Leukotriene D(4) 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 D(4) (LTD(4)) to leukotriene E(4) (LTE(4)). 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 LTD(4) to LTE(4), 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 LTD(4) to LTE(4) 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.