Fructose-1,6-bisphosphatase regulation

Stieglitz, K.A., Seaton, B.A., Head, J.F., Stec, B., and Roberts, M.F., 2003, Unexpected similarity in regulation between an archaeal inositol monophosphatase/fructose bisphosphatase and chloroplast fructose bisphosphatase. Protein Sci. 12 760-767. 

Describe the allosteric regulation of phosphofructokinase. Explain the role of fructose 2,6-bisphosphate in its regulation. Describe the fused-domain structure of phosphofructokinase 2 (PFK2)/fructose bisphosphatase 2 that forms and degrades fructose 2,6-bisphosphate. 

Fig. 3.8. Regulation of 6-phosphofructokinase and fructose bisphosphatase. PF-2-kinase, 6-pho phofructo-2-kina e F-2,6-BPase, fructose 2,6-bisphosphatase F-2i6-BP, fructose 2,6-bisphosphate PK-l-kinase, 6-phosphofructo-l-kina e F-I,6-BPase, fructose 1,6-bisphosphatase.

Since is positive, cycling will increase the sensitivity of the flux to regulator X provided that s j>r ,), that is, if the sensitivity of the subsequent reaction of the system to the concentration of the product, P, is greater than the sensitivity of the reverse reaction of the cycle to the concentration of P. This situation can be met in several ways (9). For example, in the fructose 6-phosphate/fructose bisphosphate cycle, fructose bisphosphatase (equivalent to C above) has aK for fructose 1,6-bis-phosphate of about 1 pM (or at least two orders of magnitude lower than many other glycolytic enzymes for their glycolytic substrates) so that it is probably saturated with fructose bisphosphate in vivo (equivalent to P in... 

The hydrolysis of fructose-1,6-bisphosphate to fructose-6-phosphate (Eigure 23.7), like all phosphate ester hydrolyses, is a thermodynamically favorable (exergonic) reaction under standard-state conditions (AG° = —16.7 kj/mol). Under physiological conditions in the liver, the reaction is also exergonic (AG = —8.6 kJ/mol). Fructose-1,6-bisphosphatase is an allosterically regulated enzyme. Citrate stimulates bisphosphatase activity, hut fructose-2,6-bisphosphate is a potent allosteric inhibitor. / MP also inhibits the bisphosphatase the inhibition by / MP is enhanced by fructose-2,6-bisphosphate. 

Fructose 2,6-bisphosphate is not a metabolic intermediate but an allosteric regulator. It has two important roles it increases the activity of PFK-1 but decreases the activity of fructose 1,6-bisphosphatase (FBPase). Consequently an increase in the concentration of fructose 2,6-bisphosphate favours glycolysis but restricts gluconeogenesis. 

The reaction catalyzed by fructose 1,6-bisphosphatase is an important regulation point in gluconeogenesis (see p. 158). 

FIGURE 15-21 Regulation of fructose 1,6-bisphosphatase-1 (FBPase-1) and phosphofructokinase-1 (PFK-1). The important role of fructose 2,6-bisphosphate in the regulation of this substrate cycle is detailed in subsequent figures. 

The flow of triose phosphates into sucrose is regulated by the activity of fructose 1,6-bisphosphatase (FBPase-1) and the enzyme that effectively reverses its action, PPrdependent phosphofructokinase (PP-PFK-1 p. 527). These enzymes are therefore critical points for determining the fate of triose phosphates produced by photosynthesis. Both enzymes are regulated by fructose 2,6-bisphosphate (F2,6BP), which inhibits FBPase-1 and stimulates PP-PFK-1. In vascular plants, the concentration of F2,6BP varies inversely with the rate of photosynthesis (Fig. 20-26). Phosphofructokinase-2,... 

Regulation by fructose 2,6-bisphosphate Fructose 2,6-bisphos-phate is the most potent activator of PFK-1 (see Figure 8.16). This compound also acts as an inhibitor of fructose 1,6-bisphosphatase... 

Figure 11-2 Roles of phosphofructose kinase and fructose 1,6-bisphosphatase in the control of the breakdown and storage (—+) of glycogen in muscle. The uptake of glucose from blood and its release from tissues is also illustrated. The allosteric effector fructose 2,6-bisphosphate (Fru-2,6-P2) regulates both phosphofructokinase and fructose 2,6-bisphosphatase. These enzymes are also regulated by AMP if it accumulates. The activity of phosphofructokinase-2 (which synthesizes Fru-2,6-P2) is controlled by a cyclic AMP-dependent kinase and by dephosphorylation by a phosphatase.

Jacquot, J.P., Lopez-Jaramillo, J., Miginiac-Maslow, M., Lemaire, S., Cherfils, J., Chueca, A., and Lopez, J., 1997, Cysteine-153 is required for redox regulation of pea chloroplast fructose-1,6-bisphosphatase. FEBS Lett. 401 143-147. 

Shin DJ and McGrane MM (1997) Vitamin A regulates genes involved in hepatic gluconeogenesis in mice phosphoenolpyruvate carboxykinase, fructose-l,6-bis-phosphatase and 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase./owmaZ of Nutrition 127, 1274-8. 

---