prentice hall c2002chapter 111 principles of biochemistry third edition horton moran ochs rawn...
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Prentice Hall c2002 Chapter 11 1
Principles ofPrinciples of BIOCHEMISTRYBIOCHEMISTRYThird EditionThird Edition
HORTON MORAN OCHS RAWN SCRIMGEOUR
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Prentice Hall c2002 Chapter 11 2
Chapter 11 - Glycolysis
• For centuries, bakeries and breweries have exploited the conversion of glucose to ethanol and CO2 by glycolysis in yeast
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Prentice Hall c2002 Chapter 11 3
11.1 Glycolysis Is a Ubiquitous Pathway
Converts: 1 glucose 2 pyruvate
• Pyruvate can be further metabolized to: (1) Lactate or ethanol (anaerobic) (2) Acetyl CoA (aerobic)
• Acetyl CoA is further oxidized to CO2 and H2O via the citric acid cycle
• Much more ATP is generated from the citric acid cycle than from glycolysis
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Prentice Hall c2002 Chapter 11 4
Fig 11.1
• Catabolism of glucose via glycolysis and the citric acid cycle
(continued next slide)
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Prentice Hall c2002 Chapter 11 5
Fig 11.1 (continued)
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Prentice Hall c2002 Chapter 11 6
Net reaction of glycolysis
• Two molecules of ATP are produced
• Two molecules of NAD+ are reduced to NADH
Glucose + 2 ADP + 2 NAD+ + 2 Pi
2 Pyruvate + 2 ATP + 2 NADH + 2 H+ + 2 H2O
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Prentice Hall c2002 Chapter 11 7
Table 11.1
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Prentice Hall c2002 Chapter 11 8
Glycolysis (10 reactions) can be divided into two stages
• Hexose stage: 2 ATP are consumed per glucose
• Triose stage: 4 ATP are produced per glucose
Net: 2 ATP produced per glucose
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Prentice Hall c2002 Chapter 11 9
Fig 11.2
• Glycolysis (next 4 slides)
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Prentice Hall c2002 Chapter 11 10
Phosphofructokinase-1
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Prentice Hall c2002 Chapter 11 11
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Prentice Hall c2002 Chapter 11 12
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Prentice Hall c2002 Chapter 11 13
11.2 Glycolysis Has 10 Enzyme-Catalyzed Steps
• Each chemical reaction prepares a substrate for the next step in the process
• A hexose is cleaved to two trioses
• Interconversion of the trioses allows both to be further metabolized via glycolytic enzymes
• ATP is both consumed and produced in glycolysis
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Prentice Hall c2002 Chapter 11 14
1. Hexokinase
• Transfers the -phosphoryl of ATP to glucose C-6 oxygen to generate glucose 6-phosphate (G6P)
• Mechanism: attack of C-6 hydroxyl oxygen of glucose on the -phosphorous of MgATP2- displacing MgADP-
• Four kinases in glycolysis: steps 1,3,7, and 10
• All four kinases require Mg2+ and have a similar mechanism
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Prentice Hall c2002 Chapter 11 15
Fig 11.3 Hexokinase reaction
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Prentice Hall c2002 Chapter 11 16
Properties of hexokinases
• Broad substrate specificity - hexokinases can phosphorylate glucose, mannose and fructose
• Yeast hexokinase undergoes an induced-fit conformational change when glucose binds
• Conformational change helps prevent hydrolysis of ATP to ADP and Pi (Fig 6.13)
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Prentice Hall c2002 Chapter 11 17
Isozymes of hexokinase
• Isozymes - multiple forms of hexokinase occur in mammalian tissues and yeast
• Hexokinases I, II, III are active at normal glucose concentrations (Km values ~10-6 to 10-4M)
• Hexokinase IV (Glucokinase, Km ~10-2M) is active at higher glucose levels, allows the liver to respond to large increases in blood glucose
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Prentice Hall c2002 Chapter 11 18
2. Glucose 6-Phosphate Isomerase
• Converts glucose 6-phosphate (G6P) (an aldose) to fructose 6-phosphate (F6P) (a ketose)
• Enzyme preferentially binds the -anomer of G6P (converts to open chain form in the active site)
• Enzyme is highly stereospecific for G6P and F6P
• Isomerase reaction is near-equilibrium in cells
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Prentice Hall c2002 Chapter 11 19
Fig 11.4 Conversion of G6P to F6P
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Prentice Hall c2002 Chapter 11 20
3. Phosphofructokinase-1 (PFK-1)
• Catalyzes transfer of a phosphoryl group from ATP to the C-1 hydroxyl group of F6P to form fructose 1,6-bisphosphate (F1,6BP)
