Structure Elucidation and Total Synthesis of the Leukotrienes

Corey, E. J.

doi:10.1016/b978-0-12-166750-4.50006-6

Cited by 9 publications

(3 citation statements)

References 127 publications

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“…The methyl esters of LTA3 (23), LTA5 (24), 5-epi-LTA4, 6-epi-LTA4, and 5-epi-, 6-epi-LTA4 (25) were synthesized as described, and the lithium salts of these epoxide-leukotrienes were prepared (17). [14,15-3H]LTA4-me (50 Ci/mmol) was obtained from New England Nuclear (Boston, MA); LTC4, LTD4, LTE4, and LTC4-me were synthesized as previously described (26 …”

Section: Methodsmentioning

confidence: 99%

Properties of highly purified leukotriene C4 synthase of guinea pig lung.

Yoshimoto¹,

Soberman²,

Spur³

et al. 1988

J. Clin. Invest.

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Leukotriene C4 (LTC4) synthase, which conjugates LTA4 and LTA4-methyl ester (LTA4-me) with glutathione (GSH) to form LTC4 and LTC4-me, respectively, has been solubilized from the microsomes of guinea pig lung and purified 91-fold in four steps to a specific activity of 692 nmol/10 min per mg protein using LTA4-me as substrate. LTC4 synthase of guinea pig lung was separated from microsomal GSH S-transferase by Sepharose CI-4B chromatography and further purified by DEAESephacel chromatography, agarose-butylamine chromatography, and DEAE-3SW fast-protein liquid chromatography. It was also differentiated from the microsomal GSH S-transferase, which utilized 1-chloro-2,4-dinitrobenzene as a substrate, by its heat lability and relative resistance to inhibition by Shexyl-GSH. The K. value of guinea pig lung LTC4 synthase for LTA. was 3 ,uM and the V., was 108 nmol/3 min per gg, the K, values for LTA3 and LTA5 were similar, and the V., values were about one-half those obtained with LTA4. The conversion of LTA4-me to LTC4-me was competitively inhibited by LTA3, LTA4, and LTA5, with respective K, values of 1.5, 3.3, and 2.8 MM, suggesting that these substrates were recognized by a common active site. IC50 values for the inhibition of the conjugation of 20 ,uM LTA4-me with 5 mM GSH were 2.1 ,uM and 0.3 MuM for LTC4 and LTC3, respectively. In contrast, LTD4 was substantially less inhibitory (IC5o > 40 MuM), and LTE4 and LTB4 had no effect on the enzyme, indicating that the mixed type product inhibition observed was specific for sulfidopeptide leukotrienes bearing the GSH moiety.

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Section: Methodsmentioning

confidence: 99%

Properties of highly purified leukotriene C4 synthase of guinea pig lung.

Yoshimoto¹,

Soberman²,

Spur³

et al. 1988

J. Clin. Invest.

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“…respectively. Synthetic LTB4 and 6-trans-LTB4 diastereoisomers were prepared as described (20); synthetic 5-HETE, 20-hydroxy-LTB4, and 20-carboxy-LTB4 were obtained from Cayman Chemical Co. Inc. (Ann Arbor, MI). The generation of 5-lipoxygenase pathway products is reported in ng/ 106 cells, as the mean ±SEM, corrected for recovery.…”

Section: Introductionmentioning

confidence: 99%

Dietary omega-3 polyunsaturated fatty acids inhibit phosphoinositide formation and chemotaxis in neutrophils.

