BIOC 311
Glycolysis:
Metabolic reactions occur at equilibrium, the whole system is not:
- Irreversible steps
- Basal metabolic rate (always losing energy)
ΔG° => Nature of a reaction (endergonic vs exergonic)
ΔG° > 0, (+) => endergonic (requires energy)
ΔG° < 0, (-) => exergonic (releases energy)
ΔG => reversibility in vivo
ΔG = 0: reaction is at equilibrium => reversible
ΔG < 0, (-): releases energy => irreversible
Glucose Uptake:
- Transport
o Symport uses sodium diffusion to also drive glucose from blood inside (passive
transport – 2ndary active transport)
- Uptake:
o Pancreatic beta-cells
o When [glucose]_blood > 5.5mM => Glucose is released into the blood
o Glut2 glucose channel always present
▪ When [glucose]_blood > 5.5mM glucose diffuses in via glut-2 -> ATP
production -> Potassium channel expelling channel out is inhibited ->
depolarization -> Calcium enters -> insulin (hormone) is released (synapse
style) into the bloodstream
o Insulin – Stimulates glucose uptake in cells
▪ Triggers liver to produce glycogen
▪ Glut4 glucose receptor recruited to cell surface when insulin present
Energy Expenditure:
1. ATP stored in muscles
2. P-Creatine
3. Anaerobic glycolysis
4. Aerobic glycolysis
5. Aerobic lipolysis
Glycolysis:
- Not require O2
- 1 Glucose generates: 2 ATPs, 2 NADH, 2 pyruvates
- Requires a fresh supply of NAD+
o In presence of O2 done via ox-phos
o In absence of O2
▪ Muscle: pyruvate -> lactate
Glucagon: hormone stimulating glycogen breakdown
Glycogen: glucose polysaccharide
,BIOC 311
▪ Yeats & bacteria: pyruvate -> ethanol (fermentation)
- Pathway
1. Glucose -------- Hexokinase or Glucokinase ---------> G-6-P
(glucose phosphorylated once inside cell)
a. Hexokinase:
i. Processes any 6C sugar into G6P (including fructose)
ii. Present in all cells
iii. High affinity
iv. Modulator: G6P
b. Glucokinase (back up enzyme if too much glucose for hexokinase capacity)
i. Processes only glucose
ii. Present only in liver and pancreas
iii. Low affinity
iv. Modulator: Glucokinase regulator protein (GKRP)
• Binding partner to glucokinase that keeps GK in the nucleus when
[glucose]_blood is low
• When glucose levels increase GKRP releases glucokinase to the
cytoplasm where it can produce G6P
v. Stores extra glucose as glycogen
2. G-6-P <-------- phosphoglucose isomerase ---------> F-6-P
a. Directionality depends on abundance
3. F-6-P -------- Phosphofructokinase (PFK1) ---------> FBP (fructose-1,6-bisphosphate)
a. Committing step to glycolysis
b. Activators: AMP; F2,6P
c. Inhibitors: ATP; citrate
d. AMP activation is more potent than ATP inhibition
e. Allosteric regulation
i. Adenylate kinase (ADK) (converts 2 ADP → 1 ATP + AMP)
• During exercise ~ 10% ATP is converted to ADP
• Adenylate kinase converts ADP to back to ATP with AMP
• Keeps ATP abundant for exercise
• Generates AMP to activate (PFK1)
f. Substrate Cycles
• At rest: Equilibrium
• Exercise: F2,6P activates PFK AND inhibits
FBPase
• F2,6P is not an intermediate in glycolysis
1PFK2 converts FBP to F2,6P
FBPase2 converts F2,6P to FBP
g. Covalent modification
Glucagon: hormone stimulating glycogen breakdown
Glycogen: glucose polysaccharide
,BIOC 311
4. Reversible steps
a. FBP <---------Aldolase--------> GAP + DHAP
i. GAP & DHAP are interchanged
ii. GAP is the one that proceeds with glycolysis (2 GAPs/glucose)
b. Last product of reversible is PEP (phosphoenolpyruvate)
5. PEP (High energy intermediate) -------- Pyruvate kinase --------> Pyruvate
a. Activator: F1,6B
b. Inhibitors: ATP, glucagon, cAMP, PKA (through F2,6P)
- 3 committed/irreversible steps to glycolysis
o Hexokinase
o PFK1
o Pyruvate kinase
- ATP & Energy
o Used: 2 ATP
o Made: 4 ATP, 2 NADH (2.5 ATP/NADH)
▪ Net product:
• Aerobic glycolysis (use NADH): 7 ATP
• Anaerobic glycolysis (no NADH used): 2 ATP
- Differential Hormonal regulation of PFK2
o LIVER ISOZYME
▪ Need to supply blood with fresh glucose
▪ When Fasting/prolonged exercise (glucose deprived) => F2,6P decreases
• Glucagon & cAMP increase => PKA is activated
o PKA shuts down kinase activity of PFK2
o Phosphatase activity takes over
o Reaction reverted to regenerate F6P
o HEART ISOZYME
