1. Chapter 22 Gluconeogenesis, Glycogen Metabolism, and the Pentose Phosphate Pathway

2. Outline What is gluconeogenesis, and how does it operate ?
How is gluconeogenesis regulated ?
How are glycogen and starch catabolized in animals ?
How is glycogen synthesized ?
How is glycogen metabolism controlled ?
What are functions of the hexose shunt and how does it operate ?

3. 22.1 What Is Gluconeogenesis, and How Does It Operate ?
Gluconeogenesis is the generation (genesis) of "new (neo) glucose" from common metabolites
Humans consume 160 g of glucose per day.
75% of that is in the brain.
Body fluids contain only 20 g of glucose.
Glycogen stores yield g of glucose.
Glycogen stores are at least partially depleted in strenuous exercise.
The body must be able to make its own glucose.
It is used to restore the depleted glycogen and to sustain normal activity.

4. The Gluconeogenesis Pathway
Figure 22.1

5. The Gluconeogenesis Pathway
Figure 22.1

6. Substrates for Gluconeogenesis
Pyruvate, lactate, glycerol, amino acids and all TCA intermediates can be utilized
Fatty acids cannot be used.
Why ?
Most fatty acids yield only acetyl-CoA.
Acetyl-CoA (through TCA cycle) is converted to CO2 , water and energy but cannot provide for net synthesis of sugars.

7. Features of Gluconeogenesis
This is primarily a liver pathway.
liver (~90%) and kidneys (~10%).
Not a reversal of glycolysis for 2 reasons:
1) The ΔG of glycolysis is -74 kJ/mol.
The reverse = +74 kJ/mol (unfavorable).
Energetics must change to make ΔG of gluconeogenesis favorable.
2) There is reciprocal regulation of glycolysis and gluconeogenesis:
When glycolysis is active, gluconeogenesis is turned off, and when gluconeogenesis is proceeding, glycolysis is turned off.

8. Gluconeogenesis - Something Borrowed, Something New
Gluconeogenesis retains seven steps of glycolysis:
Steps 2 and 4-9.
Three steps are replaced:
Glucose-6-phosphatase replaces the hexokinase reaction of glycolysis.
Fructose-1,6-bisphosphatase replaces the phosphofructokinase reaction of glycolysis.
Pyruvate carboxylase and PEP carboxykinase replace the pyruvate kinase reaction of glycolysis.
The new reactions provide for a spontaneous pathway (DG negative in the direction of sugar synthesis), and they provide new mechanisms of regulation.

9. The Reversal of Pyruvate Kinase requires two Enzymes
Pyruvate Carboxylase
The pyruvate  oxaloacetate reaction requires ATP and bicarbonate as substrates.
This is a “hint” that biotin is required.
Biotin is covalently linked to an active site lysine
Acetyl-CoA is a potent allosteric activator.
The mechanism (Figure 22.3) is typical of biotin chemistry.
Regulation: when ATP or acetyl-CoA are high, pyruvate enters gluconeogenesis.

10. Pyruvate Carboxylase is a Biotin-Dependent Enzyme
Pyruvate carboxylase is a mitochondrial enzyme and its reaction is the initiation of the gluconeogenesis pathway.
Carboxylations that use bicarbonate as the carbon source require biotin as a coenzyme.
In most organisms, pyruvate carboxylase is a homotetramer of 130 kD subunits. Each subunit is composed of three functional domains.

11. Pyruvate Carboxylase is a Biotin-Dependent Enzyme
Figure 22.2
Biotin (a vitamin) when covalently linked to an active-site lysine forms biotinyllysine or biocytin (a coenzyme).
The nitrogen at the bottom of this structure is the one that transfers the one-carbon unit to pyruvate.
Biocytin

12. Pyruvate Carboxylase is a Biotin-Dependent Enzyme
Figure A mechanism for the pyruvate carboxylase reaction. Bicarbonate must be activated for attack by the pyruvate carbanion. This activation is driven by ATP.

13. Pyruvate Carboxylase is a Compartmentalized Reaction.
Figure 22.4
Pyruvate is converted to oxaloacetate in the mitochondria. Because oxaloacetate cannot be transported across the mitochondrial membrane, it must be reduced to malate, transported to the cytosol, and then oxidized back to oxaloacetate before gluconeogenesis can continue.

