LEUKOTRIENE D-4 AND CYSTINYL-BIS-GLYCINE METABOLISM IN MEMBRANE-BOUNDDIPEPTIDASE-DEFICIENT MICE

We have developed mice deficient in membrane-bound dipeptidase (MBD, E C 3.4.13.19), the enzyme believed to be responsible for the conversion of leukotriene D-4 (LTD4) to leukotriene E-4 (LTE4). The MBD mutation generated by us was demonstrated to be a null mutation by Northern bl ot analysis and the absence of beta-lactamase activity in lung, kidney , small intestine, and heart. MBD gene deletion had no effect on viabi lity or fertility. The mutant mice retain partial ability to convert L TD4 to LTE4, ranging from 80-90% of the wild-type values in small inte stine and liver to 16% in kidney and 40% in lung, heart, and pancreas. MBD is also believed to function consecutively after gamma-glutamyl t ranspeptidase to cleave cystinyl-bis-glycine (cys-bis-gly) generated f rom glutathione cleavage. Our data indicate that kidney homogenates fr om MBD-deficient mice retain similar to 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 demonstr ate 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 tis sues.