Leukotriene D₄ and cystinyl-bis-glycine metabolism in membrane-bound dipeptidase-deficient mice

We have developed mice deficient in membrane-bound dipeptidase (MBD, EC 3.4.13.19), 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.