γ-Glutamyl Leukotrienase Cleavage of Leukotriene C4

Lieberman, Michael W.; Shields, Jefry E.; Will, Yvonne; Reed, Donald J.; Carter, Bing Z.

doi:10.1007/978-1-4615-4793-8_44

Cited by 5 publications

(8 citation statements)

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“…Both GGL and GGT are membrane-bound ␥-glutamyl peptidases that cleave S-substituted GSHs, including LTC 4 (24,27); however, GGL has a narrower spectrum of substrates and does not cleave GSH (4,5,24). In addition, GGL is expressed at very low levels in most organs (4).…”

Section: Discussionmentioning

confidence: 99%

“…A human cysteinyl LT 2 receptor has recently been cloned (16) and found to have binding properties and a tissue distribution different from those of cysteinyl LT 1 . Recent studies of two enzymes that metabolize LTC 4 provide an opportunity to assess these issues (4,5,23,24). A second member of the ␥-glutamyl transpeptidase (GGT) gene family, termed ␥-glutamyl leukotrienase (GGL), has recently been cloned and characterized (4, 5).…”

mentioning

confidence: 99%

“…A second member of the ␥-glutamyl transpeptidase (GGT) gene family, termed ␥-glutamyl leukotrienase (GGL), has recently been cloned and characterized (4,5). GGT and GGL share 41% amino acid sequence identity and are tightly linked on the same chromosome (4,5,24). LTC 4 (the GSH conjugate of LTA 4 ) is known to be cleaved by GGT to form LTD 4 by removal of a ␥-glutamyl group.…”

mentioning

confidence: 99%

“…LTC 4 (the GSH conjugate of LTA 4 ) is known to be cleaved by GGT to form LTD 4 by removal of a ␥-glutamyl group. Although the older literature suggests that GGT is the only enzyme capable of performing this function (for an example, see reference 27), it has been demonstrated that GGL can also cleave LTC 4 (hence the name, ␥-glutamyl leukotrienase) (4,5,24). Because GGT is widely expressed and more abundant than GGL (4,5,23,24), it is unclear what role, if any, GGL plays in vivo.…”

mentioning

confidence: 99%

“…Although the older literature suggests that GGT is the only enzyme capable of performing this function (for an example, see reference 27), it has been demonstrated that GGL can also cleave LTC 4 (hence the name, ␥-glutamyl leukotrienase) (4,5,24). Because GGT is widely expressed and more abundant than GGL (4,5,23,24), it is unclear what role, if any, GGL plays in vivo. Yet GGL is expressed at a relatively higher level than GGT in some organs, such as the liver and spleen, and has a 10-fold-lower K m for LTC 4 than GGT, suggesting that GGL may function in vivo to convert LTC 4 to LTD 4 .…”

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Disruption of γ-Glutamyl Leukotrienase Results in Disruption of Leukotriene D₄ Synthesis In Vivo and Attenuation of the Acute Inflammatory Response

Shi¹,

Han²,

Habib³

et al. 2001

Molecular and Cellular Biology

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To study the function of ␥-glutamyl leukotrienase (GGL), a newly identified member of the ␥-glutamyl transpeptidase (GGT) family, we generated null mutations in GGL (GGL tm1 ) and in both GGL and GGT (GGL tm1 -GGT tm1 ) by a serial targeting strategy using embryonic stem cells. Mice homozygous for GGL tm1 show no obvious phenotypic changes. Mice deficient in both GGT and GGL have a phenotype similar to the GGT-deficient mice, but ϳ70% of these mice die before 4 weeks of age, at least 2 months earlier than mice deficient only in GGT. These double-mutant mice are unable to cleave leukotriene C 4 (LTC 4 ) to LTD 4 , indicating that this conversion is completely dependent on the two enzymes, and in some organs (spleen and uterus) deletion of GGL alone abolished more than 90% of this activity. In an experimental model of peritonitis, GGL alone is responsible for the generation of peritoneal LTD 4 . Further, during the development of peritonitis, GGL-deficient mice show an attenuation in neutrophil recruitment but not of plasma protein influx. These findings demonstrate an important role for GGL in the inflammatory response and suggest that LTC 4 and LTD 4 have distinctly different functions in the inflammatory process.Leukotrienes (LT) are a group of biologically active metabolites of arachidonic acid and have been implicated in the pathophysiology of many inflammatory diseases, including asthma, arthritis, psoriasis, and inflammatory bowel disease (8,17,20). Unlike many other inflammatory mediators, LT are not stored but synthesized de novo in response to inflammatory stimuli (17). Synthesis of LT is an intracellular process initiated by the conversion of free arachidonic acid to LTA 4 , an epoxide intermediate, by the key enzyme 5-lipoxygenase and the accessory protein 5-lipoxygenase-activating protein. LTA 4 can be converted to LTB 4 by LTA 4 hydrolase or conjugated with glutathione (GSH) by LTC 4 synthase to form LTC 4 . LTC 4 is then transported to the extracellular microenvironment where it is converted to LTD 4 (the cysteinyl glycine conjugate of LTA 4 ) and then to LTE 4 (the cysteinyl conjugate of LTA 4 ).LTC 4 and its metabolites, LTD 4 and LTE 4 , are referred to as cysteinyl LT and were originally identified as the active components of the slow reacting substance of anaphylaxis. They are known to stimulate a wide spectrum of inflammatory processes, including vasoconstriction, increases in postcapillary venule permeability, local recruitment of eosinophils, bronchoconstriction, and mucous secretion (8,9,17,19,20). LT have been the focus of extensive investigation in recent years because of the potency of their inflammatory effects, particularly in asthma, and promising therapeutic results with novel inhibitors of their synthesis and/or antagonists of their receptors (9,19).Cysteinyl LT exert their effects through specific receptors;however, there has been significant uncertainty about the interaction of cysteinyl LT with their receptors and the relative potencies of individual cysteinyl LT. In vivo studies...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Disruption of γ-Glutamyl Leukotrienase Results in Disruption of Leukotriene D₄ Synthesis In Vivo and Attenuation of the Acute Inflammatory Response

