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J. Biol. Chem., Vol. 266, Issue 16, 10148-10154, 06, 1991
RR Traxinger and S Marshall
We reported previously that glutamine:F-6-P amidotransferase (GFAT) plays
an integral role in the development of insulin resistance by directing the
flow of incoming glucose into the hexosamine biosynthesis pathway. To
determine whether the enzymatic activity of GFAT is altered during
desensitization of the glucose transport system, we treated isolated rat
adipocytes with various combinations of insulin, glucose, and glutamine.
Treatment with insulin or glucose alone (or in combination) failed to
reduce cytosolic GFAT activity after 4 h, whereas combined treatment with
all three components elicited a progressive loss of GFAT activity that was
rapid (t1/2 of 2 h) and extensive (70% loss). A pronounced loss of GFAT
activity was also seen in cells exposed to glucosamine, an agent known to
directly enter the hexosamine pathway (55% loss at 4 h, ED50 of 360
microM). Moreover, a close correlation was observed between the induction
of desensitization and the loss of GFAT activity as a function of glucose,
insulin, glutamine, and glucosamine concentrations. When total
intracellular hexosamine products were measured, we found that hexosamine
formation was unaltered by insulin or glucose (or a combination) but was
elevated by greater than 4-fold in the presence of insulin, glucose, and
glutamine (t1/2 of 22 min), a condition known to cause both desensitization
and loss of GFAT activity. Additional studies indicated that the loss of
GFAT activity under desensitizing conditions is not due to allosteric
regulation since removal of potential allosteric factors from the cytosol
of desensitized cells by G-25 column chromatography failed to restore
enzyme activity. Overall, these studies indicate that 1) GFAT is an
insulin-regulated enzyme; however, control of enzyme activity is not due to
a direct action of insulin, but rather is mediated by insulin-induced
enhancement of glucose uptake; 2) the routing of incoming glucose through
the hexosamine pathway and the formation of hexosamine products appears to
regulate GFAT activity; and 3) the progressive loss of GFAT activity over
several hours is probably not due to allosteric regulation.
Coordinated regulation of glutamine:fructose-6-phosphate amidotransferase activity by insulin, glucose, and glutamine. Role of hexosamine biosynthesis in enzyme regulation
Department of Biochemistry, University of Tennessee, Memphis 38163.
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