Metabolism of leukotriene C4 in gamma-glutamyl transpeptidase-deficient mice.
We have investigated the metabolism of leukotriene C4 (LTC4) in gamma-glutamyl transpeptidase (GGT)-deficient mice (Lieberman, M. W., Wiseman, A. L., Shi, Z-Z., Carter, B. Z., Barrios, R., Ou, C-N., Chevez-Barrios, P., Wang, Y., Habib, G. M., Goodman, J. C., Huang, S. L., Lebovitz, R. M., and Matzuk, M. M. (1996) Proc. Natl. Acad. Sci. U. S. A. 93, 7923-7926) and have found substantial conversion of LTC4 to leukotriene D4 by high performance liquid chromatography and continuous flow fast atom bombardment-tandem mass spectrometric analyses. LTC4-converting activity has a tissue distribution different from GGT with highest activity in spleen followed by small intestine, kidney, and pancreas and lower activity in liver and lung. The activity is membrane-bound and is inhibited by acivicin, a known inhibitor of GGT. The enzyme was partially purified from the small intestine of GGT-deficient mice by papain treatment and gel filtration chromatography. The partially purified fragment released by papain has an apparent molecular mass of 65-70 kDa and the same substrate specificity as the tissue homogenate. In addition to LTC4, S-decyl-GSH is also cleaved. GSH itself, oxidized GSH, and the synthetic substrates used to analyze GGT activity (gamma-glutamyl-p-nitroanilide and gamma-glutamyl-4-methoxy-2-naphthylamide) are not substrates for this newly discovered enzyme. These data demonstrate that in addition to GGT at least one other enzyme cleaves LTC4 in mice. To reflect this enzyme's preferred substrate, we suggest that it be named gamma-glutamyl leukotrienase.
Carter
B Z
BZ
Department of Pathology, Baylor College of Medicine, Houston, Texas 77030, USA.
Wiseman
A L
AL
Orkiszewski
R
R
Ballard
K D
KD
Ou
C N
CN
Lieberman
M W
MW
D000818:Animals; D002851:Chromatography, High Pressure Liquid; D005978:Glutathione / Q000031:analogs & derivatives / Q000378:metabolism; D019803:Glutathione Disulfide; D007668:Kidney / Q000378:metabolism; D017997:Leukotriene C4 / Q000378:metabolism*; D051379:Mice; D016339:Spectrometry, Mass, Fast Atom Bombardment; D005723:gamma-Glutamyltransferase / Q000172:deficiency*
D017997:Leukotriene C4; D005723:gamma-Glutamyltransferase; D005978:Glutathione; D019803:Glutathione Disulfide