincorporation (IC 50 about 10 µM), whereas a variety of other long-chain fatty acids and their derivatives (e.g., arachidinic acid, arachidonic acid methyl ester, lipoxins A 4 and B 4 ) had no effect. The inhibitory arachidonate action on labeling was not affected by blocking the substratebinding site by micromolar amounts of the competitive inhibitor L-739,010. Therefore, we suggest that AKBA binds in presence of calcium to a site which is distinct from the substrate binding site of 5-lipoxygenase. The AKBA-binding site is likely to be identical with a regulatory, second arachidonate binding site of the enzyme.Keywords : 5-lipoxygenase ; leukotriene synthesis inhibitor ; arachidonic acid; boswellic acid ; terpenoid.5-Lipoxygenase, a 78-kDa protein, is the key enzyme for the biosynthesis of leukotrienes from arachidonic acid [1,2]. Leukotrienes have been implicated as important mediators in inflammatory, allergic and obstructive processes [3,4]. Therefore, 5-lipoxygenase has become the subject of intensive research for inhibitors, which might represent putative remedies for the treatment of chronic inflammatory disorders [5,6]. The in vitro active leukotriene-synthesis inhibitors so far identified belong to three main classes. Redox-type inhibitors reduce product formation by either inhibiting the reversible alteration between ferrous and ferric states of 5-lipoxygenase's essential nonheme iron or by interacting with radical or peroxide intermediates. Competitive-type inhibitors interfere with 5-lipoxygenase action by blocking arachidonate binding either to FLAP (fivelipoxygenase-activating protein) or to 5-lipoxygenase. The thirdCorrespondence to H. Safayhi, Institute of Pharmaceutical Sciences, Department of Pharmacology, Auf der Morgenstelle 8, D-72076 Tübingen, Germany E-mail: hasan.safayhi@uni-tuebingen.de Abbreviations. AKBA, acetyl-11-keto-β-bosw...

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“…Recently we have shown that a derivative of BAs, i.e. acetyl-1 1-keto-fi-BA (AKBA), inhibits the 5-lipoxygenase by an enzyme directed, non-competitive mechanism via binding to a pentacyclic triterpene-selective effector site (Safayhi et al, 1995).…”

mentioning

confidence: 99%

Acetyl‐11‐keto‐β‐boswellic acid (AKBA): structure requirements for binding and 5‐lipoxygenase inhibitory activity

Sailer

Subramanian

Rall

et al. 1996

British J Pharmacology

155

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1 5-Lipoxygenase (5-LOX) products from endogenous arachidonic acid in ionophore-stimulated peritoneal polymorphonuclear leukocytes (PMNL) and from exogenous substrate (20 gM) in 105,000 g supernatants were measured. 2 The effects of natural pentacyclic triterpenes and their derivatives on 5-LOX activity were compared with the inhibitory action of acetyl-l -keto-p-boswellic acid (AKBA), which has been previously shown to inhibit the 5-LOX by a selective, enzyme-directed, non-redox and non-competitive mechanism. 3 The 5-LOX inhibitory potency of AKBA was only slightly diminished by deacetylation of the acetoxy group or reduction of the carboxyl function to alcohol in intact cells (ICs = 1.5 vs. 3 and 4.5 pM, respectively) and in the cell-free system (8 vs. 20 and 45 gM).5 fl-Boswellic acid (f-BA), lacking the 1 1-keto function, inhibited 5-LOX only partially and incompletely, whereas the corresponding alcohol from fl-BA, as well as amyrin, acetyl-ll-keto-amyrin, 1 l-keto-f-boswellic acid methyl ester had no 5-LOX inhibitory activity up to 50 pM in either system. 5 fl-BA only partially prevented the AKBA-induced 5-LOX inhibition, whereas the non-inhibitory compounds, amyrin and acetyl-1 l-keto-amyrin, almost totally antagonized the AKBA effect and shifted the concentration-inhibition curve for the incomplete inhibitor fl-BA to the right. In contrast, the noninhibitory 1 1-keto-fl-BA methyl ester exerted no antagonizing effect.6 The results demonstrate that the pentacyclic triterpene ring system is crucial for binding to the highly selective effector site, whereas functional groups (especially the 11 -keto function in addition to a hydrophilic group on C4 of ring A) are essential for 5-LOX inhibitory activity.

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5-Lipoxygenase inhibition by acetyl-11-keto-β-boswellic acid (AKBA) by a novel mechanism

Cited by 98 publications

References 7 publications

Inhibition of 5-Lipoxygenase Product Synthesis by Natural Compounds of Plant Origin

Inhibition of 5-Lipoxygenase Product Synthesis by Natural Compounds of Plant Origin

Characterization of an acetyl‐11‐keto‐β‐boswellic acid and arachidonate‐binding regulatory site of 5‐lipoxygenase using photoaffinity labeling

Acetyl‐11‐keto‐β‐boswellic acid (AKBA): structure requirements for binding and 5‐lipoxygenase inhibitory activity

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