Liver fructose

D. Erion, S- J- Pilkis, M. R. El-Maghrabi, and W. N. Lipscomb, The allosteric site of human liver fructose 1,6-bisphosphatase. Analysis of six AMP site mutants based on the crystal structure, J. Biol. Chem. 269 27732 (1994). 

Naerum, L. Norskov-Lauridsen, P. B. Rasmussen, L. Thim, F. C. Wiberg, and K. Lundgren, Characterization of the allosteric binding pocket of human liver fructose 1,6-bisphosphatase by protein crystallography and inhibitor activity studies, Protein Sci. 6 971 (1997). 

Figure 11.2 Pathway for conversion of fructose to acetyl-CoA. The enzyme fructokinase phosphorylates fructose to form fructose 1-phosphate. (The enzyme is present only in the liver.) Fructose 1-phosphate is cleaved by aldolase to form glyceraldehyde and dihydroxyacetone phosphate. Glyceraldehyde is phos-phorylated to form glyceraldehyde 3-phosphate, catalysed by the enzyme triokinase. Dihydroxyacetone phosphate is converted to glyceraldehyde 3-phosphate, catalysed by the isomerase. Glyceraldehyde 3-phosphate is converted to pyruvate by the glycolytic reactions (Chapter 6).

Sugar The hydrolysis of sucrose in the intestine produces both glucose and fructose, which are transported across the epithelial cells by specific carrier proteins. The fructose is taken up solely by the liver. Fructose is metabolised in the liver to the triose phosphates, dihydroxy-acetone and glycer-aldehyde phosphates. These can be converted either to glucose or to acetyl-CoA for lipid synthesis. In addition, they can be converted to glycerol 3-phosphate which is required for, and stimulates, esterification of fatty acids. The resulting triacylglycerol is incorporated into the VLDL which is then secreted. In this way, fructose increases the blood level of VLDL (Chapter 11). 

Outside of the liver, fructose is channeled into the sugar metabolism by reduction at C-2 to yield sorbitol and subsequent dehydration at C-1 to yield glucose (the polyol pathway not shown). 

Table 4.6.8 Normal liver fructose-1,6-bisphosphatase activities [36]... 

Fructose-2,6-bisphosphate is a potent activator of the liver phosphofructokinase (PFK-1) and a potent inhibitor of liver fructose-1,6-bisphosphate phosphatase (FBPase-1). Fructose-2,6-bisphosphate is the product of a second phosphofructokinase (PFK-2) and is hydrolyzed to fructose-6-phosphate by FBPase-2. The activities of PKF-2 and FBPase-2 reside on a single, bifunctional protein in liver. The bifunctional protein is under glucagon control imposed via cAMP. 

In liver, the cells contain mainly glucokinase instead of hexokinase and this enzyme phosphorylates only glucose. Thus in liver, fructose is metabolized instead by the fructose 1-phosphate pathway (Fig. 2). 

Winder, W. W., Yang, H. T., and Arogyasami,). (19fWt). Liver fructose 2,6-bisphosphate in rats running different treadmill speeds. Am. ]. Physiol. 255, R3S-R41. 

Melloni et al. (22, 23) obtained three distinct enzymes from rabbit liver lysosomes that catalyze limited proteolysis of rabbit liver fructose-1,6-bisphosphatase, converting the neutral form to a form with an alkaline pH optimum. One of these proteinases (Mr = 70,000) is associated with the lysosomal membrane fraction. Since cathepsin B, H, and L are all present in the soluble fraction of lysosomes 61), this enzyme seems to be a new thiol proteinase of lysosomes. The enzyme is activated by cysteine, but not inhibited by leupeptin. Since it has only... 

Certain allosteric effectors have reciprocal effects on enzymes that catalyse directly opposite reactions. For example, AMP activates phosphofructokinase and hence promotes glycolysis and the formation of ATP, while at the same time it inhibits liver fructose 1,6-bisphosphatase, thereby suppressing gluconeogenesis and this form of ATP expenditure. This is one means by which futile cycling may be prevented. 

In contrast to hereditary fructose intolerance where lack of fructose-1-phosphate aldolase (Levin et al. 1963) in serum and liver is a prominent feature, liver fructose-1-phosphate aldolase activity in TSD is only reduced to approximately 60%, and fructose tolerance is not impaired in the latter disorder (Schneck et al. 1965), while in the former accumulation of fructose-1-phosphate and hypoglycemia... 

Mechanism and Regulation of Bovine Liver Fructose-1,6-bisphosphatase Nancy J. Ganson and Herbert J. Fromm... 

---