1. Lecture 10 Glucose Disposal: Liver and Molecular Mechanisms

2. Hexose Metabolism P glucose Using ATP hexokinase glucose 6-phosphate P glucose 1-phosphate P PP fructose 6-phosphate fructose 1,6-bisphosphate PP U PFK UDP glucose Using UTP Releases PP PP hydrolysis pulls reaction to completion Pyrophosphate hydrolyses to two phosphates Pulls UDP-glucose conversion over “Activated Glucose”

3. Splitting F16BP PP fructose 1,6-bisphosphate CH 2 OP CHOH CHO CH 2 OP C=O CH 2 OH Glyceraldehyde 3- phosphate Dihydroxyactone phosphate aldolase Triose phosphate Isomerase Rest of Glycolysis to pyruvate Involves oxidation of G3P and generation of ATP

4. Glycogen Synthesis PP U UDP glucose PP U UDP Glycogen Glycogen with one more glucose Note synthesis is C1  C4 C1 end of glycogen attached to glycogenin UDP needs to be made back into UTP Use ATP for this UDP + ATP  UTP + ADP

5. Liver Glucose Uptake GLUT-2 used to take up glucose from bloodstream –Very high activity and very abundant –[Glucose] blood = [Glucose] liver Glucokinase –Rapidly converts G  G6P –Not inhibited by build up of G6P –High Km (10 mM) for glucose – not saturated by high levels of liver glucose –So [G6P] rapidly increases as blood [glucose] rises G6P can stimulate inactive GS –Even phosphorylated GS –Glucose itself also stimulates the dephosphorylation of GS Via a slightly complex process that involves other kinases and phosphatases which we needn’t go into right now

6. Glycogenesis In liver –The “push” mechanism Glycogenesis responds to blood glucose without the need of insulin Although insulin WILL stimulate glycogenesis further In muscle –[G6P] never gets high enough to stimulate GS “Push” method doesn’t happen in muscle More of a “pull’ as insulin stimulates GS In both cases –2 ATPs required for the incorporation of a glucose into glycogen chain G  G6P and UDP  UTP –Branching enzyme needed to introduce a1  6 branch points –Transfers a segment from one chain to another –Limit to the size of glycogen molecule Branches become too crowded, even if they become progressively shorter Glycogen synthase may need to interact with glycogenin to be fully active

7. A Tale of Two Kinases Glucokinase (GK) –Only works on glucose –High Km for glucose (~10mM) –Not inhibited by G6P –Only presents in liver, beta-cells –Responsive to changes in [glucose] blood Hexokinase (HK) –Works on any 6C sugar –Km for glucose ~0.1mM –Strongly inhibited by its product G6P –Present in all other tissues –If G6P is not used immediately, its build up and inhibits hexokinase –Easily saturated with glucose

8. Fructose Metabolism fructose Using ATP hexokinase P fructose 6-phosphate fructose 1-phosphate PFK P ‘normal glycolysis’ fructokinase CH 2 OH CHOH CHO CH 2 OP C=O CH 2 OH Glyceraldehyde Dihydroxyactone phosphate CH 2 OP CHOH CHO Aldolase B Triose Kinase ‘normal glycolysis’ Glyceraldehyde 3- phosphate

9. Fructose Metabolism Fructose entry into cells does not require insulin In muscle, fructose just enters glycolysis –Or could be made into glycogen if insulin stimulus available! F6P  G6P  G1P  UDP-glucose  Glycogen In liver, fructokinase traps fructose –FK produces F1P –FK is quite fast in comparison to the aldolase B that uses the F1P –F1P can build up –But more seriously producing ‘dead’ F1P traps phoshpate FK reaction consumes ATP Lack of phosphate akes new ATP synthesis difficult ATP levels in liver fall –Even more serious in people with a deficiency in Aldolase B