METABOLISM OF LEUKOTRIENE C-4 IN GAMMA-GLUTAMYL TRANSPEPTIDASE-DEFICIENT MICE

We have investigated the metabolism of leukotriene C-4 (LTC4) in gamma -glutamyl transpeptidase (GGT)-deficient mice (Lieberman, M. W., Wisem an, A. L., Shi, Z-Z., Carter, B. Z., Barrios, R., Ou, C-N., Chevez-Bar rios, P., Wang, Y., Habib, G. M., Goodman, J. C., Huang, S. L., Lebovi tz, R. Fd., and Matzuk, M. M. (1996) Proc. Natl. Acad. Sci. U.S.A. 93, 7923-7926) and have found substantial conversion of LTC4 to leukotrie ne D-4 by high performance liquid chromatography and continuous flow f ast atom bombardment-tandem mass spectrometric analyses. LTC4-converti ng activity has a tissue distribution different from GGT with highest activity in spleen followed by small intestine, kidney, and pancreas a nd lower activity in liver and lung. The activity is membrane-bound an d is inhibited by acivicin, a known inhibitor of GGT. The enzyme was p artially purified from the small intestine of GGT-deficient mice by pa pain treatment and gel filtration chromatography. The partially purifi ed fragment released by papain has an apparent molecular mass of 65-70 kDa and the same substrate specificity as the tissue homogenate. In a ddition to LTC4, S-decyl-GSH is also cleaved. GSH itself, oxidized GSH , and the synthetic substrates used to analyze GGT activity (gamma-glu tamyl-p-nitroanilide and gamma-glutamyl-4-methoxy-2-naphthylamide) are not substrates for this newly discovered enzyme. These data demonstra te that in addition to GGT at least one other enzyme cleaves LTC4 in m ice. To reflect this enzyme's preferred substrate, we suggest that it be named gamma-glutamyl leukotrienase.