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Vol. 294, Issue 2, 753-761, August 2000
-Lyase/Glutamine Transaminase
K1
Leiden/Amsterdam Center for Drug Research, Division of Molecular
Toxicology, Department of Pharmacochemistry, Vrije Universiteit
Amsterdam, Amsterdam, the Netherlands
Selenocysteine Se-conjugates have recently been proposed as
potential prodrugs to target pharmacologically active selenol compounds
to the kidney. Although rat renal cytosol displayed a high activity of
-elimination activity toward these substrates, the enzymes involved
in this activation pathway as yet have not been identified. In the
present study, the possible involvement of cysteine conjugate
-lyase/glutamine transaminase K (-lyase/GTK) in cytosolic
activity was investigated. To this end, the enzyme kinetics of 15 differentially substituted selenocysteine Se-conjugates and 11 cysteine
S-conjugates was determined using highly purified rat
renal -lyase/GTK. The results demonstrate that most selenocysteine Se-conjugates are -eliminated at a very high activity by purified -lyase/GTK, implicating an important role of this protein in the
previously reported -elimination reactions in rat renal cytosol. As
indicated by the rapid consumption of 
-keto-
-methiolbutyric acid,
purified -lyase/GTK also catalyzed transamination reactions, which
appeared to even exceed that of -elimination. The corresponding sulfur analogs also showed significant transamination but were -eliminated at an extremely low rate. Comparison of the obtained enzyme kinetic data of purified -lyase/GTK with previously obtained data from rat renal cytosol showed a poor correlation. By determining the activity profiles of cytosolic fractions applied to anion exchange
fast protein liquid chromatography and gel filtration chromatography,
the involvement of multiple enzymes in the -elimination of
selenocysteine Se-conjugates in rat renal cytosol was demonstrated. The
identity and characteristics of these alternative selenocysteine conjugate -lyases, however, remain to be established.
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