• PFK-1 is metabolically irreversible and a critical regulatory point for glycolysis in most cells (PFK-1 is the first committed step of glycolysis)
• A second phosphofructokinase (PFK-2) synthesizes fructose 2,6-bisphosphate (F2,6BP)
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Prentice Hall c2002 Chapter 11 21
PFK-1 Reaction
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Prentice Hall c2002 Chapter 11 22
4. Aldolase
• Aldolase cleaves the hexose F1,6BP into two triose phosphates: glyceraldehyde 3-phosphate (GAP) and dihydroxyacetone phosphate (DHAP)
• Reaction is near-equilibrium, not a control point
• Mechanism is common for cleaving C-C bonds in biological systems (and C-C bond formation in the reverse direction)
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Prentice Hall c2002 Chapter 11 23
Aldolase Reaction
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Prentice Hall c2002 Chapter 11 24
Fig 11.5 Mechanism of aldolases
(continued next slide)
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Prentice Hall c2002 Chapter 11 25
Fig 11.5 (continued)
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Prentice Hall c2002 Chapter 11 26
5. Triose Phosphate Isomerase (TPI)
• Conversion of DHAP into glyceraldehyde 3-phosphate (GAP)
• Reaction is very fast (diffusion controlled), and only the D-isomer of GAP is formed
• Radioisotopic tracer studies show:One GAP molecule: C1,2,3 from Glucose C4,5,6Second GAP: C1,2,3 from Glucose C3,2,1
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Prentice Hall c2002 Chapter 11 27
Reaction of Triose phosphate isomerase
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Prentice Hall c2002 Chapter 11 28
Fig 11.6 Fate of carbon atoms from hexose stage to triose stage
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Prentice Hall c2002 Chapter 11 29
6. Glyceraldehyde 3-Phosphate Dehydrogenase (GAPDH)
• Conversion of GAP to 1,3-bisphosphoglycerate (1,3BPG)
• Molecule of NAD+ is reduced to NADH
• Oxidation of the aldehyde group of GAP proceeds with large negative free-energy change
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Prentice Hall c2002 Chapter 11 30
Conservation of oxidative energy
• Energy from oxidation of GAP aldehyde is conserved in acid-anhydride linkage of 1,3BPG
• Next step of glycolysis uses the high-energy phosphate of 1,3BPG to form ATP from ADP
• Mechanism of GAPDH shows how an energy-rich compound forms in an oxidation reaction
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Prentice Hall c2002 Chapter 11 31
Reaction of GAPDH: GAP converted to 1,3BPG
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Prentice Hall c2002 Chapter 11 32
Fig 11.7
• Mechanism of GAPDH (3 slides)
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Prentice Hall c2002 Chapter 11 33
Fig 11.7 (continued)
(2)(4)
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Prentice Hall c2002 Chapter 11 34
Fig 11.7 (continued)
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Prentice Hall c2002 Chapter 11 35
Box 11.2 Arsenate (AsO43-) poisoning
• Arsenate can replace Pi as a substrate for G3PDH
• Arseno analog which forms is unstable
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Prentice Hall c2002 Chapter 11 36
7. Phosphoglycerate Kinase (PGK)
• Transfer of phosphoryl group from the energy-rich mixed anhydride 1,3BPG to ADP yields ATP and 3-phosphoglycerate (3PG)
• Substrate-level phosphorylation - Steps 6 and 7 couple oxidation of an aldehyde to a carboxylic acid with the phosphorylation of ADP to ATP
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Prentice Hall c2002 Chapter 11 37
Phosphoglycerate kinase reaction
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Prentice Hall c2002 Chapter 11 38
8. Phosphoglycerate Mutase
• Catalyzes transfer of a phosphoryl group from one part of a substrate molecule to another
• Reaction occurs without input of ATP energy
• Mechanism requires 2 phosphoryl-group transfer steps
• Enzymes from animal muscle and yeast have a different mechanism than does plant enzyme
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Prentice Hall c2002 Chapter 11 39
Phosphoglycerate mutase reaction
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Prentice Hall c2002 Chapter 11 40
Fig 11.8 Phosphoglycerate mutase mechanism: animals and yeast
(continued)
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Prentice Hall c2002 Chapter 11 41
Fig 11.8 (continued)
(1)
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Prentice Hall c2002 Chapter 11 42
Fig 11.8 (continued)
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Prentice Hall c2002 Chapter 11 43
9. Enolase: 2PG to PEP
• 3-Phosphoglycerate (3PG) is dehydrated to phosphoenolpyruvate (PEP)
• Elimination of water from C-2 and C-3 yields the enol-phosphate PEP
