Inositol 1,4-bisphosphate is an allosteric activator of muscle-type 6-phosphofructo-1-kinase.
The allosteric effects of various inositol biphosphate (InsP2) isomers and other inositol phosphates, of glycerophosphoinositol phosphates (GroPInsPx) and of phosphoinositides (PtdInsPx) on muscle-type 6-phosphofructo-1-kinase (PFK) were investigated. The binding of these substances to PFK was indirectly estimated by their ability to stabilize the tetrameric enzyme. At near-physiological concentrations of other allosteric effectors, muscle PFK was activated AMP-dependently by Ins(1,4)P2 (Ka = 43 microM), Ins(2,4)P2 (Ka = 70 microM) and GroPIns4P (Ka = 20 microM). These compounds activated PFK by a mechanism similar to that established for activating hexose bisphosphates. Indirect binding experiments indicated minimal Kd,app. values of about 5 microM for the binding of Ins(1,4)P2 in the presence of 0.1 mM-AMP at pH 7.4. This apparent affinity was comparable with that of fructose 1,6-bisphosphate and glucose 1,6-bisphosphate at identical conditions. The enzyme was also found to interact specifically with PtdIns4P (Kd,app. = 37 microM), the inositol phospholipid carrying Ins(1,4)P2 as its head group. The regulatory behaviour of muscle-type PFK in vitro and the concentrations of Ins(1,4)P2 in vivo (between 4 and greater than 50 nmol/g wet wt. of tissue) are consistent with the hypothesis that there is a functional interaction in vivo. Furthermore, a role of PtdIns4P in membrane compartmentation of PFK is suggested. Comparative experiments with liver PFK indicate that these regulatory properties may be relatively specific for the muscle isoform. Unlike muscle PFK, the liver isoform was slightly activated by sub-micromolar concentrations of Ins(1,4,5)P3.
Mayr
G W
GW
Abteilung für Biochemie Supramolekularer Systeme, Medizinische Fakultät, Ruhr-Universität Bochum, Federal Republic of Germany.
D000249:Adenosine Monophosphate / Q000378:metabolism; D000494:Allosteric Regulation; D000818:Animals; D004789:Enzyme Activation; D007295:Inositol Phosphates / Q000378:metabolism*; D009132:Muscles / Q000201:enzymology*; D010716:Phosphatidylinositols / Q000378:metabolism; D010732:Phosphofructokinase-1 / Q000378:metabolism*; D011817:Rabbits; D013403:Sugar Phosphates / Q000378:metabolism*
D007295:Inositol Phosphates; D010716:Phosphatidylinositols; D013403:Sugar Phosphates; D000249:Adenosine Monophosphate; C044259:inositol 1,4-bis(phosphate); D010732:Phosphofructokinase-1