14. PEP Carboxykinase Uses GTP and a Decarboxylation to Drive PEP Synthesis
This reaction converts oxaloacetate to PEP.
Lots of energy is needed to drive this reaction.
Energy is provided in 2 ways:
Decarboxylation is a favorable reaction.
GTP is hydrolyzed.
The GTP used here is equivalent to an ATP.

15. PEP Carboxykinase Uses GTP and a Decarboxylation to Drive PEP Synthesis
The CO2 added to pyruvate in the pyruvate carboxylase reaction is removed in the PEP carboxykinase reaction.
The use of GTP here (by mammals and several other organisms) is equivalent to the consumption of an ATP, due to the activity of the nucleoside diphosphate kinase (see Figure 19.2).

16. Fructose-1,6-bisphosphatase
Hydrolysis of F-1,6-bisPase to F-6-P
Thermodynamically favorable: the G in liver is -8.6 kJ/mol.
This is an allosterically regulated enzyme:
citrate stimulates.
fructose-2,6-bisphosphate inhibits
AMP inhibits.
The inhibition by AMP is enhanced by fructose-2,6-bisphosphate.

17. Fructose-1,6-bisphosphatase
The fructose-1,6-bisphosphatase reaction
The value of ΔG in the liver is -8.6 kJ/mol

18. Glucose-6-Phosphatase converts glucose-6-P to Glucose in the ER
Presence of G-6-Pase in the ER of liver and kidney cells makes gluconeogenesis possible.
Muscle and brain do not do gluconeogenesis.
G-6-P is hydrolyzed after uptake into the ER.
The glucose-6-phosphatase system includes the phosphatase itself and three transport proteins, T1, T2, and T3.
T1 takes glucose-6-P into the ER, where it is hydrolyzed by the phosphatase.
T2 and T3 export glucose and Pi, respectively, to the cytosol.
Glucose is exported to the circulation by GLUT2.

19. Glucose-6-Phosphatase converts glucose-6-P to Glucose in the ER
Figure Glucose-6-phosphatase is localized in the ER.

20. The Mechanism of Glucose-6-Phosphatase
Figure The glucose-6-phosphatase reaction involves nucleophilic attack by a histidine nitrogen and formation of a phosphohistidine intermediate. A general base on the enzyme facilitates attack by hydroxide ion on phosphorus, completing the reaction.

21. How your liver helps you during exercise:
Lactate Formed in Muscles is Recycled to Glucose in the Liver
How your liver helps you during exercise:
Recall that vigorous exercise can lead to a buildup of lactate and NADH, due to oxygen shortage and the need for more glycolysis.
NADH can be reoxidized during the reduction of pyruvate to lactate.
Lactate is then returned to the liver, where it can be reoxidized to pyruvate by liver LDH.
Liver provides glucose to muscle for exercise and then reprocesses lactate into new glucose.
This is referred to as the Cori cycle (Figure 22.7).

22. Lactate Formed in Muscles is Recycled to Glucose in the Liver
Figure 22.7
The Cori cycle.

23. 22.2 Regulation of Gluconeogenesis
Reciprocal control with glycolysis
When glycolysis is turned on, gluconeogenesis should be turned off.
When energy status of cell is high, glycolysis should be off and pyruvate, etc., should be used for synthesis and storage of glucose.
When energy status is low, glucose should be rapidly degraded to provide energy.
The regulated steps of glycolysis are the very steps that are regulated in the reverse direction!

24. Regulation of Gluconeogenesis
Figure 22.8
The principal regulatory mechanisms in glycolysis and gluconeogenesis. Activators are indicated by plus signs and inhibitors by minus signs.

25. Allosteric and Substrate-Level Control
Regulation of Gluconeogenesis
Allosteric and Substrate-Level Control
Glucose-6-phosphatase is under substrate-level control, not allosteric control.
The fate of pyruvate depends on acetyl-CoA.
Fructose-1,6-bisphosphatase is inhibited by AMP, activated by citrate - the reverse of glycolysis.
Fructose-2,6-bisphosphate is an allosteric inhibitor of fructose-1,6-bisphosphatase.

26. Regulation of Gluconeogenesis
Emile Van Schaftingen and Henri-Géry Hers showed in 1980 that fructose-2,6-bisphosphate is a potent stimulator of phosphofructokinase and a powerful inhibitor of fructose-1,6-bisphosphatase.

27. Fructose-2,6-bisphosphate is a powerful inhibitor of fructose-1,6-bisphosphatase
Figure 22.9(a)
Inhibition of fructose-1,6-bisphosphatase by fructose-2,6-bisphosphate in the absence of 25 mM AMP.
Concentrations of fructose-2,6-bisphosphate are indicated above each curve.

