J. Biol. Chem., Vol. 255, Issue 22, 10787-10792, Nov, 1980
L-gamma-(Threo-beta-methyl)glutamyl-L-alpha-aminobutyrate, a selective substrate of alpha-glutamyl cyclotransferase
RJ Bridges, OW Griffith and A Meister
L-gamma(Threo-beta-methyl)glutamyl-L-alpha-aminobutyrate was was prepared
and found to be an excellent substrate of gamma-glutamyl cyclotransferase;
in contrast to gamma-glutamyl-glutamine and other good substrates of
cyclotransferase, the new substrate is not acted upon by gamma-glutamyl
transpeptidase. gamma-Glutamyl cyclotransferase converts the new substrate
to alpha-aminobutyrate and 3-methyl-5- oxoproline; the latter compound is
not a substrate of 5-oxoprolinase. These properties of
L-gamma-(threo-beta-methyl)glutamyl-L-alpha- aminobutyrate facilitate its
use in selectively determining cyclotransferase activity in biological
materials that have transpeptidase activity. Thus, the new substrate was
used here for the determination of the cyclotransferase activity of
homogenates of various mouse tissues. The new substrate was also used to
examine gamma- glutamyl cyclotransferase activity in vivo; thus, the rate
of respiratory 14CO2 formation after administration of L-gamma-(threo-beta-
methyl)glutamyl-L-alpha-amino[14C]butyrate to mice provides a valid measure
of cyclotransferase activity. beta-Aminoglutaryl-L-alpha- aminobutyrate is
a competitive inhibitor of cyclotransferase (apparent Ki, 0.6 mM).
Administration of beta-amino-glutaryl-L-alpha- aminobutyrate to mice out
only decreased the level of 5-oxoproline in the kidney of control mice, but
also of mice in which kidney 5- oxoproline levels were increased by
administration of methionine. Administration of
beta-aminoglutaryl-L-alpha-aminobutyrate to mice decreased the in vivo
metabolism of L-(threo-beta-methyl)glutamyl-L- alpha-amino[14C]butyrate as
indicated by a marked decrease in the rate of respiratory 14CO2 formation.
The findings indicate that gamma- glutamyl cyclo-transferase is a major in
vivo catalyst for the formation of 5-oxoproline.
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