Kinetics and mechanisms of activation and inhibition of porcine liver fructose-1,6-bisphosphatase by monovalent cations

Biochemistry
R ZhangH J Fromm

Abstract

K+ and Li+ were used to study the kinetic effects of monovalent cations on porcine liver fructose-1,6-bisphosphatase (FBPase). At saturating fructose 1,6-bisphosphate (FBP) concentrations, Li+ was found to be a linear noncompetitive inhibitor with respect to Mg2+. K+ was found to activate the wild-type enzyme at low concentrations (K(m) = 17 mM) and to inhibit the enzyme at high concentrations (K(IK+) = 68mM). A steady-state random ter mechanism was proposed, and a mathematical equation was derived to account for the Mg2+ and K+ kinetics and activation of FBPase. Interestingly, when Glu280 was mutated to glutamine by site-directed mutagenesis, K+ lost the ability to activate the enzyme and became a noncompetitive inhibitor with respect to Mg2+. These kinetic data suggest that K+ has two distinct sites. One is a high-affinity activation site and the other a low-affinity inhibition site. Glu280 is essential for allowing K+ to bind at the activation site. Due to the geometric constraints and its small atomic radius, Li+ can bind only at the inhibitory site. It is postulated that monovalent cations activate FBPase by helping the Arg276 residue "deshield" the partial negative charge on the 1-phosphoryl group of the substrate so that...Continue Reading

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