28. Fructose-2,6-bisphosphate is a powerful inhibitor of fructose-1,6-bisphosphatase
Figure 22.9(b)
Inhibition of fructose-1,6-bisphosphatase by fructose-2,6-bisphosphate in the presence of 25 mM AMP.
Concentrations of fructose-2,6-bisphosphate are indicated above each curve.

29. Fructose-2,6-bisphosphate is a powerful inhibitor of fructose-1,6-bisphosphatase
Figure 22.9
The effect of AMP (concentrations as indicated above each curve) on the inhibition of fructose-1,6-bisphosphatase by fructose-2,6-bisphosphate.

30. PFK-2 and F-2,6-Bpase Are Two Activities of a Bifunctional, or Tandem, Enzyme
Figure 22.10(a) Synthesis and degradation of fructose-2,6-bisphosphate are catalyzed by the same bifunctional enzyme. (b) The structure of PFK-2/F-2,6-BPase from rat liver. PFK-2 activity resides in the N-terminal portion of the protein (left) and the C-terminal domain (right) contains F-2,6-Bpase activity. The PFK-2 domain has a bound ATP analog; the F-2,6-BPase has two phosphates bound.

31. 22.3 How Are Glycogen and Starch Catabolized in Animals ?
Obtaining glucose from diet (digestion)
-Amylase is an endoglycosidase.
It cleaves dietary amylopectin or glycogen randomly to maltose, maltotriose and other small oligosaccharides.
It is active on either side of a branch point, but activity is reduced near the branch points.
Debranching enzyme cleaves "limit dextrins“.
Note the 2 activities of the debranching enzyme:
It transfers trisaccharide groups.
It cleaves the remaining single glucose units from the main chain.

32. 22.3 How Are Glycogen and Starch Catabolized in Animals ?
Figure 22.11(a)
The sites of hydrolysis of starch by α- and β-amylases are indicated.
α-amylase cleaves randomly but stops four residues from a branch point.
β-amylase cleaves maltose from non-reducing ends of starch.
Amylases can cleave only α (1-4) glycosidic bonds.

33. 22.3 How Are Glycogen and Starch Catabolized in Animals ?
Figure 22.12
Reactions of the debranching enzyme:
Transfers a group of three glucose residues from a limit branch to another branch. Then cleaves the α (1-6) bond of the residue left at the branch point.
Oligo(α1,4-α1,4)
glucanotransferase
activity

34. Metabolism of Tissue Glycogen is Regulated
Digestive breakdown is unregulated - nearly 100% of ingested food is absorbed and metabolized
Tissue glycogen (storage) is an important energy reservoir - its breakdown is carefully controlled.
Glycogen is stored as large cytosolic "granules".
Glycogen phosphorylase cleaves glucose from the nonreducing ends of glycogen molecules.
This is a phosphorolysis, not a hydrolysis, so phosphate is used rather than water.
Metabolic advantage: the product is a glucose-1-P which is a potential glycolysis substrate.

35. Metabolism of Tissue Glycogen is Regulated
ΔGo' = +3.1 kJ/mol
Figure The glycogen phosphorylase reaction. Phosphate is the attacking nucleophile, so this reaction is a phosphorolysis.

36. Connecting Glycogen and Glycolysis
Glucose-1-P from glycogen breakdown is converted to glucose-6-P by phosphoglucomutase. This reversible reaction proceeds through a bisphospho intermediate.
ΔGo' = +7.3 kJ/mol
Making glycogen from excess glucose-6-P: Glucose-6-P is converted to glucose-1-P. Glucose-1P then reacts with UTP forming UDP-glucose, a high energy carrier.

37. 22.4 How Is Glycogen Synthesized ?
UDP-glucose is one of the sugar nucleotides. Discovered by Luis Leloir in the 1950s, this is an “activated form of sugar”.

38. 22.4 How Is Glycogen Synthesized ?
Glucose units are activated for transfer by formation of sugar nucleotides
Glucose-6-P is the starting point and is converted to glucose-1-P then activated.
What are other examples of "activation“ ?
acetyl-CoA, biotin, THF (FH4).
Luis Leloir showed in the 1950s that glycogen synthesis depends on sugar nucleotides.
UDP-glucose pyrophosphorylase catalyzes a phosphoanhydride exchange (Figure 22.14)
driven by pyrophosphate hydrolysis.

