Arachidonic acid metabolism 35 pathway

Hydroxyhept-6-enoates have been key intermediates in the synthesis of a variety of natural products, especially of the arachidonic acid metabolic pathway, including prostaglandins, leukotrienes, and isoprostanes [105, 113-118]. The usage of two enantiocomplementary enzymes allowed convenient access to both enantiomers via an ADH-catalyzed reduction of 5-oxo-hept-6-enoate. Alcohol dehydrogenase from Lactobacillus brevis (ADH-LB) furnished the (S )-enantiomer, Thermoanaerobacter sp. ADH (ADH-T) the (7 )-enantiomer in excellent enantiomeric access respectively [119]. A cross-metathesis reaction followed by cyclopropanation led to the formal synthesis of constanolactones C and D (Fig. 16) [86, 120, 121]. 

Hinokitiol is a tropolone type natural compound isolated from the wood of Chymacyparis taiwanesis. The compound has been utilized as a natural antimicrobial agent in hair tonics, toothpastes, cosmetics and food supplements. Hinokitiol was evaluated on five different arachidonic acid metabolic pathways for the mechanism of action of anti-inflammatory effects. It has been found to be a potent inhibitor with IC50 values of 0.1 pM against platelet-type 12-LOX and 50 pM against leukocyte-type 12-LOX. It also inhibited soybean 5-LOX enzyme (IC50 = 17 pM). However, hinokitiol had almost no effects on COX-1 and COX-2 enzymes. Similar inhibition profiles were also observed on synthetic tropolone derivatives [168]. 

By interfering with any one of the many phases associated with these second messenger pathways, toxins may alter channel gating. For example, the blue green algal toxins, aplysiatoxin, and lyngbyatoxin bind to and activate protein kinase C in a manner similar to phorbol esters (73). They also stimulate arachidonic acid metabolism (74). The coral toxin, palytoxin, also stimulates arachidonic acid breakdown albeit by an unknown mechanism (74) and affects other biochemical activities of the cell (see chapters by Fujiki et al., Wattenberg et al., and Levine et al., this volume). 

The title compound 160, a biologically potent metabolite of arachidonic acid metabolism, produced in the 5-lipoxygenase pathway in some mammalian cells127 128, has been synthesized129-131 by the reaction of leukotriene E4, 161, with [l-nC[acetyl chloride in 1.3% yield based on [l-nC] acetyl chloride129 (equation 55). 

The 5-lipoxygenase pathway of arachidonic acid metabolism is responsible for production of cysteinyl leukotrienes. Leukotrienes C4, D4, and E4 are released during inflammatory processes in the lung and produce broncho-spasm, mucus secretion, microvascular permeability, and airway edema. 

M. Moghaddam, K. Motoba, B. Borhan, F. Pinot, B. D. Hammock, Novel Metabolic Pathways for Linoleic and Arachidonic Acid Metabolism , Biochim. Biophys. Acta 1996, 1290, 327 - 339. 

F i g u re 18.1 One pathway of arachidonic acid metabolism. The branches of this pathway lead to the prostaglandins (PGs), prostacyclins (PGIs), and thromboxanes (TxBs). The key reaction is the formation of PGH2, creating five chiral centers from an achiral molecule. (Modified from D. Voet and J. G. Voet, Biochemistry, 3rd edn, 2004. Reprinted with permission John Wiley and Sons Inc.)... 

SMP-114 (licofelone) is a drug candidate for rheumatoid arthritis, currently in Phase II clinical trials (Figure 8.57). It inhibits all three of the major enzymes involved in the arachidonic acid pathway (5-LOX, COX-1, and COX-2), thereby preventing production of both leukotrienes and prostaglandins. This mode of action could therefore lead to a better tolerability than that of conventional cyclooxygenase (COX-1 and COX-2) inhibitors because of the shunt of arachidonic acid metabolism toward the production of proinflammatory leukotrienes, via 5-lipoxygenase (LOX). 

