Sequential conversion of the glutathionyl side chain of slow reacting substance (SRS) to cysteinyl-glycine and cysteine in rat basophilic leukemia cells stimulated with A-23187

Parker, Charles W.; Falkenhein, Sandra F.; Huber, Mary

doi:10.1016/0090-6980(80)90139-2

Cited by 73 publications

(9 citation statements)

References 13 publications

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“…Since LTC 4 is the only intracellular cys-LT generated by LTC 4 synthase (LTC 4 S) (7), it seemed likely that LTD 4 was formed extracellularly from LTC 4 by deletion of glutamic acid (by a γ-glutamyl transpeptidase or γ-glutamyl leukotrienase) following the export of the former compound to the extracellular space. Further removal of glycine from the remaining dipeptide adduct of LTD 4 by dipeptidases accounted for LTE 4 with a remaining cysteine adduct (6, 8). That LTC 4 underwent enzymatic modification in the extracellular space accounted for the fact that it was the only component of SRS-A to be detected in single cell systems, whereas all three components were detected in biologic fluids.…”

Section: Discovery Of Lte4mentioning

confidence: 99%

The leukotriene E4 puzzle: Finding the missing pieces and revealing the pathobiologic implications

Austen

Maekawa

Kanaoka

et al. 2009

Journal of Allergy and Clinical Immunology

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The intracellular parent of the cysteinyl leukotrienes (cys-LTs), leukotriene (LT) C4, is formed by conjugation of LTA4 and reduced glutathione by LTC4 synthase in mast cells, eosinophils, basophils, and macrophages. After extracellular export, LTC4 is converted to LTD4 and LTE4 by sequential enzymatic removal of glutamic acid and then glycine. Only LTE4 is sufficiently stable to be prominent in biologic fluids, such as urine or bronchoalveolar lavage fluid of asthmatic individuals and at sites of inflammation in animal models. LTE4 has received little attention because it binds poorly to the classical receptors, CysLT1R and CysLT2R, and was much less active on normal airways than LTC4 or LTD4. However, early studies indicated that LTE4 caused skin swelling in humans as potently as LTC4 and LTD4, that airways of asthmatic subjects (particularly those that were aspirin-sensitive) were selectively hyperresponsive to LTE4, and that a potential distinct LTE4 receptor was present in guinea pig trachea. Recent studies have begun to uncover receptors selective for LTE4; P2Y12, an ADP receptor, and CysLTER, observed functionally in skin of mice lacking CysLT1R and CysLT2R. These findings prompt a renewed focus on LTE4 receptors as therapeutic targets that are not currently addressed by available receptor antagonists.

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Section: Discovery Of Lte4mentioning

confidence: 99%

The leukotriene E4 puzzle: Finding the missing pieces and revealing the pathobiologic implications

Austen

Maekawa

Kanaoka

et al. 2009

Journal of Allergy and Clinical Immunology

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“…Conversion of LTD4 to LTE4 by cleavage of the carboxy terminal glycine has been separately achieved with highly purified rat kidney dipeptidase and aminopeptidase (10). LTC4 is also converted to LTD4 and to LTE4 in vitro by a number of cell types and tissue extracts (11)(12)(13)(14)(15)(16) and these bioconversions are suppressed by agents capable of inhibiting y-glutamyl transpeptidase and dipeptidases, respectively (9,12,17).…”

Section: Introductionmentioning

confidence: 99%

Bioconversion of C-6 Sulfidopeptide Leukotrienes by the Responding Guinea Pig Ileum Determines the Time Course of its Contraction