39. UDP-Glucose Pyrophosphorylase
The mechanism of the UDP-glucose pyrophosphorylase reaction.
Attack at the α-phosphorus of UTP by a phosphate oxygen of glucose-1-P is followed by departure of the pyrophosphate anion. Subsequent hydrolysis of the PPi pulls the reaction to completion.
ΔGo' = ~0 kJ/mol

40. Glycogen Synthase Reaction
Figure Glycogen synthase catalyzes loss of UDP with formation of a carbocation which is attacked by a 4’ OH on a nonreducing end of glycogen. The enzyme requires a short primer, (4-8 residues).
ΔGo' = kJ/mol

41. Forms -(1 4) glycosidic bonds in glycogen
Glycogen Synthase Catalyzes Formation of α(1→4) Glycosidic Bonds in Glycogen
Forms -(1 4) glycosidic bonds in glycogen
De novo synthesis of glycogen is built on a protein, glycogenin, (a tyrosine glucosyltransferase).
The first glucose is linked to a tyrosine -OH on the protein.
A few more glucose residues are added to form a short primer, then glycogen synthase takes over.
Glycogen synthase transfers glucosyl units from UDP-glucose to C-4 hydroxyl at a nonreducing end of a glycogen strand.
Note the oxonium ion intermediate (Fig ).

42. 22.3 How Are Glycogen Synthesized in Animals (Anabolism) ?
Figure 22.11(b) The protein “Glycogenin” initiates de novo glycogen synthesis.
Existing glycogen molecules are increased in size by glycogen synthase and glycogen branching enzyme.

43. Glycogen Branching Reaction
Figure 22.16
Glycogen branching enzyme forms the α (1-6) branch points. (This enzyme is distinct from the catabolic debranching enzyme.)
Six- or seven-residue segments of a growing glycogen chain are transferred to the C-6 hydroxyl group of a glucose residue on the same or a nearby chain. This leaves 4 residues at the branch point to act as substrate for glycogen synthase.

44. 22.5 Control of Glycogen Metabolism
A highly regulated process, involving reciprocal control of glycogen phosphorylase and glycogen synthase
GP is allosterically activated by AMP & inhibited by ATP, glucose-6-P and caffeine (See Ch 15).
GS is stimulated by glucose-6-P.
Both enzymes are regulated by covalent modification – phosphorylation.
Both enzymes respond to hormonal control.

45. Glycogen Synthase is Regulated by Covalent Modification
Glycogen synthase exists in two distinct forms.
Active, dephosphorylated GS-I.
Less active, phosphorylated GS-D.
The phosphorylated form is allosterically activated by glucose-6-P.
At least 9 serine residues are phosphorylated.
Four different protein kinases are involved.
Dephosphorylation is carried out by phosphoprotein phosphatase-1 (PP1).
PP1 inactivates glycogen phosphorylase and activates glycogen synthase.

46. Glycogen Phosphorylase is Regulated by Covalent Modification
Glycogen phosphorylase exists in two forms.
Active, phosphorylated GP-P.
Less active, dephosphorylated GP.
The phosphorylated form favors the”R”state (most active). Glucose(-), Caffeine(-)
The dephosphoryled form favors the “T” state
(least active). AMP(+), ATP(-), Glucose-6-P(-)
Dephosphorylation is carried out by phosphoprotein phosphatase-1 (PP1).
The enzyme requires pyridoxal phosphate for activity.

47. Hormones Regulate Glycogen Synthesis and Degradation
Storage and utilization of tissue glycogen and other aspects of metabolism are regulated by hormones, including glucagon, epinephrine, and the glucocorticoids.
Glucagon (liver) and epinephrine (liver and muscle) stimulate glycogen breakdown.
Insulin is a response to increased blood glucose.
Insulin triggers glycogen synthesis when blood glucose rises.
Between meals, blood glucose is mg/dL.
Glucose rises to 150 m/dL after a meal and then returns to normal within 2-3 hours.

48. Glucagon and Epinephrine Stimulate Glycogen Breakdown and Inhibit Glycogen Synthesis
Glucagon and epinephrine stimulate glycogen breakdown – the opposite effect of insulin.
Glucagon (a 29-residue peptide) is also secreted by pancreas.
Glucagon acts in liver and adipose tissue only.
Epinephrine (adrenaline) is released from adrenal glands. Epinephrine is a catechol amine from Tyr.
Epinephrine acts on liver and muscles.
When either hormone binds to its receptor on the outside surface of the cell membrane, a phosphorylase cascade amplifies the signal.