In susceptibie individuais, NSAIDs may precipitate acute bronchospasm. It affects 10-20% of adults with asthma but is rare in asthmatic children. The mechanism is related to cyclooxygenase inhibition, with shunting of arachidonic acid metabolism from the prostaglandin pathway to the biosynthesis of ieukotrienes with increased mucosal permeability and bronchospasm. Susceptible patients should avoid NSAIDs since the bronchospasm may be severe and has been fatal. Paracetamol in doses up to 1000 mg daiiy wiii be toierated by most patients. True type I allergic reactions to NSAIDs, with specific IgE, are rare but anaphyloactoid reactions have occasionally been described in patients with a history of aiiergy or bronchiai asthma. 

Some polyphenols inhibit platelet aggregation reducing the risk of thrombosis [171-173]. This effect may be due to a series of interaction of flavonoids in different biochemical pathways, such as by inhibition of cyclooxygenase and lipoxygenase, that are involved in the arachidonic acid metabolism in the platelets, or by inhibition of the formation of tromboxane and of the receptor function of the same [173-176]. Regular consumption of wine, tea and chocolate has been associated to the reduction of platelet aggregation, cardio-vascular diseases and thrombosis [171,177-179]. 

The mechanisms by which antitumor-promoters suppress the tumor promotion are not known, but may be due to the following effects (i) inhibition of polyamine metabolism (ii) inhibition of arachidonic acid metabolism (iii) protease inhibition (iv) induction of differentiation (v) inhibition of oncogene expression (vi) inhibition of PKC and (vii) inhibition of oxidative DNA damage [3,6,91]. The polyamine content of cells is correlated to their proliferative, and often, their neoplastic capabilities. A key enzyme in the polyamine biosynthetic pathway, ornithine decarboxylase (ODC), catalyzes the convertion of ornithine to putrescine. Phorbol ester promoters such as TPA cause increased ODC activity and accumulation of polyamines in affected tissues. Diacylglycerol activated PKC, and the potent tumor promoter, TPA, binds to, and activates PKC, in competition with diacylglycerol. PKC stimulation results in phosphorylation of regulatory proteins that affect cell proliferation. Some chemopreventive agents have inhibitory activity towards PKC. Refer to recent review articles for further discussion [3,6,91]. 

The lipoxygenase system also competes for released arachidonic acid in a way that seems to be tissue-selective, giving rise to hydroperoxy fatty acids (HPETE) which can be converted into leukotrienes or reduced to hydroxy fatty acid (HETE) products [115]. The basic scheme for these metabolic conversions involving arachidonic acid is presented in Figure 5.2. Both of the main enzymatic pathways of arachidonic acid metabolism are thought to involve free-radical-mediated reactions [108] and the antioxidant capacity of vitamin E could therefore allow the vitamin to modify the products of these pathways. 

Zeldin, D. C. Epoxygenase pathways of arachidonic acid metabolism. /. Biol. Chem. 276, 36059-36062, 2001. 

Thromboxane A2 (TXi ), is a product of the cyclooxygenase pathway of arachidonic acid metabolism with platelet... 

Scheme 1.4. Arachidonic acid metabolism Principal products of the 5-lipoxygenase pathway.

The mechanism by which cyclooxygenase inhibition produces bronchospasm in susceptible individuals is unknown. Arachidonic acid metabolism through the 5-lipoxygenase pathway may lead to the excess production of leukotrienes C4 and D4. Leukotrienes C4, D4, and E4 produce bronchospasm and promote histamine release from mast cells, whereas the administration of leukotriene receptor antagonists and 5-lipoxygenase inhibitors ablate the pulmonary and nonpuhnonary responses to aspirin in aspirin-sensitive asthmatics. The precise mechanism by which augmented leukotriene production occurs is unknown, and available hypotheses do not explain why only a small number of asthmatic patients react to aspirin and NSAIDs. 

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