Shi¹,

Han²,

Habib³

et al. 2001

Molecular and Cellular Biology

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Leukotriene C4 induces bronchoconstriction and airway vascular hyperpermeability via the cysteinyl leukotriene receptor 2 in S-hexyl glutathione-treated guinea pigs

Yonetomi

Sekioka

Kadode

et al. 2015

European Journal of Pharmacology

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The mercapturic acid pathway

Hanna

Anders

2019

Critical Reviews in Toxicology

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The mercapturic acid pathway is a major route for the biotransformation of xenobiotic and endobiotic electrophilic compounds and their metabolites. Mercapturic acids (N-acetyl-L-cysteine S-conjugates) are formed by the sequential action of the glutathione transferases, c-glutamyltransferases, dipeptidases, and cysteine S-conjugate N-acetyltransferase to yield glutathione S-conjugates, L-cysteinylglycine S-conjugates, L-cysteine S-conjugates, and mercapturic acids; these metabolites constitute a "mercapturomic" profile. Aminoacylases catalyze the hydrolysis of mercapturic acids to form cysteine S-conjugates. Several renal transport systems facilitate the urinary elimination of mercapturic acids; urinary mercapturic acids may serve as biomarkers for exposure to chemicals. Although mercapturic acid formation and elimination is a detoxication reaction, L-cysteine S-conjugates may undergo bioactivation by cysteine Sconjugate b-lyase. Moreover, some L-cysteine S-conjugates, particularly L-cysteinyl-leukotrienes, exert significant pathophysiological effects. Finally, some enzymes of the mercapturic acid pathway are described as the so-called "moonlighting proteins," catalytic proteins that exert multiple biochemical or biophysical functions apart from catalysis.

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γ-Glutamyl Leukotrienase Cleavage of Leukotriene C4

Cited by 5 publications

References 15 publications

Disruption of γ-Glutamyl Leukotrienase Results in Disruption of Leukotriene D₄ Synthesis In Vivo and Attenuation of the Acute Inflammatory Response

Disruption of γ-Glutamyl Leukotrienase Results in Disruption of Leukotriene D₄ Synthesis In Vivo and Attenuation of the Acute Inflammatory Response

Leukotriene C4 induces bronchoconstriction and airway vascular hyperpermeability via the cysteinyl leukotriene receptor 2 in S-hexyl glutathione-treated guinea pigs

The mercapturic acid pathway

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γ-Glutamyl Leukotrienase Cleavage of Leukotriene C4

Cited by 5 publications

References 15 publications

Disruption of γ-Glutamyl Leukotrienase Results in Disruption of Leukotriene D4 Synthesis In Vivo and Attenuation of the Acute Inflammatory Response

Disruption of γ-Glutamyl Leukotrienase Results in Disruption of Leukotriene D4 Synthesis In Vivo and Attenuation of the Acute Inflammatory Response

Leukotriene C4 induces bronchoconstriction and airway vascular hyperpermeability via the cysteinyl leukotriene receptor 2 in S-hexyl glutathione-treated guinea pigs

The mercapturic acid pathway

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Disruption of γ-Glutamyl Leukotrienase Results in Disruption of Leukotriene D₄ Synthesis In Vivo and Attenuation of the Acute Inflammatory Response

Disruption of γ-Glutamyl Leukotrienase Results in Disruption of Leukotriene D₄ Synthesis In Vivo and Attenuation of the Acute Inflammatory Response