Regulation of Glycolysis and Gluconeogenesis Flashcards Preview

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Flashcards in Regulation of Glycolysis and Gluconeogenesis Deck (18)
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1

describe the irreversible steps of glycolysis and gluconeogenesis

2

describe how glycolysis in skeletal muscle is coupled to glycogen degradation

  • glycolysis starting with glucose from the blood needs hexokinase and ATP to form G6P
  • glycolysis can follow glycogen degradation and use the generated glucose 1-P to form G6P without usage of ATP
  • starting with G6P saves 1 ATP in the glycolysis investment phase and the overall gain of 3 ATP for anaerobic glycolysis is achieved

3

describe the regulation of glycolysis in skeletal muscle

  • the first regulated enzyme is hexokinase which is activated by glucose provided by GLUT-4 (insulin) and which is inhibited by its accumulating product G6P
  • the committed step of glycolysis is performed by PFK-1 which is inhibited by ATP
    • the inhibition of PFK-1 is overcome by AMP and F2,6-BP formed by PFK-2 activity of the bifunctional enzyme
  • pyruvate kinase is always highly active and does not need feed-forward activation by the committed step of glycolysis

4

contrast hexokinase and glucokinase

  • hexokinase has a high affinity for glucose
    • very efficient for small amounts of glucose that is saturated with glucose during hypoglycemia
  • glucokinase has a low affinity for glucose 
    • large Vmax which makes it very efficient to phosphorylate large amounts of glucose

5

how is insulin release regulated?

  • B-cells take up glucose (GLUT-2) and glucokinase forms G6P which is used in oxidative metabolism for ATP formation
    • glucokinase is not product inhibited 
  • Blood glucose levels >5 mM generate a high level of ATP which leads to the closing of ATP-sensitive K channels, which leads to membrane depolarization, calcium influx and triggers insulin release

6

describe glucokinase deficiency in B-cells of pancreas

  • Genetic deficiency of glucokinase can lead to maturity onset diabetes of the young type 2 (MODY-2) which is characterized by impaired insulin secretion from B-cells
  • results in chronic mild hyperglycemia
  • in MODY-2 patients, a higher blood glucose level (7-8 mM) is needed for insulin release

7

how is hepatic glucokinase regulated?

  • the hepatic glucokinase regulatory protein (GKRP) transports glucokinase into the nucleus at high levels of F6P and back into the cytosol at high free glucose levels 
  • glucokinase is induced by insulin and is not inhibited by its product G6P

8

how is PFK-1 regulated

  • PFK-1 catalyzes the committed step of glycolysis and is allosterically inhibited at normal physiological ATP levels in all cells
    • in many cells, ATP is end goal of glycolysis so if ATP levels achieved, it inhibits glycolysis
  • glycolysis provides 1,3-BPG and PEP for SLP and is essential for ATP formation during anoxia or for cells without mt

9

how is it possible to perform glycolysis in hepatocytes at normal ATP levels

  • the liver has to perform glycolysis after a meal in order to reduce high blood glucose level
  • insulin stimulates glycolysis as it leads to the dephosphorylation of the hepatic bifunctional enzyme
  • PFK-2 is active and forms F2,6-BP that overcomes the inhibition of PFK-1 by ATP

10

the allosteric inhibition of PFK-1 by ATP is overcome by 1) _____ and 2) ______

  1. AMP
    • formed in skeletal muscle during exercise 
      • glycolysis + glycogenolysis are activated
    • is formed in hepatocytes when ATP declines
      • glycolysis is activated and gluconeogenesis inhibited
  2. Fructose 2,6-BP (only the liver)
    • formed by the bifunctional enzyme in skeletal muscle, heart and liver

11

describe the feed-forward activation of pyruvate kinase during glycolysis

  • PFK-1 forms F1,6 BP which is a feed-forward activator for pyruvate kinase 
  • F1,6-BP continues in glycolysis but some molecules will allosterically bind to pyruvate kinase
  • pyruvate kinase is normally allosterically inhibited by ATP but F1,6-BP overcomes this inhibition

12

describe hepatic pyruvate kinase inactivation during gluconeogenesis

  • hepatic pyruvate kinase is inhibited by phosphorylation during gluconeogenesis
    • glucagon -> cAMP -> PKA -> phosphorylates pyruvate kinase leading to inhibition (you want gluconeogenesis, therefore turn off glycolysis enzymes)
  • the inhibition now saves PEP for gluconeogenesis

13

how is gluconeogenesis regulated?

  • gluconeogenesis is regulated by the availability of energy for the pathway which is mostly provided by degradation of fatty acids
    • B-oxidation provides NADH and acetyl CoA for regulations to inhibit PDH and TCA cycle and stimulate gluconeogenesis 
      • does not provide carbons for glucose formation

14

describe the substrates for gluconeogenesis

  • glycerol
  • lactate 
  • alanine
  • glutamine

15

describe insulin vs glucagon regulation of the bifunctional enzyme

16

name the enzymes that insulin induces the synthesis of

  • the irreversible steps:
    • glucokinase
    • PFK-1
    • pyruvate kinase

17

name the enzymes that glucagon induces the synthesis of

  • PEP carboxykinase 
  • Fructose 1,6 -bisphosphatase 
  • glucose 6 phosphatase

 

  • pyruvate carboxylase is needed for gluconeogenesis but is NOT INDUCED by glucagon

18

give a summary of allosteric effectors of glycolysis and gluconeogenesis