▪ Gluconeogenesis doesn’t happen in the heart
▪ When stress => F2,6P increases
• Epinephrine and cAMP increase => PKA activated
o PKA phosphorylates PFK2 activating its kinase activity
o PKA shuts down phosphatase activity
Glucagon: hormone stimulating glycogen breakdown
Glycogen: glucose polysaccharide
, BIOC 311
- Investment phase: HK, PFK1
- Payoff phase: GAP ------> Pyruvate (2 ATP/GAP converted ∴ 4 ATP/Glucose since 2
GAPs/glucose)
Carbohydrates:
Glucose, Galactose, Fructose => 6C sugars
Generate 32 ATP via aerobic catabolism
Sucrose (Glucose-Fructose), Lactose (Glucose-Galactose), Maltose (Glucose-Glucose) => 12C
Generate 64 ATP via aerobic catabolism
Fructose
- Muscle (minor)
o Fructose ----- Hexokinase -----> F6P (glycolysis intermediate)
o F6P ----- PFK -----> Fructose-1,6-phosphate
o Fructose-1,6-phosphate ----- Fructose-1,6-phosphate aldolase -----> GAP+ DHAP
o GAP ➔ ➔ ➔ Glycolysis
- Liver (major)
o Fructose ----- Fructokinase (not regulated) -----> Fructose-1-Phosphate
Fructose-1-phosphate interconverts to its open chain form (equilibrium)
o Fructose-1-Phosphate ----- Fructose-1-phosphate aldolase -----> Glyceraldehyde + DHAP
▪ Option 1
• Glyceraldehyde => GAP ➔ Glycolysis
• DHAP => GAP ➔ Glycolysis
▪ Option 2
• Glyceraldehyde => Glycerol => Glycerol-3-phosphate => DHAP =>
GAP ➔ Glycolysis
o Glycerol-3-phosphate: glycerophospholipid
(triacylglycerol)
- Points of entry into glycolysis
o Muscle: F6P (Before PFK point of control)
o Liver: GAP (After PFK point of control – could contribute to dyslipidemia seen
nowadays)
- Glucose vs Fructose in liver: FED
o In Fed, liver is an anabolic organ => generates glycogen
▪ Anabolic organ: organ that makes/synthesizes larger molecules from
smaller ones
o Glycogen is before PFK control
▪ Glucose ---------> G-6-P --------> G-1-P --------> Glycogen
o Fructose bypasses PFK control, so it will proceed to CAC
▪ If fed & at rest (no ATP generation required (excess ATP) – CAC inhibited),
Fructose will be converted to FA
Glucagon: hormone stimulating glycogen breakdown
Glycogen: glucose polysaccharide
Glycolysis:
Metabolic reactions occur at equilibrium, the whole system is not:
- Irreversible steps
- Basal metabolic rate (always losing energy)
ΔG° => Nature of a reaction (endergonic vs exergonic)
ΔG° > 0, (+) => endergonic (requires energy)
ΔG° < 0, (-) => exergonic (releases energy)
ΔG => reversibility in vivo
ΔG = 0: reaction is at equilibrium => reversible
ΔG < 0, (-): releases energy => irreversible
Glucose Uptake:
- Transport
o Symport uses sodium diffusion to also drive glucose from blood inside (passive
transport – 2ndary active transport)
- Uptake:
o Pancreatic beta-cells
o When [glucose]_blood > 5.5mM => Glucose is released into the blood
o Glut2 glucose channel always present
▪ When [glucose]_blood > 5.5mM glucose diffuses in via glut-2 -> ATP
production -> Potassium channel expelling channel out is inhibited ->
depolarization -> Calcium enters -> insulin (hormone) is released (synapse
style) into the bloodstream
o Insulin – Stimulates glucose uptake in cells
▪ Triggers liver to produce glycogen
▪ Glut4 glucose receptor recruited to cell surface when insulin present
Energy Expenditure:
1. ATP stored in muscles
2. P-Creatine
3. Anaerobic glycolysis
4. Aerobic glycolysis
5. Aerobic lipolysis
Glycolysis:
- Not require O2
- 1 Glucose generates: 2 ATPs, 2 NADH, 2 pyruvates
- Requires a fresh supply of NAD+
o In presence of O2 done via ox-phos
o In absence of O2
▪ Muscle: pyruvate -> lactate
Glucagon: hormone stimulating glycogen breakdown
Glycogen: glucose polysaccharide
,BIOC 311
▪ Yeats & bacteria: pyruvate -> ethanol (fermentation)
- Pathway
1. Glucose -------- Hexokinase or Glucokinase ---------> G-6-P
(glucose phosphorylated once inside cell)
a. Hexokinase:
i. Processes any 6C sugar into G6P (including fructose)
ii. Present in all cells
iii. High affinity
iv. Modulator: G6P
b. Glucokinase (back up enzyme if too much glucose for hexokinase capacity)
i. Processes only glucose
ii. Present only in liver and pancreas
iii. Low affinity
iv. Modulator: Glucokinase regulator protein (GKRP)
• Binding partner to glucokinase that keeps GK in the nucleus when
