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1 Mary Nell and Ralph B. Rogers
Magnetic Resonance Center,
The nonspecific transaminase inhibitor
aminooxyacetate (AOA) has multiple influences on the dynamics of
13C appearance in glutamate in rat
hearts as measured by 13C nuclear
magnetic resonance (NMR) without altering
O2 consumption or tricarboxylic
acid (TCA) cycle flux. These include the following: 1) a reduced rate of
13C enrichment at glutamate C3 and
C4; 2) a near coalescence of the C3
and C4 fractional enrichment curves;
3) a dramatic alteration in the
time-dependent evolution of the glutamate C4 multiplets, C4S and C4D34;
and 4) a decrease in the NMR
visibility of glutamate. A fit of the
13C fractional enrichment curves
of glutamate C4 and C3 in the absence of inhibitor to a kinetic model
of the TCA cycle gave values for transaminase flux of 7.5 µmol · min
1 · g
dry wt1 and TCA cycle flux
of 7.5 µmol · min1 · g
dry wt1, thereby confirming
reports by others that the kinetics of
13C enrichment of glutamate C3 and
C4 in heart tissue is significantly affected by flux through reactions
other than TCA cycle. The 13C
fractional enrichment data collected in the presence of 0.5 mM AOA
could not be fitted using this same kinetic model. However, kinetic
simulations demonstrated that the time-dependent changes in C4S and
C4D34 are only consistent with a 10-fold reduction in the size of
intermediate pools undergoing rapid turnover in the TCA cycle. We
conclude that inhibition of glutamic-oxalacetic transaminase by AOA
effectively reduces the size of the 
-ketoglutarate pool in rapid
exchange with the TCA cycle. Our data indicate that changes in
glutamate multiplet areas in the
13C NMR spectra of heart (as
demonstrated by glutamate C4S and C4D34) are more sensitive to
alterations in metabolic pool sizes in exchange with the TCA cycle than
are measurements of 13C fractional
enrichment at glutamate C3 and C4.
13C fractional enrichments; tricarboxylic acid cycle flux; malate-aspartate shuttle
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