γ-Glutamyl Leukotrienase, a γ-Glutamyl Transpeptidase Gene Family Member, Is Expressed Primarily in Spleen

Abstract

We have recently identified a mouse enzyme termed ␥-glutamyl leukotrienase (GGL) that converts leukotriene C 4 (LTC 4 ) to leukotriene D 4 (LTD 4 ). It also cleaves some other glutathione (GSH) conjugates, but not GSH itself (Carter, B. Z., Wiseman, A. L., Orkiszewski, R., Ballard, K. D., Ou, C.-N., and Lieberman, M. W. (1997) J. Biol. Chem. 272, 12305-12310). We have now cloned a fulllength mouse cDNA coding for GGL activity and the corresponding gene. GGL and ␥-glutamyl transpeptidase constitute a small gene family. The two cDNAs share a 57% nucleotide identity and 41% predicted amino acid sequence identity. Their corresponding genes have a similar intron-exon organization and are located 3 kilobases apart. A search of Genbank and reverse transcription-polymerase chain reaction analysis failed to identify additional family members. Mapping of the GGL transcription start site revealed that the GGL promoter is TATA-less but contains an initiator, a control element for transcription initiation. Northern blots for GGL expression were negative. As judged by ribonuclease protection, in situ hybridization, and measurement of enzyme activity, spleen had the highest level of GGL expression. GGL is also expressed in thymic lymphocytes, bronchiolar epithelial cells, pulmonary interstitial cells, renal proximal convoluted tubular cells, and crypt cells of the small intestine as well as in cerebral, cerebellar, and brain stem neurons but not in glial cells. GGL is widely distributed in mice, suggesting an important role for this enzyme.Glutathione conjugates play a central role in normal physiology and in responses to injury (1-6). Among the more important GSH derivatives are conjugates of eicosanoids, xenobiotics, and carcinogens. At least three types of eicosanoid-GSH conjugates have been identified, including derivatives of leukotriene A 4 , prostaglandins, and hepoxilins. The LTA 4 -GSH conjugate (LTC 4 ) 1 and its cleavage products, LTD 4 and LTE 4 , are powerful mediators of bronchoconstriction, vasoconstriction, mucus formation, and edema. As a result, they are important mediators of asthma, coronary artery spasm, and nephropathies (7-15). Prostaglandins play diverse biological roles and are involved in the development of the inflammatory response, inhibition of platelet aggregation, and regulation of immune responses (6). Prostaglandins are inactivated and cleared by conjugation to GSH (3, 6). Hepoxilin A 3 forms a GSH conjugate, hepoxilin A 3 -C, that is known to be a potent regulator of hippocampal neurons (4). In addition, several neurotransmitters, including serotonin and dopamine, form GSH conjugates, suggesting an additional role for this pathway in the central nervous system (16,17). GSH conjugation along with glucuronide formation is the major pathway by which toxins, drugs, and carcinogens such as CH 3 Hg, acetaminophen, and aflatoxin are detoxified and excreted (5, 18 -21).Until recently, it was thought that the sequential cleavage of GSH conjugates and their derivative cysteinyl-glycine conjugates were c...

Thematic Review Series: Proteomics. An integrated omics analysis of eicosanoid biology

“…This activity was originally termed g-glutamyl leukotrienase (GGL) due to its selectivity for LTC 4 as a substrate. Subsequent cloning and sequencing confirmed that murine GGL was a homolog to human GGT-rel gene (97). Both GGT and GGL appear to play a functional role in LTC 4 metabolism, as demonstrated by metabolism studies using single and double knockout mice (98).…”

Cysteinyl Leukotrienes and Their Receptors: Cellular Distribution and Function in Immune and Inflammatory Responses

“…LTC 4 is exported to the cell surface via a specific, energy-dependent step (14) that requires multidrug resistance-associated protein 1 (MRP1) (15). It is converted extracellularly to LTD 4 by a ␥-glutamyl transpeptidase (␥-GT) (16) or by a more functionally specific enzyme, ␥-glutamyl leukotrienase (␥-GL) (17), and then to LTE 4 by a dipeptidase (18). LTE 4 is excreted in the urine without further chemical modification.…”

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

“…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).…”

“…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). GGT and GGL share 41% amino acid sequence identity and are tightly linked on the same chromosome (4,5,24).…”

“…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…”