glucose utilization
DESCRIPTION
Glucose Utilization. Metabolic Mainstreet. Glucose. Glycolysis. Pyruvate. Bridging Rx. AcetylCoA. NAD + /FAD. NADH/FADH 2. C 6. C 4. OP. Krebs Cycle. ADP O 2. C 5. C 4. ATP. PATHWAYS: 4 W’s. W hat = Net Reaction. W hy = Purpose(s) of Pathway. - PowerPoint PPT PresentationTRANSCRIPT
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Glucose Utilization
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PATHWAYS: 4 W’sWhat = Net ReactionWhy = Purpose(s) of Pathway
Where = Organism/Tissue/Organelle
When = Regulation of Pathway
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Glucose
AcetylCoA
Pyruvate
NADH/FADH2
KrebsCycle
C6
C4
C5
C4
ATP
Glycolysis
Bridging Rx.
Oxidative PhosphorylationADP
O2
NAD+/FAD
Metabolic Mainstreet
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GLUCOSE + 2ADP + 2NAD+
2PYRUVATE + 2ATP + 2NADH
GLYCOLYSIS: Net Reaction (What)
10 Enzymes
Glucose gets oxidized - NAD+ gets reducedTwo ADP molecules get phosphorylated
Glycolysis is a a) catabolic b) anabolic pathway?
Do bacteria have a glycolysis pathway? a) yes b) no c) only anaerobic bacteria
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1. Generate ATP a. immediate (2 “anaerobic” ATP) b. future - more ATP from pyruvate & NADH
GLYCOLYSIS: Purpose (Why)
2. Provide intermediates/pyruvate for synthesis reactions
Where?All Organisms: bacteria, plants, animalsAll Cell Types: liver, muscle, neurons, adipose, etc.
Cytoplasm
Low Energy Charge phosphofructokinase (-) ATP
(+) F2,6-BP hexokinase (-) G-6-P pyruvate kinase (-) ATP
When?
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HO
OH
OOH
OH
OH
OH
O
OH
HO
OH
OH
a - Glucose b - Fructose
CH2 – OH |CH – OH |CH2 – OH glycerol
CHO | CH – OH | CH2 – OHglyceraldehyde
COO-
| CH – OH | CH2 – OH glycerate
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COO-
|CH – OH |CH2 – O - PO3
2-
Name this molecule.
a) Glycerol phosphate b) Glyceraldehyde 3 phosphate c) 3 – phosphoglycerate d) 1 - phosphoglycerate
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COO-
| C=O | CH3 pyruvate
COO-
| C-OH || CH2 enol pyruvate
CH2 - OH | C=O | CH2 - OH Dihydroxy acetone
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GLYCOLYSIS
Glucose
Glucose-6-Phosphate
Fructose-6-Phosphate
Fructose 1,6 Bisphosphate
DHAP + Glyceraldehyde-3-P
Glyceraldehyde-3-P
Pyruvate
PEP
2-Phosphoglycerate
3-Phosphoglycerate
1,3-BPG
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2 ATP → 2 ADP
C6 → 2C3
2 NAD+ reduced → 2 NADH 4 ADP → 4 ATP
Glucose in
2 pyruvate out
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Glycolysis: The Preparatory Phase
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Glycolysis: The Payoff Phase
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GLUCOSE + 2ADP + 2NAD+
2PYRUVATE + 2ATP + 2NADH
GLYCOLYSIS: Net Reaction (What)
10 Enzymes
Glucose gets oxidized - NAD+ gets reducedTwo ADP molecules get phosphorylated
What is the limiting reagent for glycolysis?a) Glucose b) ADP c) NAD+
fuel in
SH2 NADH ATP
S NAD+ ADP
work output
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Glucose
AcetylCoA
Pyruvate
NADH/FADH2
KrebsCycle
C6
C4
C5
C4
ATP
Glycolysis
Bridging Rx.
OP
ADP O2
Metabolic MainstreetNAD+
NADH
Lactate
Aerobic~ 36 ATP
How do you supplyNAD+ to glycolysisWhen a lack of O2
Prevents OP!