49. Glucagon and Epinephrine Actions in Liver and Muscle
Figure Glucagon and epinephrine each activate glycogen breakdown and inhibit glycogen synthesis in liver and muscles, respectively.
In both tissues, binding of glucagon or epinephrine activates adenylyl cyclase, via a G-protein initiating the cascade.

50. Glucagon and Epinephrine Actions in Liver and Muscle
Figure In liver, glucagon inhibits glycolysis and stimulates gluconeogenesis. In muscles, epinephrine stimulates glycolysis to provide energy for contraction.

51. Epinephrine and Glucagon
The difference:
Both are glycogenolytic in liver, but for different reasons.
Epinephrine is the fight or flight hormone.
It rapidly mobilizes large amounts of energy.
Glucagon is for long-term maintenance of steady-state levels of glucose in the blood.
It activates glycogen breakdown.
It activates liver gluconeogenesis.

52. Hormones Regulate Glycogen Synthesis and Degradation
Insulin is secreted from the pancreas (to liver) in response to an increase in blood glucose.
Note that the portal vein is the only vein in the body that feeds an organ.
Insulin acts to lower blood glucose rapidly in several ways, stimulating glycogen synthesis and inhibiting glycogen breakdown.

53. Insulin Modulates the Action of Glycogen Synthase in Several Ways
Binding of insulin to plasma membrane receptors in the liver and muscles triggers protein kinase cascades that stimulate glycogen synthesis.
Insulin’s effect include stimulation of lipid synthesis, glycogen synthesis, protein synthesis, glycolysis, and active transport, and inhibition of gluconeogenesis and lipid breakdown.
Glucose uptake provides substrate for glycogen synthesis and glucose-6-P, which allosterically activates the otherwise inactive form of glycogen synthase.

54. Insulin Modulates the Action of Glycogen Synthase in Several Ways
Figure 22.17(a) Insulin triggers protein kinases that stimulate glycogen synthesis.
Insulin activates tyrosine kinase rather than a G-protein.

55. The Actions of Insulin on Metabolism
Figure 22.17(b) The metabolic effects of insulin are mediated through protein phosphorylation and second messenger modulation.

56. Carbohydrate Utilization in Exercise
(a) Contributions of the various energy sources to muscle activity during mild exercise. (b) Consumption of glycogen stores in fast-twitch muscles during light, moderate, and heavy exercise. (c) Rate of glycogen replenishment following exhaustive exercise.

57. 22.6 Can Glucose Provide Electrons for Biosynthesis ?
Cells are provided with a constant supply of NADPH for fatty acid synthesis by the pentose phosphate pathway.
Also called the hexose monophosphate shunt (HMS) and the phosphogluconate pathway.
This pathway also produces ribose-5-P.
This pathway consists of two oxidative processes (Part I) and then five non-oxidative steps (Part II).
It operates mostly in the cytosol of liver and adipose cells.
Part I is irreversible and Part II is reversible.

58. 22.6 Pentose Phosphate Pathway (Hexose Shunt or Phosphogluconate)
Part I
Oxidative steps.
Figure The pentose phosphate pathway. The numerals in the blue circles indicate the steps discussed in the text.

59. 22.6 Pentose Phosphate Pathway (Hexose Shunt or Phosphogluconate)
Figure 22.22
The pentose phosphate pathway.
Part II
Rearrangement of sugars.

60. The Oxidative Steps of the Pentose Phosphate Pathway
Glucose-6-P Dehydrogenase.
Irreversible 1st step - highly regulated!
Gluconolactonase.
The uncatalyzed reaction happens too.
6-Phosphogluconate Dehydrogenase.
An oxidative decarboxylation (in that order).
Note: ATP is not a participant in the HMS.

61. The Oxidative Steps of the Pentose Phosphate Pathway
Figure The glucose-6-phosphate dehydrogenase reaction is the committed step in the pentose phosphate pathway.

62. Figure 22.24 The Gluconolactonase Reaction
Figure The gluconolactonase reaction. The uncatalyzed reaction also occurs (spontaneous hydrolysis).

63. The Oxidative Steps of the Pentose Phosphate Pathway
Mn++
Figure The 6-phosphogluconate dehydrogenase reaction. The initial NADP+-dependent dehydrogenation yields a β-keto acid, 3-keto-6-phosphogluconate, which is very susceptible to decarboxyation (the second step). The resulting product, D-ribulose-5-P, is the substrate for the nonoxidative reactions of the pentose phosphate pathway.

