Open AccessLeukotriene D 4 and cystinyl-bis-glycine metabolism in membrane-bound dipeptidase-deficient mice
Author(s) -
Geetha M. Habib,
Zheng Zheng Shi,
Allan A. Cuevas,
Qiu Guo,
Martin M. Matzuk,
Michael W. Lieberman
Publication year - 1998
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.95.9.4859
Subject(s) - dipeptidase , kidney , biochemistry , leukotriene d4 , leukotriene e4 , glutathione , enzyme , mutant , biology , small intestine , microbiology and biotechnology , chemistry , leukotriene , endocrinology , gene , immunology , receptor , asthma , antagonist
We have developed mice deficient in membrane-bound dipeptidase (MBD, EC3.4.13.19 ), the enzyme believed to be responsible for the conversion of leukotriene D4 (LTD4 ) to leukotriene E4 (LTE4 ). The MBD mutation generated by us was demonstrated to be a null mutation by Northern blot analysis and the absence of β-lactamase activity in lung, kidney, small intestine, and heart. MBD gene deletion had no effect on viability or fertility. The mutant mice retain partial ability to convert LTD4 to LTE4 , ranging from 80–90% of the wild-type values in small intestine and liver to 16% in kidney and 40% in lung, heart, and pancreas. MBD is also believed to function consecutively after γ-glutamyl transpeptidase to cleave cystinyl-bis-glycine (cys-bis-gly) generated from glutathione cleavage. Our data indicate that kidney homogenates from MBD-deficient mice retain ∼40% of their ability to cleave cys-bis-gly, consistent with only modest elevations (3–5-fold) of cys-bis-gly in urine from MBD-deficient mice. These observations demonstrate that the conversion of LTD4 to LTE4 and the degradation of cys-bis-gly are catalyzed by at least two alternative pathways (one of which is MBD) that complement each other to varying extents in different tissues.