[glucose]_blood is low
• When glucose levels increase GKRP releases glucokinase to the
cytoplasm where it can produce G6P
v. Stores extra glucose as glycogen
2. G-6-P <-------- phosphoglucose isomerase ---------> F-6-P
a. Directionality depends on abundance
3. F-6-P -------- Phosphofructokinase (PFK1) ---------> FBP (fructose-1,6-bisphosphate)
a. Committing step to glycolysis
b. Activators: AMP; F2,6P
c. Inhibitors: ATP; citrate
d. AMP activation is more potent than ATP inhibition
e. Allosteric regulation
i. Adenylate kinase (ADK) (converts 2 ADP → 1 ATP + AMP)
• During exercise ~ 10% ATP is converted to ADP
• Adenylate kinase converts ADP to back to ATP with AMP
• Keeps ATP abundant for exercise
• Generates AMP to activate (PFK1)
f. Substrate Cycles
• At rest: Equilibrium
• Exercise: F2,6P activates PFK AND inhibits
FBPase
• F2,6P is not an intermediate in glycolysis
1PFK2 converts FBP to F2,6P
FBPase2 converts F2,6P to FBP
g. Covalent modification
Glucagon: hormone stimulating glycogen breakdown
Glycogen: glucose polysaccharide
,BIOC 311
4. Reversible steps
a. FBP <---------Aldolase--------> GAP + DHAP
i. GAP & DHAP are interchanged
ii. GAP is the one that proceeds with glycolysis (2 GAPs/glucose)
b. Last product of reversible is PEP (phosphoenolpyruvate)
5. PEP (High energy intermediate) -------- Pyruvate kinase --------> Pyruvate
a. Activator: F1,6B
b. Inhibitors: ATP, glucagon, cAMP, PKA (through F2,6P)
- 3 committed/irreversible steps to glycolysis
o Hexokinase
o PFK1
o Pyruvate kinase
- ATP & Energy
o Used: 2 ATP
o Made: 4 ATP, 2 NADH (2.5 ATP/NADH)
▪ Net product:
• Aerobic glycolysis (use NADH): 7 ATP
• Anaerobic glycolysis (no NADH used): 2 ATP
- Differential Hormonal regulation of PFK2
o LIVER ISOZYME
▪ Need to supply blood with fresh glucose
▪ When Fasting/prolonged exercise (glucose deprived) => F2,6P decreases
• Glucagon & cAMP increase => PKA is activated
o PKA shuts down kinase activity of PFK2
o Phosphatase activity takes over
o Reaction reverted to regenerate F6P
o HEART ISOZYME
▪ Gluconeogenesis doesn’t happen in the heart
▪ When stress => F2,6P increases
• Epinephrine and cAMP increase => PKA activated
o PKA phosphorylates PFK2 activating its kinase activity
o PKA shuts down phosphatase activity
Glucagon: hormone stimulating glycogen breakdown
Glycogen: glucose polysaccharide
, BIOC 311
- Investment phase: HK, PFK1
- Payoff phase: GAP ------> Pyruvate (2 ATP/GAP converted ∴ 4 ATP/Glucose since 2
GAPs/glucose)
Carbohydrates:
Glucose, Galactose, Fructose => 6C sugars
Generate 32 ATP via aerobic catabolism
Sucrose (Glucose-Fructose), Lactose (Glucose-Galactose), Maltose (Glucose-Glucose) => 12C
Generate 64 ATP via aerobic catabolism
Fructose
- Muscle (minor)
o Fructose ----- Hexokinase -----> F6P (glycolysis intermediate)
o F6P ----- PFK -----> Fructose-1,6-phosphate
o Fructose-1,6-phosphate ----- Fructose-1,6-phosphate aldolase -----> GAP+ DHAP
o GAP ➔ ➔ ➔ Glycolysis
- Liver (major)
o Fructose ----- Fructokinase (not regulated) -----> Fructose-1-Phosphate
Fructose-1-phosphate interconverts to its open chain form (equilibrium)
o Fructose-1-Phosphate ----- Fructose-1-phosphate aldolase -----> Glyceraldehyde + DHAP
▪ Option 1
• Glyceraldehyde => GAP ➔ Glycolysis
• DHAP => GAP ➔ Glycolysis
▪ Option 2
• Glyceraldehyde => Glycerol => Glycerol-3-phosphate => DHAP =>
GAP ➔ Glycolysis
o Glycerol-3-phosphate: glycerophospholipid
(triacylglycerol)
- Points of entry into glycolysis
o Muscle: F6P (Before PFK point of control)
o Liver: GAP (After PFK point of control – could contribute to dyslipidemia seen
nowadays)
- Glucose vs Fructose in liver: FED
o In Fed, liver is an anabolic organ => generates glycogen
▪ Anabolic organ: organ that makes/synthesizes larger molecules from
smaller ones
o Glycogen is before PFK control
▪ Glucose ---------> G-6-P --------> G-1-P --------> Glycogen
o Fructose bypasses PFK control, so it will proceed to CAC
▪ If fed & at rest (no ATP generation required (excess ATP) – CAC inhibited),
Fructose will be converted to FA
Glucagon: hormone stimulating glycogen breakdown
Glycogen: glucose polysaccharide
