Coordinated regulation of glycolysis/gluconeogenesis

High blood glucose Synthesis of hexokinase II, PFK-1, pyruvate kinase Movement of GLUT4 to plasma membrane of myocyte Activation of insulin- sensitive protein kinase Activation of protein kinase B Insulin secretion

p.903

p.887

Glucose Pancreatic  cell GLUT2 Glucose Glycolysis pyruvate Citric acid cycle NADH,FADH 2 ATP Oxidative phosphorylation ATP-gated K + channel K+K Membrane depolarization closed Voltage-dep. Ca 2+ channel Ca 2+ Open Ca 2+ Insulin secretion p.903

Glc p.396 Insulin receptor Insulin GLUT4 Glc Cytosol of myocyte Movement of GLUT4 to plasma membrane of myocyte

Activation of insulin-sensitive kinase p. 588 Insulin receptor Insulin Insulin- sensitive kinase Insulin- sensitive kinase GMGM GMGM PP1 Glycogen synthase a Glycogen synthase b Phosphorylase kinase Phosphorylase kinase Glycogen phosphorylase Glycogen phosphorylase Glycogen synthesis  Glycogen degradation 

Activation of protein kinase B (PKB) Insulin receptor Insulin p.587 IRS-1 GSK-3 IRS-1 PIP 2 PIP 3 PI3-K PDK-1 PI3-K PDK-1 GSK-3 Glycogen synthase a Glycogen synthase a Glycogen synthase b Glycogen synthesis PKB

GSK3 inactivate glycogen synthase by phosphorylation PP GSK3 P P p.587 Phosphorylation by Casein kinase II

PKB GSK3 can be inactivated by phosphorylation P P p.587

Fru Glc Regulator protein High blood glucose affect hexokinase IV activity GLUT2 Hexokinase IV nucleus Regulator protein Fru Glc Regulator protein Hexokinase IV Regulator protein Fru Hexokinase IV Glc Hepatocyte p.578

Insulin receptor Insulin Insulin regulate PFK-1 activity Phosphoprotein phosphatase Phosphoprotein phosphatase PFK-2 FBPase-2 PFK-2 FBPase-2 Fru F2,6BP Fru F6P PFK-2 FBPase-2 PFK-1 Fru F1,6BP Fru F6P FBPase-1 Fru F2,6BP

Low blood glucose Inactivation of pyruvate kinase L (liver form) Activation of FBPase-2 and inactivation of PFK-2 Inactivation of glycogen synthase Activation of glycogen phosphorylase Glucagon secretion

p.436 Glucagon receptor glucagon    GDP  GTP Glucagon receptor Adenylyl cyclase Adenylyl cyclase ATP cAMP Protein kinase A Protein kinase A Regulation pathway initiated by glucagon secretion GMGM GMGM PFK-2 FBPase-2 PFK-2 FBPase-2 Pyruvate kinase L Pyruvate kinase L

Regulation of PFK-1 by glucagon Protein kinase A PFK-2 FBPase-2 PFK-2 FBPase-2 Protein kinase A Fru F2,6BP Fru F6P PFK-1 FBPase-1 Fru F2,6BP FBPase-1 Fru F6P Fru F1,6BP

Regulation of glycogen synthesis and breakdown by glucagon p. 588 PP1 Glycogen synthase a Glycogen synthase b Phosphorylase kinase Phosphorylase kinase Glycogen phosphorylase Glycogen phosphorylase Glycogen synthesis  Glycogen degradation  GMGM Protein kinase A GMGM Protein kinase A Inhibitor-1

Hexokinase There are four isozymes (I, II, III and IV) of hexokinase encoded by four different genes. Hexokinase I and II are allosterically inhibited by their product, glucose 6- phosphate. Hexokinase IV is not inhibited by G-6-P.

Hexokinase Hexokinase I and II are the predominant forms existing in muscle. Hexokinase IV is the predominant form in liver. Hexokinase I and II will be half-saturated at about 0.1mM, but hexokinase IV will not be half-saturated until 10mM.

Hexokinase Hexokinase has different functions in liver and muscle. Muscle consumes glucose, using it for energy production. Liver maintains blood glucose homeostasis by removing or producing glucose.

Muscle hexokinase Because blood glucose concentration is about 4 to 5 mM, hexokinase in the muscle (which will be half saturated at 0.1mM) is always working at or near its maximal rate.

Liver hexokinase However, liver hexokinase (half- saturated at 10mM) will not ever reach its maximal rate even after meal.

Phosphofructokinase-1 PFK-1 catalyze the committing step of glycolysis. This enzyme is regulated by ATP, AMP, ADP, citrate and fructose 2,6- bisphosphate.

ATP regulate the affinity of PFK-1 towards its substrate F-6-P Not only as a substrate, ATP is also one of the end product of the glycolytic pathway. ATP inhibit PFK-1 by binding to an allosteric site and lowering the affinity of the enzyme for F-6-P.

Molecules regulate PFK-1 and FBPase-1 activity ADP and AMP relieve the inhibition by ATP. Citrate increases the inhibitory effect of ATP. F-2,6-BP is the strongest activator of PFK-1. PFK-1 FBPase-1 ATP citrate ADP AMP F2.6BP PFK-1

Regulation of gluconeogenesis Pyruvate carboxylase FBPase-1

Pyruvate carboxylase Pyruvate carboxylase is being positively regulated by acetyl- CoA. The accumulation of acetyl- CoA signals that cell’s energy demands are met. Acetyl-CoA also indirectly inhibit pyruvate dehydrogenase complex.