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Glycolysis
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Fundamentals of Biochemistry
Fourth Edition
Chapter 15Glucose Catabolism
Glycolysis
Copyright © 2013 by John Wiley & Sons, Inc. All rights reserved.
Donald Voet • Judith G. Voet • Charlotte W. Pratt
Glycolysis –Central to carbohydrate metabolism but works in conjunction with other pathways
Glycolysis
A. 1st step in glucose metabolism
B. Ultimate goal is to make ATP from glucose
C. Overall:
glucose + 2 ADP + 2 NAD+ + 2 Pi 2 pyruvate + 2 ATP + 2 NADH + 2 H2O + 2 H+
Glycolysis
Key Points
1. Energya.
glucose G-6-PF-6-P F-1,6-bisP
b. 1,3-bisphosphoglycerate 3-phosphoglycerate (x 2)PEP pyruvate (x 2)
c. glyceraldehyde 3-P 1,3-bisphosphoglycerate (x 2)
Glycolysis
Key Points
2. Carbon Compounds
Glycolysis
Key Points
3. Control PointsEnzyme Activator Inhibitor
a. glucose G-6-P hexokinase ------- G-6-P
b. F-6-P F-1,6-bisP phosphofructokinase-1 F-2,6-bisP citrateAMP,ADP ATP
c. PEP pyruvate pyruvate kinase F-1,6-bisP ATP acetylCoAfatty acids
phosphorylation
Know these enzymes
Glycolysis
Key Points
4. Glycolysis occurs in cell cytosol
5. Phosphorylation of glycolytic intermediates is importanta. helps keep compounds in cellb. ATP formation coupled to breakdown of some
phospho compoundsc. Phosphoryl group important for enzyme binding.
The two phases of glycolysis
2
2
2
2
2
The two phases of glycolysis
The two phases of glycolysis
Glycolysis
Let’s look at the reactions of glycolysis
Look for steps where
-- energy compounds are consumed or made
-- regulation occurs
-- other notes as we discuss them
Step 1
Phosphorylation of Glucose
Hexokinase
Step 2
Phosphoglucose Isomerase Mechanism
Phosphoglucose Isomerase Mechanism
Phosphoglucose Isomerase Mechanism
Phosphoglucose Isomerase Mechanism
Phosphoglucose Isomerase Mechanism
Phosphoglucose Isomerase Mechanism
Phosphoglucose Isomerase Mechanism
Step 3
The committed step
Actually Phosphofructokinase-1
Step 4
Step 5
Step 6
The glyceraldehyde 3-phosphate dehydrogenase reaction
Step 7
Substrate level phosphorylation
Arsenate can act as an uncoupler.
AsO43- similar to…..
Step 6Arsenate reacts like in this reaction
Step 7
Substrate level phosphorylation
Step 8
Step 9
Step 10
Pyruvate Kinase Reaction
Pyruvate Kinase Reaction
Pyruvate Kinase Reaction
Glycolysis
2
2
2
2
2
What is the fate of pyruvate?
Aerobic conditions:
Anaerobic conditions:
Possible Fates of Pyruvate
Anaerobic conditions
Anaerobic conditions -- yeast
Anaerobic conditions: 2 ATP/glucose
Aerobic conditions: many more ATP (~30-32 ATP/glucose)
The 2,3 bisphosphoglycerate Story
How does glycolysis affect O2 binding to Hb?
Regulation
General Aspects
Reactions at equilibrium are essentially substrate-limited (increase [S] increases vo).
Regulation occurs at reactions far from equilibrium.
Reactions far from equilibrium are enzyme-limited.– Rate of reaction depends on enzyme activity.
Regulation
Enzyme Limited Reactions
Rate of a sequence of reactions depends on activity of enzymes at “rate limiting steps”.
These reactions are largely irreversible steps.
These steps are often targets for regulation
a) Allosteric regulation
b) Can be hormonal regulation
c) Reversible covalent modification
Regulated enzymes often at “committed steps” of pathways
Regulation of Glycolysis
Hexokinase
1) 1st step
2) Inhibited by Glucose-6-phosphate.
Regulation of Glycolysis
Pyruvate Kinase
1) Last step
2) Feedforward activation by Fructose-1,6-bisphosphate
3) Inhibited by ATP, long chain fatty acids, acetyl CoA (Ala)
4) Phosphorylation by ATP (liver enzyme)
Feedforward Activation
2
2
2
2
2
Regulation of Glycolysis
Phosphofructokinase-1
1) 3rd step -- Committed step
2) Most highly regulated enzyme
3) Inhibited by citrate and ATP
4) Stimulated by ADP and AMP
5) Stimulated by Fructose-2,6-bisphosphate
(in liver– the main glucose control organ in body)
Regulation
Substrate Cycling
Substrate cycling can influence net flux.
phosphatase)
Energetics
Energetics
What about other sugars?
We get glucose from starches and sucrose.
We also ingest other sugars
How do other sugars fit in with glycolysis?
Fructose metabolism is simple in muscle, more complex in liver
What Happens after Glycolysis?
One Application of Your Glycolysis Knowledge
Positron Emission Tomography(PET Scans)
Used to study tissue metabolism
Especially for identifying cells with abnormal metabolism, i.e., cancers and epileptic regions.
2-deoxy-2-(18F)fluoro-D-glucose
– 18F half-life is 110 minutes.
p. 555
Figure 1. “The Case of the Forgetful Professor”Brain scans from a patient with transient epileptic amnesia. (A) Fluid-attenuated inversion-recovery MRI scanning during a prolonged amnestic episode reveals hyperintensity in the left hippocampus. (B) 2-Fluoro-2-[18F]-deoxy-d-glucose PET
scanning during the same episode shows hypermetabolism localized to the left anterior hippocampus. (C) Metabolism in the left anterior hippocampus returned to normal 1 month later. Abbreviation: L = left.
PET Scans and2-deoxy-2-(18F)fluoro-D-glucose
Behaves very similarly to glucose.
Absorbed by cells and phosphorylated by hexokinase.
Distribution “the same” as glucose in tissues.
But what about step 2 of glycolysis????
Fig. 18-8, p. 541
Isomerization of Glucose-6-P to Fructose-6-P
PET Scans and2-deoxy-2-(18F)fluoro-D-glucose
So 18FDG, taken up by cells, phosphorylated and .
What happens to this radioactive glucose analog?
PET Scans and2-deoxy-2-(18F)fluoro-D-glucose
18F decays by losing a positron.(a positive antimatter particle from a
proton.)
Converts a nuclear proton into a neutron resulting in….
PET Scans and2-deoxy-2-(18F)fluoro-D-glucose
18O- picks up a proton from surrounding aqueous environment forming glucose (with “heavy” but non-radioactive oxygen).
Differences between Slow-twitch muscle and Fast-twitch muscle
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