• PEP has a very high phosphoryl group transfer potential because it exists in its unstable enol form
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Prentice Hall c2002 Chapter 11 44
Enolase reaction
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Prentice Hall c2002 Chapter 11 45
10. Pyruvate Kinase (PK)
• Catalyzes a substrate-level phosphorylation
• Metabolically irreversible reaction
• Regulation both by allosteric modulators and by covalent modification
• Pyruvate kinase gene can be regulated by various hormones and nutrients
PEP + ADP Pyruvate + ATP
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Prentice Hall c2002 Chapter 11 46
Fig 11.9
• Pyruvate kinase reaction
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Prentice Hall c2002 Chapter 11 47
11.3 The Fate of Pyruvate
1. Aerobic conditions: oxidized to acetyl CoA which enters the citric acid cycle for further oxidation
2. Anaerobic conditions (microorganisms): conversion to ethanol
3. Anaerobic conditions (muscles, red blood cells): conversion to lactate
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Prentice Hall c2002 Chapter 11 48
Fig 11.10
• Three major fates of pyruvate
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Prentice Hall c2002 Chapter 11 49
A. Metabolism of Pyruvate to Ethanol (yeast - anaerobic)
• Two reactions required:
(1) Pyruvate carboxylase
(2) Alcohol dehydrogenase
Pyruvate Acetaldehyde Ethanol (1) (2)
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Prentice Hall c2002 Chapter 11 50
Fig 11.11
• Anaerobic conversion of pyruvate to ethanol (yeast)
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Prentice Hall c2002 Chapter 11 51
Fig 11.11 (cont)
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Prentice Hall c2002 Chapter 11 52
B. Reduction of Pyruvate to Lactate (muscles - anaerobic)
• Muscles lack pyruvate dehydrogenase and cannot produce ethanol from pyruvate
• Muscle lactate dehydrogenase converts pyruvate to lactate
• This reaction regenerates NAD+ for use by GAPDH in glycolysis
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Prentice Hall c2002 Chapter 11 53
Recycling of lactate
• Lactate formed in skeletal muscles during exercise is transported to the liver
• Liver lactate dehydrogenase can reconvert lactate to pyruvate
• Lactic acidosis can result from insufficient oxygen (an increase in lactic acid and decrease in blood pH)
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Prentice Hall c2002 Chapter 11 54
Reduction of pyruvate to lactate
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Prentice Hall c2002 Chapter 11 55
Overall reactions for glucose degradation to lactate
• Two ATP per molecule glucose consumed
• No oxygen is required
Glucose + 2 Pi2- + 2 ADP3-
2 Lactate- + 2 ATP4- + 2 H2O
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Prentice Hall c2002 Chapter 11 56
11.4 Free-Energy Changes in Glycolysis
• Actual free-energy changes (G) large only for:#1 (hexokinase)#3 (phosphofructokinase)#10 (pyruvate kinase)
• These steps are metabolically irreversible, and these enzymes are regulated
• G for all other steps are close to zero (they are near-equilibrium in cells)
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Prentice Hall c2002 Chapter 11 57
Fig 11.12 Cumulative standard and actual free energy changes for the reactions of glycolysis
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Prentice Hall c2002 Chapter 11 58
11.5 Regulation of Glycolysis
1. When ATP is needed, glycolysis is activated
• AMP and fructose 2,6-bisphosphate (F2,6BP) relieve the inhibition of PFK-1 by ATP
2. When ATP levels are sufficient, glycolysis activity decreases
• PFK-1 is inhibited by ATP and citrate
• Hexokinase inhibited by excess glucose 6-phosphate
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Prentice Hall c2002 Chapter 11 59
Fig 11.13 Metabolic regulation of glycolysis
(continued)
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Prentice Hall c2002 Chapter 11 60
Fig 11.13 (continued)
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Prentice Hall c2002 Chapter 11 61
A. Regulation of Hexose Transporters
• Glucose enters mammalian cells by passive transport down a concentration gradient from blood to cells
• GLUT is a family of six passive hexose transporters
• Glucose uptake into skeletal and heart muscle and adipocytes by GLUT 4 is stimulated by insulin
• Other GLUT transporters mediate glucose transport in and out of cells in the absence of insulin
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Prentice Hall c2002 Chapter 11 62
Fig 11.14 Regulation of glucose transport by insulin
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Prentice Hall c2002 Chapter 11 63
B. Regulation of Hexokinase
• Hexokinase reaction is metabolically irreversible
