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

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• 3rd Step, requires ATP

– Pyruvate dehydrogenase Rx

• Conversion of pyruvate to Acetyl-CoA

1

3

2

4Acetyl-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 (1st 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