Carbohydrate metabolism

CHO supply Diet Endogenous reserves –Liver –Muscle –Blood Limited Anaerobic glycolysis –Anaerobic Does not need oxygen Occurs in the cytoplasm Glucose degradated to: –2 pyruvate –Then pyruvate converted to lactate

Anaerobic glycolysis

Anaerobic Glycolysis Pathway is the same regardless of end-product –Lactate is the end product of anaerobic glycolysis –Pyruvate is the end-product of aerobic glycolysis Pyruvate then converted to –Acetyl-CoA –Enters Kreb’s cycle

Anaerobic glycolysis Step 1 –Glucose uptake from blood Rate limiting step #1 GLUT 4 –Transporter than facilitates passage of glucose into the cell Glucose then phosphorylated Energy added –Hexokinase –Irreversible –If Glycogen is the start point Broken down to glucose-1-P –Phosphorylase –Activated by epinephrine, Calcium –Requires ATP

Step 2 Conversion of G-6-P to F-6-P Phosphoglucose isomerase Step 3 (energy added) Phosphorylation F-6-P to F 1,6- biphosphate Phosphofructokinase Rate limiting step #2 Anaerobic glycolysis

Step 4 –Splitting of one molecule into 2 Aldolase G-3-P and DAP –Interconvertable –G-3-P is what proceeds Step 5 –G-3-P to 1,3 BPG –Pi comes from within the cell –First payoff step NADH + H + Step 6 –ATP formation 1 –Phosphoglycerate kinase 3-phosphoglycerate formed

Anaerobic glycolysis Step 7 –Phosphoglycerate mutase 3PG to 2-phosphoglycerate Step 8 –Enolase 2PG to Phosphoenolpyruvate (PEP) Step 9 –Second energy formation step (ATP) –PEP to pyruvate –Pyruvate kinase

Anaerobic glycolysis Step 10 –Conversion of Pyruvate to Lactate –Oxidation of NAD + Recycles NAD + for Step 5 NAD + is a co-factor in the G- 3P dehydrogenase Rx This allows glycolysis to continue at a fast rate Net ATP from one cycle of anaerobic glycolysis –2ATP needed (Steps 1 and 3) –4 ATP produced 2 each at steps 6 and 9 –2 Net ATP Thus, anaerobic glycolysis –Inefficient –Fast

Aerobic Glycolysis Glucose to pyruvate –NET 2 ATP 2 NADH + H + –These are shuttled into the mitochondria by the GP shuttle system »2 ATP Pyruvate converted to acetyl-CoA –Pyruvate dehydrogenase complex –Enters Kreb’s cycle –15 ATP –Total 2 ATP directly 4 ATP from NADH 30 ATP from pyruvate

Regulation of glycolysis Regulated at various points in the cycle –Glycogen breakdown Glycogen phosphorylase –Glucose entry into the cell Hexokinase –Phosphofructokinase 3 rd Step, requires ATP –Pyruvate dehydrogenase Rx Conversion of pyruvate to Acetyl-CoA Acetyl-CoA

Glycogen phosphorylase Regulation is complex Two forms –Phosphorylase a (active) –Phosphorylase b (inactive) Activation (Step 1) –Epinephrine –Ca ++ This allows rapid breakdown of glycogen only during activity Step 2 –Activates adenylate cyclase Converts ATP to cAMP –Intercellular messenger –Activates protein kinase

Glycogen phosphorylase Step 3 –Activation of phosphorylase kinase ATP required Step 4 –Activation of Phosphorylase a ATP required Deactivation –Generally, a reverse of above Ca ++ levels fall Epinephrine levels fall cAMP levels fall

Hexokinase Reaction wherein glucose is taken up from the blood and phosphorylated –Requires GLUT-4 transporter Facilitates diffusion of glucose into cell Activated by insulin AND exercise –ATP Activated by –Contractions –Pi Inhibited by –G-6-P GLUT-4

Phosphofructokinase First energy requiring step of glycolysis –ATP –“rate-limiting” enzyme –Inhibited by High ATP and PCr levels Citrate (1 st product of Kreb’s cycle) –Activated by Elevated ADP, AMP, Pi, ammonia

Possible connection between fat and CHO metabolism When fatty acid metabolism is accelerated –Long-term exercise Acetyl-Coa builds up –Fatty acids are essentially broken down to acetyl-CoA This causes an increase in Citrate, which inhibits glycolysis –Important, as it conserves glucose at a time when it is starting to run out

Gluconeogenesis Prolonged exercise >2hrs –Deplete muscle and liver glycogen In the absence of dietary CHO –Liver can use non-CHO sources to help maintain blood glucose levels –Gluconeogenesis Lactate Glycerol Some amino acids

Gluconeogenesis Takes place mostly in the liver –Kidney (much less) –Skeletal muscle? Glycogen but not glucose Gluconeogenesis –Essentially “reverse” glycolysis –Couple of slightly different steps

Gluconeogenesis Conversion of pyruvate to PEP (phosphoenolpyruvate) –Pyruvate kinase Rx is irreversible –Pyruvate carboxylase and PEP carboxykinase Pyruvate carboxylase –Pyruvate to Oxaloacetate »ATP PEP carboxykinase –Oxaloacetate to PEP »GTP –PFK step is also irreversible Fructose 1,6 biphosphatase –Hexokinase step is irreversible Glucose-6-phosphatase

Gluconeogenesis Skeletal muscle –No glucose-6- phosphatase Can convert G6P to G1P –Phosphoglucomutase G1P converted to UDP- glucose –Glucose 1-phosphate uridyltransferase Glucose residue is attached glycogen primer –Formed as a part of this Rx –UDP is recycled