2. Glucose Metabolism

What are the physiological roles of muscle and liver glycogen?

Glucose storage

• Liver: maintain blood glucose levels, usually 3-8 mM

• Muscle: easy access of glucose storage for energy

What is glycogenesis?

Formation of glycogen from glucose

• Formation of glycosidic bond requires energy

• Energy from breaking bond between glucose and UDP

• Glucose added to non reducing ends

What is glycogenolysis?

Break down of glycogen into glucose

• Glucose are removed from non-reducing ends

What is the significance of branching in glycogen metabolism?

It increases the efficiency of glycogenesis and glycogenolysis

What happens in McArdle’s disease?

Can’t perform glycogenolysis (can’t mobilize glucose from glycogen)

• High glycogen

• Absence of glucose in blood

What is the treatment for McArdle’s disease?

Drink glucose solutions as needed

How does McArdle’s disease inform about the role of glycogen in skeletal muscle?

Glycogen is a critical local energy reserve used directly by the muscle

What is the general reaction of glycolysis?

Glucose (6 Carbons) —> 2 Pyruvates (3 Carbon Each)

• Net 2 ATPs (Invest 2 ATP Produce 2 ATP)

• 2 NADH

What are the attributes of glycolysis with respect to oxygen requirement, ATP yield (high/low + fast/slow), and production of NADH ?

• Oxygen Requirement: doesn’t require oxygen

• ATP Yield: Fast, inefficient (Only 2 ATP yield)

• NADH: 2 NADH produced

Why is the phosphorylation of glucose important?

Phosphorylation (Glucose —> G6P) removes its charge and prevents it from passing through the GLUT transporter which keeps it in the cell

Why does the phosphorylation of glucose require ATP to serve as a phosphoryl group donor?

Adding a phosphate to glucose requires an input of energy (thermodynamically unfavorable) and the coupled hydrolysis of ATP releases energy and a phosphate group.

Why is Step 1 not exploited as a control point for entry into glycolysis (fates of G6P)?

G6P is not committed to glycolysis only trapped inside the cell, G6P can be converted into

• 2 Pyruvate - Glycolysis

• Glucose - Gluconeogenesis

• Glycogen - Glycogenesis

• Pentose - Pentose Phosphate Pathway

What is the importance of isomerization/ring opening in Step 2?

It allows the reposition of the carbonyl group (C1 —> C2) and prepares F6P for splitting molecule into 2 equal 3-Carbon fragments

Why is Step 3 of glycolysis the main point of glycolysis regulation?

It is the first committed step of glycolysis that is irreversible and only proceeds when energy is needed

How is Step 3 of glycolysis regulated?

• PFK1 will be regulated by downstream and off pathway metabolites that will bind and stimulate or inhibit the rate of the enzyme

• PFK2 is a regulatory enzyme that makes F6P —> F2,6P

• F2,6P activates PFK1 which promotes glycolysis and inhibits the rate of the enzyme that promotes gluconeogenesis

Why is the carbonyl group at C2 of F1,6B necessary for C-C bond cleavage in Step 4?

It stabilizes the electrons that move during C3-C4 bond cleavage and ensure symmetrical 3-carbon products are formed.

What are the coupled reaction in Step 6?

Phosphorylation:

• G3P + P_i —> 1,3 BPG + 2 H⁺

• ΔG°’ = + 4.8kJ/mol

Redox Rxn:

• NAD⁺ + 2 e^- + H⁺ —> NADH

• ΔG°’ = - 50kJ/mol

What is the thermodynamic driver for the formation of the acylphosphate in 1,3 BPG and for reduction of NAD⁺ to NADH?

The oxidation of G3P

What are the reduced cofactors that capture free energy in glycolysis?

NADH

What are the types of reactions in Steps 8 and 9?

Step 8 is an isomerization reaction and Step 9 is a dehydration reaction.

What is the coupled reaction in Step 10?

PEP —> enol pyruvate —> (tautomerization) —> pyruvate

How does tautomerization drive favorable thermodynamics in Step 10?

It turns pyruvate into a stable keto form which prevents the reverse reaction and creating a large -ΔG

Why does Step 10 of glycolysis drive Steps 4-9 forward?

Step 10 is so energetically favorable (large -ΔG) that it pulls step 4-9 forward and keeps substrates at low concentrations

Why are red blood cells so susceptible to defects in glucose metabolic pathways?

They heavily depend on glycolysis for energy.

What is the net yield of ATP if there is a hexokinase deficiency?

Net ATP = 0

• Unable to proceed past Step 1

What is the net yield of ATP if there is a pyruvate kinase deficiency?

Net ATP = 0

• Use 1 ATP in Steps 1 and 3

• Make 2 ATP in Step 7

What is the Warburg effect?

Cancer cells rely on aerobic glycolysis for ATP even with oxygen available

Why does the Warburg effect benefit many types of cancer cells?

It allows cancer cells to diverts glycolysis intermediates into biomolecules incell division for rapid cell division

What is the fate of pyruvate under aerobic conditions?

Pyruvate dehydrogenase —> 2 Acetyl-CoA —> Citric Acid Cycle

What is the fate of pyruvate under anaerobic conditions in human muscles?

Lactic Acid Fermentation —> 2 Lactate

What is the fate of pyruvate under anaerobic conditions in yeast?

Alcoholic Fermentation —> 2 ethanol + 2 CO₂

What is the fate of pyruvate under anabolic conditions (energy surplus)?

Gluconeogenesis —> Form Glucose

Why is lactate production essential for sustaining glycolysis when a muscle is performing at a high level of exertion?

It regenerates NAD⁺

How does gluconeogenesis contribute to human physiology in 2 ways?

Helps maintain blood glucose when stores are depleted

• After long periods of fasting - blood glucose and glycogen stores depleted

• Long period of exercise - muscles use glycogen and blood glucose rapidly

• Keto diet - Low glucose diet

Why is gluconeogenesis not simply reversal of all ten steps of glycolysis?

Steps 1,3 and 10 are metabolically irreversible

What is the purpose of carboxylation of pyruvate in workaround of Step 10 of glycolysis for gluconeogenesis?

To capture the energy of hydrolysis of ATP to create a high-energy intermediate to bypass the irreversible step and make it favorable

What is the ATP equivalents required for gluconeogenesis to the yield of ATP from glycolysis?

Gluconeogenesis: Require 2 Pyruvate + 6 ATP + 2 NADH —> Glucose

Glycolysis: Glucose —> 2 ATP and 2 NADH + 2 Pyruvate