Abstract
Isolated rat hepatocytes convert 2,5-anhydromannitol to 2,5-anhydromannitol-1-P and 2,5-anhydromannitol-1,6-P2. Cellular concentrations of the monophosphate and bisphosphate are proportional to the concentration of 2,5-anhydromannitol and are decreased by gluconeogenic substrates but not by glucose. Rat liver phosphofructokinase-1 phosphorylates 2,5-anhydromannitol-1-P; the rate is less than that for fructose-6-P but is stimulated by fructose-2,6-P2. At 1 mM fructose-6-P, bisphosphate compounds activate rat liver phosphofructokinase-1 in the following order of effectiveness: fructose-2,6-P2 much greater than 2,5-anhydromannitol-1,6-P2 greater than fructose-1,6-P2 greater than 2,5-anhydroglucitol-1,6-P2. High concentrations of fructose-1,6-P2 or 2,5-anhydromannitol-1,6-P2 inhibit phosphofructokinase-1. Rat liver fructose 1,6-bisphosphatase is inhibited competitively by 2,5-anhydromannitol-1,6-P2 and noncompetitively by 2,5-anhydroglucitol-1,6-P2. The AMP inhibition of fructose 1,6-bisphosphatase is potentiated by 2,5-anhydroglucitol-1,6-P2 but not by 2,5-anhydromannitol-1,6-P2. Rat liver pyruvate kinase is stimulated by micromolar concentrations of 2,5-anhydromannitol-1,6-P2; the maximal activation is the same as for fructose-1,6-P2. 2,5-Anhydroglucitol-1,6-P2 is a weak activator. 2,5-Anhydromannitol-1-P stimulates pyruvate kinase more effectively than fructose-1-P. Effects of glucagon on pyruvate kinase are not altered by prior treatment of hepatocytes with 2,5-anhydromannitol. Pyruvate kinase from glucagon-treated hepatocytes has the same activity as the control pyruvate kinase at saturating concentrations of 2,5-anhydromannitol-1,6-P2 but has a decreased affinity for 2,5-anhydromannitol-1,6-P2 and is not stimulated by 2,5-anhydromannitol-1-P. The inhibition of gluconeogenesis and enhancement of glycolysis from gluconeogenic precursors in hepatocytes treated with 2,5-anhydromannitol can be explained by an inhibition of fructose 1,6-bisphosphatase, an activation of pyruvate kinase, and an abolition of the influence of phosphorylation on pyruvate kinase.
Highlights
Isolated rat hepatocytes convert Z75-anhydrornan- Fructose-6-P and fructose-1,6-Pz existin solution as an nitol to 2,5-anhydromannitol-1-P and 2,5-anhydroequilibrium mixture of the a- and @-furanoseanomers with mannitol- 1,6-Pz.Cellular concentrationsof the mono- small amounts of the acyclic keto and gem-diol isomers [1]
Phosphate and bisphosphate are proportional to the Several laboratories have examined the anomeric specificities concentration of 2,5-anhydromannitoland are de- of the glycolytic and gluconeogenic enzymes that either utilize creased by gluconeogenic substrates but not by glucose. fructose phosphates as substrates or are allosterically regu
At 1 mM fructose-6-P, bisphosphatecompounds activate rat liver phosphofructokinase-1 in the following order of effectiveness:fructose-2,6-Pz >> 2,5-anhydromannithe regulation of carbohydrate metabolism via anomeric specificity have been proposed on the basis of results for rabbit muscle phosphofructokinase, rabbit liver fructose 1,6-bisphosphatase, and yeast pyruvate kinase [2, 4]. 2,5-Anhydrotol-l,6-P2 > fructose-1,6-Pz > 2,5-anhydroglucitol- D-mannitOl is an analog of the @-furanoseform of D-fructose l,6-P2.High concentrationsof fructose-1,6-Pz or 2,5- that lacks the C-2 hydroxyl and is locked in the furan anhydromannitol-l,6-Pa inhibitphosphofructokinase- ring structure
Summary
Isolated rat hepatocytes convert Z75-anhydrornan- Fructose-6-P and fructose-1,6-Pz existin solution as an nitol to 2,5-anhydromannitol-1-P and 2,5-anhydroequilibrium mixture of the a- and @-furanoseanomers with mannitol- 1,6-Pz.Cellular concentrationsof the mono- small amounts of the acyclic keto and gem-diol isomers [1]. To define more clearly the mechanism of 2,5-AM-o1 inhibition of gluconeogenesis, the accumulation of 2,5-AM01-1-P and 2,5-AM-ol-1,6-P2during 2,5-AM-ol metabolism was measured in hepatocytes, and theeffects of the 2,5-AM01 phosphates on rat liver phosphofructokinase-1, fructose 1,6-bisphosphatase, and pyruvate kinase were examined in uitro.
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