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GLUCOSE + 2ADP + 2NAD+
2PYRUVATE + 2ATP + 2NADH
GLYCOLYSIS: Anaerobic
10 Enzymes
COO-
|NAD+ + H - C - OH | CH3
COO-
| C = O + NADH | CH3
Muscle
Liver
Lactate
Lactate Dehydrogenase (LDH)
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GLYCOLYSIS : Side Reactions
Glucose
Glucose-6-Phosphate Glycogen R-5-P/Glucose Fructose-6-Phosphate 2,3 BPG Fructose 1,6 Bisphosphate
DHAP + Glyceraldehyde-3-P
Glyceraldehyde-3-P
Pyruvate
PEP
2-Phosphoglycerate
3-Phosphoglycerate
1,3-BPG Glycerol
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GLYCOLYSIS: Regulation
Glucose (-) G-6-P 2nd
Glucose-6-Phosphate Glycogen
Fructose-6-Phosphate (-) ATP 1st
Fructose 1,6 Bisphosphate
DHAP + Glyceraldehyde-3-P
Glyceraldehyde-3-P
Pyruvate(-) ATP PEP
2-Phosphoglycerate
3-Phosphoglycerate
1,3-BPG
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S PE
Metabolic Regulation
1. How Much Enzyme - Regulation of gene expression
2. Activity of Available EnzymeAllosteric EnzymesCovalent ModificationsProenzymes
Conditions in the cell (Goldilocks and the three Bears) a) Too much P – slow down pathway b) Too little P – speed up pathway c) [P] is just right – maintain steady state
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Allosteric Enzymes R state (relaxed) – active: S → P T state (tense) – inactive (or less active): very little P formed
T ↔ R + S ↔ R + P
A negative regulator (-) will bind selectively to the less active form of an enzyme, shifting the conformational equilibrium toward this form and decreasing activity.
[T] increases and [R] decreases
T- ↔ (- regulator) + T ↔ R + S ↔ R + P
A positive regulator (+) will bind selectively to the more active form of an enzyme, shifting the conformational equilibrium toward this form and increasing activity. [T] decreases and [R] increases
T ↔ R + S ↔ R + P + (+ regulator) ↔ R+ + S
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Glucose
AcetylCoA
Pyruvate
NADH/FADH2
KrebsCycle
C6
C4
C5
C4
ATP
Glycolysis
Bridging Rx.
OP
ADP O2
Metabolic MainstreetNAD+
NADH Aerobic~ 36 ATP
How do you supplyNAD+ to glycolysisWhen a lack of O2
Prevents OP!
Lactate
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GLYCOLYSIS: Regulation
Glucose (-) G-6-P 2nd
Glucose-6-Phosphate Glycogen
Fructose-6-Phosphate (-) ATP 1st
Fructose 1,6 Bisphosphate
DHAP + Glyceraldehyde-3-P
Glyceraldehyde-3-P
Pyruvate(-) ATP PEP
2-Phosphoglycerate
3-Phosphoglycerate
1,3-BPG
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1(-) G-6-P
3(-) ATP
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Phosphofructokinase has distinct active and allosteric sitesATP is a negative allosteric regulator as well as a substrate.
Muscle (M4) - ↑ATP decreases PFK activity
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[Glu]blood
Meal
Insulin
Glucagon
Fed
Fast early
late fast
Glycogen gone
6-12 hrs1-2 hrs
3 daysLong Term Fast
↑Liver Glycolysis
↓Liver Glycolysis
Liver Glycogenolysis provides glucose to blood/brain.
Liver Gluconeogenesis provides glucose to blood/brain.
Liver Glycolysis Regulation
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Phosphofructokinase has distinct active and allosteric sitesATP is a negative allosteric regulator as well as a substrate.
Muscle (M4) - ↑ATP decreases PFK activity
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Liver (L4)PhosphofructokinaseActivity in Glycolysis
Fixed [ATP]
↑[citrate] also enhances ATP (-) effect (signals sufficient building blocks)The liver runs glycolysis in the Fed state and blocks glycolysis in the Fasting State.This initially seems counterintuitive but …….
↑ATP decreases PFK activity↑ F-2,6-bP blocks ATP allosteric effect and ↑activityThe ↑F-2,6-bP is tied to insulin release (and high blood sugar)
Rat hepatocyte
Insulin & Fed state
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GLUCONEOGENESIS ― What?
2Pyruvate + 4ATP + 2NADH 2GTP
Glucose + 4ADP + 2NAD+
2GDPto blood
Where? LiverWhy? To maintain blood [glucose] after glycogen is used upWhen? Fasting state – (particularly late fast) ↑ [acetylCoA] and glucagon
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[Glu]blood
Meal
Insulin
Glucagon
Fed
Fast early
late fast
Glycogen gone
6-12 hrs1-2 hrs
3 daysLong Term Fast
Liver Gluconeogenesis provides glucose to blood/brain.
