Abstract
To clarify the physiological role of fructose 2,6-bisphosphate in the perinatal switching of myocardial fuels from carbohydrate to fatty acids, the kinetic effects of fructose 2,6-bisphosphate on phosphofructokinase purified from fetal and adult rat hearts were compared. For both enzymes at physiological pH and ATP concentrations, 1 microM fructose 2,6-bisphosphate induced a greater than 10-fold reduction in S0.5 for fructose 6-phosphate and it completely eliminated subunit cooperativity. Fructose 2,6-bisphosphate may thereby reduce the influence of changes in fructose 6-phosphate concentration on phosphofructokinase activity. Based on double-reciprocal plots and ATP inhibition studies, adult heart phosphofructokinase activity is more sensitive to physiological changes in ATP and citrate concentrations than to changes in fructose 2,6-bisphosphate concentrations. Fetal heart phosphofructokinase is less sensitive to ATP concentration above 5 mM and equally sensitive to citrate inhibition. The fetal enzyme has up to a 15-fold lower affinity for fructose 2,6-bisphosphate, rendering it more sensitive to changes in fructose 2,6-bisphosphate concentration than adult heart phosphofructokinase. Together, these factors allow greater phosphofructokinase activity in fetal heart while retaining sensitive metabolic control. In both fetal and adult heart, fructose 2,6-bisphosphate is primarily permissive: it abolishes subunit cooperativity and in its presence phosphofructokinase activity is extraordinarily sensitive to both the energy balance of the cell as reflected in ATP concentration and the availability of other fuels as reflected in cytosolic citrate concentration.
Highlights
From the $Division of Metabolism, Washington University Medical Center and the §Division of Cardiology,Jewish Hospital of St
Based on double-reciprocal plots and ATP inhibition studies, adult heart phosphofructokinase activity ismore sensitive tophysiological changes inATP and citrateconcentrations than to changes in fructose on liver phosphofructokinase by relieving inhibition imposed by physiological pH, ATP, and citrate concentratio(1ns0,ll)
Our studies show that Fru-2,6-P2 modulates myocardial phosphofructokinase activity 1)by eliminating subunit cooperativity with respect to Fru-g-P, 2) by increasing affinity for Fru-6-P by 1-2 orders of magnitude, and 3) by competing with the inhibitory metabolites ATP and citrate
Summary
RELIEF OF COOPERATIVITY AND COMPETITIONBETWEENFRUCTOSE 2,6-BISPHOSPHATE, ATP, AND CITRATE*. Fru-2,6-Pz acts kinase purified from fetal and adult rat hearts were compared For both enzymes at physiological pH and ATP concentrations, 1 M M fructose 2,6-bisphosphate induced a greater than 10-fold reduction in So.Bfor fructose 6-phosphate and ciotmpletely eliminated subunit cooperativity. The fetalenzyme has upto a 15-fold lower affinity for from adult and fetal rat hearts and examined the effects of fructose 2,6-bisphosphate, rendering itmore sensitive Fru-2,6-Pzon enzyme affinity for fructose 6-phosphate (Fruto changes in fructose 2,6-bisphosphate concentration 6-P) on subunit cooperativity and on inhibition by physiologthan adult hearpt hosphofructokinase. Together, these ical ATP and citrate concentrations.
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