• G6P (product) levels increase when glycolysis is inhibited at sites further along in the pathway
• G6P inhibits hexokinase isozymes I, II and III
• Glucokinase forms G6P in the liver (for glycogen synthesis) when glucose is abundant (activity is modulated by fructose phosphates and a regulatory protein)
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Prentice Hall c2002 Chapter 11 64
Fig 11.15 Effects of a regulatory protein on glucokinase kinetics
• Addition of a regulatory protein raises apparent Km for glucose (inhibits glucokinase)
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Prentice Hall c2002 Chapter 11 65
Box 11.3 Glucose 6-Phosphate Has a Pivotal Metabolic Role in Liver
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Prentice Hall c2002 Chapter 11 66
C. Regulation of Phosphofructokinase-1
• ATP is a substrate and an allosteric inhibitor of PFK-1
• AMP allosterically activates PFK-1 by relieving the ATP inhibition (ADP is also an activator in mammalian systems)
• Changes in AMP and ADP concentrations can control the flux through PFK-1
• Elevated levels of citrate (indicate ample substrates for citric acid cycle) also inhibit PFK-1
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Prentice Hall c2002 Chapter 11 67
Fig 11.16 Regulation of PFK-1 by ATP and AMP
• AMP relieves ATP inhibition of PFK-1
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Prentice Hall c2002 Chapter 11 68
Regulation of PFK-1 by Fructose 2,6-bisphosphate (F2,6BP)
• F2,6BP is formed from F6P by the enzyme phosphofructokinase-2 (PFK-2)
• Fig 11.17 -D-Fructose 2,6-bisphosphate
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Prentice Hall c2002 Chapter 11 69
Formation and hydrolysis of F2,6BP
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Prentice Hall c2002 Chapter 11 70
Fig. 11.18
• Effect of glucagon on liver glycolysis
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Prentice Hall c2002 Chapter 11 71
D. Regulation of Pyruvate Kinase (PK)
• Four PK isozymes exist in mammalian tissues
• PK is allosterically activated by F1,6BP, inhibited by ATP
• Glucagon stimulates protein kinase A which phosphorylates PK converting it to a less active form (liver and intestinal cells)
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Prentice Hall c2002 Chapter 11 72
Fig 11.19 Initial velocity curves of pyruvate kinase
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Prentice Hall c2002 Chapter 11 73
Fig 11.20 Pyruvate kinase with F1,6BP
• Activator F1,6BP (red)
• Active site is in large central domain
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Prentice Hall c2002 Chapter 11 74
E. The Pasteur Effect
• Under anaerobic conditions the conversion of glucose to pyruvate is much higher than under aerobic conditions (yeast cells produce more ethanol and muscle cells accumulate lactate)
• The Pasteur Effect is the slowing of glycolysis in the presence of oxygen
• More ATP is produced under aerobic conditions than under anaerobic conditions, therefore less glucose is consumed aerobically
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Prentice Hall c2002 Chapter 11 75
11.6 Other Sugars Can Enter Glycolysis
• Glucose is the main metabolic fuel in most organisms
• Other sugars convert to glycolytic intermediates
• Fructose and sucrose (contains fructose) are major sweeteners in many foods and beverages
• Galactose from milk lactose (a disaccharide)
• Mannose from dietary polysaccharides, glycoproteins
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Prentice Hall c2002 Chapter 11 76
A. Fructose Is Converted to Glyceraldehyde 3-Phosphate
Fig 11.21
(continued)
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Prentice Hall c2002 Chapter 11 77
Fig 11.21 (continued)
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Prentice Hall c2002 Chapter 11 78
B. Galactose is Converted to Glucose 1-Phosphate
Fig 11.22 (continued next slide)
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Prentice Hall c2002 Chapter 11 79
Fig 11.22 (continued)
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Prentice Hall c2002 Chapter 11 80
C. Mannose is Converted to Fructose 6-Phosphate
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Prentice Hall c2002 Chapter 11 81
11.7 Formation of 2,3-Bisphosphoglycerate in Red Blood Cells
• 2,3-Bisphosphoglycerate (2,3BPG) allosterically regulates hemoglobin oxygenation (red blood cells)
• Erythrocytes contain bisphosphoglycerate mutase which forms 2,3BPG from 1,3BPG
• In red blood cells about 20% of the glycolytic flux is diverted for the production of the important oxygen regulator 2,3BPG
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Prentice Hall c2002 Chapter 11 82
Fig 11.24
• Formation of 2,3BPG in red blood cells