Gluconeogenesis
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Glucose
AcetylCoA
Pyruvate
NADH/FADH2
KrebsCycle
C6
C4
C5
ATP
Glycolysis
Bridging Rx.
OP
ADP O2
NAD+/FAD
Metabolic Mainstreet
oxaloacetate
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Gluconeogenesis - Bypass Enzymes
Glucose oxaloacetate Glucose-6-Phosphate
Fructose-6-Phosphate
Fructose 1,6 Bisphosphate
DHAP + Glyceraldehyde-3-P
Glyceraldehyde-3-P
Pyruvate
PEP
2-Phosphoglycerate
3-Phosphoglycerate
1,3-BPG
Pyruvate carboxylase
PEP carboxykinase
Fructose 1,6-bis phosphatase
Glucose 6-phosphatase (-) ATP
(-) ATP
(-) G-6-P
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Gluconeogenesis - Bypass Enzymes
pyruvate + CO2 + ATP + H2O oxaloacetate + ADP,Pi + 2H+
oxaloacetate + GTP PEP + GDP + CO2
10. Pyruvate carboxylase & PEP carboxykinase (+) acetylCoA & (-) ADP
3. Fructose 1,6-bisphosphatase (-) fructose 2,6-bisphosphate (low fasting – high Fed) (-) AMP
fructose 1,6 bisphosphate + H2O fructose 6-phosphate + Pi
1. Glucose 6-phosphataseglucose 6-phosphate + H2O glucose + Pi
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Where does Pyruvate come from?
Amino Acids
Pyruvate
Oxaloacetate
DHAP
Glucose
Glycerol
Lactate
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Glucose
AcetylCoA
Pyruvate
NADH/FADH2
KrebsCycle
C6
C4
C5
ATP
Glycolysis
Bridging Rx.
OP
ADP O2
NAD+/FAD
Metabolic Mainstreet & fasting state
oxaloacetate
Protein
amino acids
Transamination & oxidative deamination
Fat
Fatty acids
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Liver Regulation
Fructose-6-Phos
Fructose 1,6 Bisphos
PEP
Pyruvate oxaloacetate
(-) ADP(+) AcetylCoAPyruvate carboxylase
(-) ADPPEP carboxykinase(-) ATP
(-) Alanine(+) F-1,6 BPPyruvate kinase
(-) ATP(-) citrate(+) F-2,6 BP(+) AMPphosphofructokinase
(-) AMP (-) F-2,6 BP (+) citrateFructose 1,6-bisphosphatase
GlycolysisFed State
insulin GluconeogenesisFasting State
glucagon
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Cori Cycle : Recycling Lactate
Muscle
Glucose
Lactate
Glucose
Lactate
Glycogen Glycogen
Liver
← LDH (Lactate Dehydrogenase) →
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Glycolysis (all cells) & Gluconeogenesis (liver only)
Gluconeogeneis occurs in liver to provide glucose to blood during the fasting state.
It uses 4 separate enzymes to bypass all the ‘irreversible’ steps of glycolysis.Otherwise it shares the same enzymes with glycolysis.
The regulation of Gluconeogenesis and Glycolysis are coordinated and opposite.Glycolysis: on – Fed state with insulin and ↑F-2,6-bP, ↑AMP
off – Fasting state with ↑EC/ATP, ↑citrate Gluconeogeneis: on – Fasting State with glucagon, ↑acetylCoA/citrate
off – Fed state with insulin & ↑AMP/ADP, ↑F-2,6-bP
Glucose + 2NAD+ 2Pryruvate + 2NADH 2ADP → 2ATP
4ADP + 2GDP ← 4ATP + 2GTP
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Today’s Topics: Cori Cycle & Gluconeogenesis reviewGlycogen Metabolism – Glycogenesis & GlycogenolysisPhosphorylase vs. Glycogen SynthaseHormones and Metabolic Regulation: Insulin vs. glucagonThe glucagon/epinephrine cascades
This pathway is negatively regulated by high ATP levels a) glycolysis b) gluconeogenesis c) both
This pathway is negatively regulated by high F-2,6-bP levels. a) glycolysis b) gluconeogenesis c) both
This pathway is negatively regulated (liver) during the fasting state. a) glycolysis b) gluconeogenesis c) both
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Pentose Phosphate Pathway
To be covered with Fatty Acid Metabolism And ROS.