64. The Nonoxidative Steps of the Pentose Phosphate Pathway
Five steps, but only 4 types of reaction...
Phosphopentose isomerase.
converts ketose to aldose.
Phosphopentose epimerase.
epimerizes at C-3.
Transketolase ( a TPP-dependent reaction).
transfer of two-carbon units.
Transaldolase (uses a Schiff base mechanism).
transfers a three-carbon unit.

65. The Nonoxidative Steps of the Pentose Phosphate Pathway
Figure The phosphopentose isomerase reaction converts a ketose to an aldose. The reaction involves an enediol intermediate.

66. The Nonoxidative Steps of the Pentose Phosphate Pathway
Figure The phosphopentose epimerase reaction interconverts ribulose-5-P and xylulose-5-phosphate. The mechanism involves an enediol intermediate and occurs with inversion at C-3.

67. The Nonoxidative Steps of the Pentose Phosphate Pathway
Uses TPP
Figure The transketolase reaction of step 6 in the pentose phosphate pathway. This is a two-carbon transfer reaction that requires thiamine pyrophosphate as a coenzyme. TPP chemistry was discussed in Chapter 19 (see the pyruvate dehydrogenase reaction).

68. The Nonoxidative Steps of the Pentose Phosphate Pathway
Uses
Lys
Figure The transaldolase reaction.
In this reaction, a 3-carbon unit is transferred, first to an active site lysine, and then to the acceptor molecule.

69. The Nonoxidative Steps of the Pentose Phosphate Pathway
Uses TPP
Figure The transketolase reaction of step 8 in the pentose phosphate pathway. This is another two-carbon transfer, and it also requires TPP as a coenzyme.

70. The Nonoxidative Steps of the Pentose Phosphate Pathway
Figure The mechanism of the TPP-dependent transketolase reaction. The group transferred is really an aldol. Despite this, the name “transketolase” persists.

71. TPP Dependent Transketolase
Figure 22.30
The mechanism of the TPP-dependent transketolase reaction. The group transferred is really an aldol. Despite this, the name “transketolase” persists.
Steps 6 & 8.

72. TPP Dependent Transketolase
Figure 22.32
The transaldolase mechanism involves attack on the substrate by an active-site lysine. Departure of erythrose-4-P leaves the reactive enamine, which attacks the aldehyde carbon of Gly-3-P.
Step 7.

73. Utilization of Glucose-6-P Depends on the Cell’s Need for ATP, NADPH, and Rib-5-P
Glucose can be a substrate either for glycolysis or for the pentose phosphate pathway.
The choice depends on the relative needs of the cell for biosynthesis and for energy from metabolism.
ATP can be made if G-6-P is sent to glycolysis
Or, if NADPH or ribose-5-P are needed for biosynthesis, G-6-P can be directed to the pentose phosphate pathway.
Depending on these relative needs, the reactions of glycolysis and the pentose phosphate pathway can be combined in four principal ways.

74. Four Ways to Combine the Reactions of Glycolysis and Pentose Phosphate
When both Ribose-5-P and NADPH are needed by the cell:
Enter at G-6-P. The first four reactions of the pentose phosphate pathway predominate.
NADPH is produced and ribose-5-P is the principal product of carbon metabolism.
2) When more Ribose-5-P than NADPH is needed by the cell:
Enter at F-6-P and use the nonoxidative steps in reverse to make ribose-5-P. Enter at G-6-P to make NADPH as needed and some R-5-P.

75. Four Ways to Combine the Reactions of Glycolysis and Pentose Phosphate
Case 1: Both ribose-5-P and NADPH are needed
Figure When biosynthetic demands dictate, the first four reactions of the pentose phosphate pathway predominate and the principal products are ribose-5-P and NADPH.

76. Four Ways to Combine the Reactions of Glycolysis and Pentose Phosphate
3) More NADPH than ribose-5-P is needed by the cell:
Enter at G-6-P. The excess ribose-5-P produced in the HMS continues on to produce glycolytic intermediates.
4) Both NADPH and ATP are needed by the cell, but ribose-5-P is not.
This can be done by recycling ribose-5-P, as in case 3 above. Fructose-6-P and glyceraldehyde-3-P made in this way proceed through glycolysis to produce ATP and pyruvate, and pyruvate continues through the TCA cycle to make more ATP.

77. End Chapter 22 Gluconeogenesis, Glycogen Metabolism, and the Pentose Phosphate Pathway