Krilis¹,

Lewis²,

Corey³

et al. 1983

J. Clin. Invest.

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A B S T R A C T The naturally occurring sulfidopeptide leukotrienes, leukotriene (LT) C4 (LTC4) [5(S)-hydroxy -6(R) -S -glutathionyl -7,9 -trans,1 1,14 -cis -eicosatetraenoic acid] and its cysteinylglycine (LTD4) and cysteinyl (LTE4) analogs, which are derived by peptide cleavage, differ in the concentrations required to elicit comparable contractions of the guinea pig ileum, with respective potencies of 1.2:5:1. The effect of the ongoing bioconversion of LTC4 and LTD4 on the contractile response of the guinea pig ileum to each was determined by recording the pattern of the contraction and quantitating the initial agonist and its metabolic products. The contraction was elicited by radiolabeled agonist, and its conversion products were sampled at defined intervals and resolved by their retention times on reverse-phase high performance liquid chromatography. After a latent period of 60 s, LTC4 initiated a linear response, followed by a slower, progressive response to a maximum level that was maintained without relaxation. The metabolic conversion of LTC4 was <5% during the linear phase of contraction and complete inhibition of bioconversion of LTC4 to LTD4 by the presence of serine-borate complex did not alter the pattern of the spasmogenic response. As the maximum response in the presence of serine-borate complex was three-quarters of that obtained without the inhibitor of bioconversion, the pre- Received for publication 23 August 1982 and in revised form 8 December 1982. dominant response was to LTC, itself. The spasmogenic response of the ileum to LTD4 was immediate, linear to a maximum level, and immediately followed by a marked relaxation. That the failure of LTD4 to sustain a contraction was due to its immediate, rapid, and quantitative conversion to the less potent LTE4 was established by pharmacologically inhibiting and anatomically deleting the converting activity. In the presence of L-cysteine the conversion of LTD4 to LTE4 was largely inhibited and the maximum contractile response was well maintained. After anatomic removal of the mucosa that contained the LTD4 dipeptidase activity, the longitudinal smooth muscle preparation gave a maximal response to LTD4 that was fully maintained. Thus, bioconversion is not a prerequisite for the spasmogenic activity of LTC4 and accounts for the transient response of the ileum to LTD4.

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“…Release of LTs from tissues like human lung [5] and various cell populations like neutrophils [6,7], basophils [8,9,10], eosinophils [11] and macrophages [12,13] has been described. For the quantitative determination of LTs biological, chromatographic and physicochemical methods have been used [14].…”

Section: Introductionmentioning

confidence: 99%

Release of leukotriene C₄ from human polymorphonuclear leucocytes as determined by radioimmunoassay

et al. 1982

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Rabbits were imn~unized with a conjugate of leukotriene (LT) C4 and bovine serum albumin prepared by coupling the single free amino group of the hapten to the protein using gluteraldehyde. Binding of [3H]LTC4 to the antibodies obtained is inhibited by 50% with 1.5 ng LTC4. The relative cross-reaction of LTD 4 is 16% and of LTC4-methyl ester 3.6%. The validity of the radioimmunoassay was demonstrated by comparison with bioassay using the isolated guinea pig ileum. Using the radioimmunoassay it could be shown that endogenous LTC4 is released in a dose-dependent manner by human polymorphonuclear leucocytes stimulated with the divalent cation ionophore A23187. Leukotriene C4 Radioimmunoassay Leucocyte Bioassay LipoxygenaseSlow-reacting substance

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Sequential conversion of the glutathionyl side chain of slow reacting substance (SRS) to cysteinyl-glycine and cysteine in rat basophilic leukemia cells stimulated with A-23187

Cited by 73 publications

References 13 publications

The leukotriene E4 puzzle: Finding the missing pieces and revealing the pathobiologic implications

The leukotriene E4 puzzle: Finding the missing pieces and revealing the pathobiologic implications

Bioconversion of C-6 Sulfidopeptide Leukotrienes by the Responding Guinea Pig Ileum Determines the Time Course of its Contraction

Release of leukotriene C₄ from human polymorphonuclear leucocytes as determined by radioimmunoassay

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Sequential conversion of the glutathionyl side chain of slow reacting substance (SRS) to cysteinyl-glycine and cysteine in rat basophilic leukemia cells stimulated with A-23187

Cited by 73 publications

References 13 publications

The leukotriene E4 puzzle: Finding the missing pieces and revealing the pathobiologic implications

The leukotriene E4 puzzle: Finding the missing pieces and revealing the pathobiologic implications

Bioconversion of C-6 Sulfidopeptide Leukotrienes by the Responding Guinea Pig Ileum Determines the Time Course of its Contraction

Release of leukotriene C4 from human polymorphonuclear leucocytes as determined by radioimmunoassay

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Release of leukotriene C₄ from human polymorphonuclear leucocytes as determined by radioimmunoassay