Fructose‐2,6‐bisphosphate and control of carbohydrate metabolism in eukaryotes

Abstract

Fructose-2,6-bisphosphate is an important intracellular biofactor in the control of carbohydrate metabolic fluxes in eukaryotes. It is generated from ATP and fructose-6-phosphate by 6-phosphofructo-2-kinase and degraded to fructose-6-phosphate and phosphate ion by fructose-2,6-bisphosphatase. In most organisms these enzymatic activities are contained in a single polypeptide. The reciprocal modulation of the kinase and bisphosphatase activities by post-translational modifications places the level of the biofactor under the control of extra-cellular signals. In general, these signals are generated in response to changing nutritional states, therefore, fructose-2,6-bisphosphate plays a role in the adaptation of organisms, and the tissues within them, to changes in environmental and metabolic states. Although the specific mechanism of fructose-2,6-bisphosphate action varies between species and between tissues, most involve the allosteric activation of 6-phosphofructo-1-kinase and inhibition of fructose-1,6-bisphosphatase. These highly conserved enzymes regulate the fructose-6-phosphate/fructose-1,6-bisphosphate cycle, and thereby, determine the carbon flux. It is by reciprocal modulation of these activities that fructose-2,6-bisphosphate plays a fundamental role in eukaryotic carbohydrate metabolism.

Ras transformation requires metabolic control by 6-phosphofructo-2-kinase

“…The steady-state concentration of F2,6BP depends on the activity of the homodimeric bifunctional enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK2/FBPase), which is encoded by four genes (PFKFB1-4) and is capable of phosphorylating F6P to F2,6BP and dephosphorylating F2,6BP to F6P (Okar and Lange, 1999). The enzymes derived from PFKFB1, PFKFB2 and PFKFB4 were originally found to be expressed by cells of the liver/muscle, kidney/heart and testes, respectively, and all display nearly equal kinase: phosphatase ratios (Okar and Lange, 1999).…”

“…The enzymes derived from PFKFB1, PFKFB2 and PFKFB4 were originally found to be expressed by cells of the liver/muscle, kidney/heart and testes, respectively, and all display nearly equal kinase: phosphatase ratios (Okar and Lange, 1999). The PFKFB3 gene encodes for the inducible PFK2/FBPase (Chesney et al, 1999;Atsumi et al, 2002;Mahlknecht et al, 2003), which is rapidly induced by inflammatory stimuli (Chesney et al, 1999) and hypoxia (Minchenko et al, 2002;Minchenko et al, 2004) and has also been termed placental PFK2 (Sakai et al, 1996;Sakakibara et al, 1999), ubiquitous PFK2 (Manzano et al, 1998;Kessler and Eschrich, 2001;Navarro-Sabate et al, 2001) and PGR1 (Hamilton et al, 1997)).…”

Central Cavity of Fructose-1,6-bisphosphatase and the Evolution of AMP/Fructose 2,6-bisphosphate Synergism in Eukaryotic Organisms

“…The coordinated regulation of FBPase and PFK-1 limits futile cycling in vivo. In mammals and presumably other eukaryotes, fructose 2,6-bisphosphate (Fru-2,6-P 2 ) and AMP inhibit FBPase while activating PFK-1 (3)(4)(5)(6)(7)(8)(9)(10). In vivo AMP concentrations are nearly constant due to the action of adenylate kinase (11), whereas the level of Fru-2,6-P 2 varies in response to changing nutritional states (10).…”

“…In mammals and presumably other eukaryotes, fructose 2,6-bisphosphate (Fru-2,6-P 2 ) and AMP inhibit FBPase while activating PFK-1 (3)(4)(5)(6)(7)(8)(9)(10). In vivo AMP concentrations are nearly constant due to the action of adenylate kinase (11), whereas the level of Fru-2,6-P 2 varies in response to changing nutritional states (10). AMP/ Fru-2,6-P 2 synergism in the inhibition of eukaryotic FBPases (5,6,12,13), however, lowers the apparent K i of AMP as concentrations of Fru-2,6-P 2 increase, making both AMP and Fru-2,6-P 2 dynamic physiological regulators.…”

“…Two AMP-bound intermediate states (I R -state and I T -state) have been identified, both of which have engaged loop 50 -72 and subunit pair rotations of 3 and 12°, respectively (23,24). The I R -and I T -states exist in AMP complexes because mutations Ala 54 3 Leu and Ile 10 3 Asp, respectively, destabilize the disengaged conformation of loop 50 -72.…”