Sperling¹,

Benincaso²,

Knoell³

et al. 1993

J. Clin. Invest.

309

215

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Earlier studies demonstrated that dietary w-3 polyunsaturated fatty acid (PUFA) supplementation attenuates the chemotactic response of neutrophils and the generation of leukotriene (LT) B4 by neutrophils stimulated with calcium ionophore; however, the mechanisms and relationship ofthese effects were not examined. Neutrophils and monocytes from eight healthy individuals were examined before and after 3 and 10 wk of dietary supplementation with 20 g SuperEPA daily, which provides 9.4 g eicosapentaenoic acid (EPA) and 5 g docosahexaenoic acid.The maximal neutrophil chemotactic response to LTB4, assessed in Boyden microchambers, decreased by 69% after 3 wk and by 93% after 10 wk from prediet values. The formation of 13Hlinositol tris-phosphate (IP3) by I3HIinositol-labeled neutrophils stimulated by LTB4 decreased by 71% after 3 wk (0.033±0.013% [3Hi release, mean±SEM) and by 90% after 10 wk (0.011±0.011%) from prediet values (0.114±0.030%) as quantitated by #-scintillation counting after resolution on HPLC. LTB4-stimulated neutrophil chemotaxis and IP3 formation correlated significantly (P < 0.0001); each response correlated closely and negatively with the EPA content of the neutrophil phosphatidylinositol (PI) pool (P = 0.0003 and P = 0.0005, respectively). Neither the affinities and densities of the high and low affinity LTB4 receptors on neutrophils nor LTB4-mediated diglyceride formation changed appreciably during the study. Similar results were observed in neutrophils activated with platelet-activating factor (PAF). The summed formation of LTB4 plus LTB5 was selectively inhibited in calcium ionophore-stimulated neutrophils and was also inhibited in zymosan-stimulated neutrophils. The inhibition of the summed formation of LTB4 plus LTB5 in calcium ionophorestimulated neutrophils and in zymosan-stimulated neutrophils did not correlate significantly with the EPA content of the PI pool. The data indicate that dietary w-3 PUFA supplementation inhibits the autoamplification of the neutrophil inflammatory response by decreasing LTB4 formation through the inactivation of the LTA epoxide hydrolase and independently by inhibiting LTB4-(and PAF) stimulated chemotaxis by attenuating the formation of IP3 by the PI-selective phospholipase C. This is the initial demonstration that dietary W-3 PUFA Address reprint requests to Richard I. Sperling,

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“…using a polyclonal anti-LTB, rabbit antibody (kindly provided by Merck, Rahway, NJ) with <6% cross-reactivity for other arachidonic acid-derived 5-lipoxygenase products (17,19,20). Synthetic LTB, for the standardization of the radioimmunoassay was prepared and purified as described (21). Supernatants and redissolved cell pellet extracts from control and calcium ionophore-activated samples were assayed for PAF with a commercially available PAF radioimmunoassay kit (Du Pont-New England Nuclear, Boston, MA).…”

Section: Methodsmentioning

confidence: 99%

Inhibition of Leukotriene B₄ synthesis in neutrophils from patients with rheumatoid arthritis by a single oral dose of methotrexate

et al. 1990

Arthritis & Rheumatism

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We studied the effects of a single, oral dose of methotrexate (MTX) on arachidonic acid metabolism in neutrophils from 6 patients with rheumatoid arthritis, which were obtained 1 day before and 1 day after their usual weekly MTX dose. The 6 patients had received a mean weekly MTX dose of 9.6 mg (range 5-15) for a mean of 61.7 months (range 58-64), and none received concomitant corticosteroids. Total generation of leukotriene B, (LTB,) in neutrophils stimulated ex vivo with 10 pI4 calcium ionophore A23187 for 20 minutes was significantly suppressed, by a mean of 53%, after the MTX dose compared with the predose levels (mean f SEM 13.0 f 1. 4 cells; P = 0.0019), reflecting a comparable suppression of both released and cell-retained LTB,. A 49% decrease in *oxidation products of LTB, demonstrates that decreased LTB, synthesis, rather than increased degradation, is responsible for the decrease in LTB, generation. The absence of a significant change in either 'H-labeled arachidonic acid release or plateletactivating factor generation indicates that the observed decrease in LTB, synthesis was apparently not caused by diminished phospholipase A, activity. A 28% decrease in the total formation of the 5-lipoxygenase products 5-hydroxyeicosatetraenoic acid and the 6-trans-LTB, diastereoisomers, and a 48% suppression of production of LTB, plus its *oxidation metabolites after the MTX dose suggest inhibition of 5-lipoxygenase activity and possible suppression of leukotriene A, epoxide hydrolase activity.

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Structure Elucidation and Total Synthesis of the Leukotrienes

Cited by 9 publications

References 127 publications

Properties of highly purified leukotriene C4 synthase of guinea pig lung.

Properties of highly purified leukotriene C4 synthase of guinea pig lung.

Dietary omega-3 polyunsaturated fatty acids inhibit phosphoinositide formation and chemotaxis in neutrophils.

Inhibition of Leukotriene B₄ synthesis in neutrophils from patients with rheumatoid arthritis by a single oral dose of methotrexate

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Structure Elucidation and Total Synthesis of the Leukotrienes

Cited by 9 publications

References 127 publications

Properties of highly purified leukotriene C4 synthase of guinea pig lung.

Properties of highly purified leukotriene C4 synthase of guinea pig lung.

Dietary omega-3 polyunsaturated fatty acids inhibit phosphoinositide formation and chemotaxis in neutrophils.

Inhibition of Leukotriene B4 synthesis in neutrophils from patients with rheumatoid arthritis by a single oral dose of methotrexate

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Inhibition of Leukotriene B₄ synthesis in neutrophils from patients with rheumatoid arthritis by a single oral dose of methotrexate