1. Chapter 12: Gluconeogenesis, Pentose Phosphate Pathway, &
Glycogen Metabolism
Glucose catabolism for the production of energy requires a source of Glc.
Polysaccharides are degraded and the resulting Glc is stored as glycogen in muscle and liver.
glycogen
PPP
Glc also syn from pyruvate
(lactate and amino acids)
Liver/kidney
Glc needed in brain/muscle
The pentose phosphate pathway (PPP) is the source of ribose (deoxyribose), and NADPH.
NADPH is required for biosynthesis.

2. #1 #3 #10 Pathway Glycolysis Net Reaction:
Glucose + 2 ADP + 2 NAD+ + 2 Pi
 2 Pyruvate + 2 ATP + 2 NADH + 2 H+ + 2 H2O #3
**Gluconeogenesis Net Reaction:**
2 Pyruvate + 4 ATP + 2 GTP + 2 NADH + 2 H+ + 6 H2O
 Glucose + 4 ADP + 2 GDP+ 2 NAD+ + 6 Pi
Gluconeogenesis
- glycolysis going backwards
- 3 places differ- control points in glycolysis
- 4 new enzymes (eukaryotes)
- importance of near equilibrium reactions
- ATP energy, NADH reducing equivalents consumed
#10

3. Gluconeogenesis 6 ATP needed total
4 needed to overcome barrier of production of 2 mol of PEP

4. Gluconeogenesis: The Irreversible Steps
Pyruvate  PEP; reversing the pyruvate kinase step of glycolysis.
4 subunits
Biotin
Allosteric
+ acetyl CoA
Indicates CAC
Backed-up
No allosteric reg
Hormonal induction
Transcriptional
regulation
+ glucagon (fasting)
- Insulin (fed state)

5. Gluconeogenesis No ATP needed since
Fru-1,6-bisP not high energy intermediate

6. Fru-1,6-biP  Fru-6-P; reversing the PFK-1 step of glycolysis.
Large – DG and irreversible
Allosteric modulation
- AMP
- 2,6-Fru bisP (opposing effect in glycolysis)

7. Glc-6  Glc; reversing the Glc hexokinase step of glycolysis.
Irreversible
Allosteric modulation
- AMP
Enzyme found only in liver, kidneys, small intestine.
Bound to ER lumen…leads to release of Glc into bldstream
Get to brain
And muscle
Most cases Glc-6-P is end product---used in other pathways (glycogen syn)

8. Gluconeogenesis: Precursors
Major precurser in mammals: Lactate and Amino Acids,
Since the body does not transfer pyruvate
Lactate
Amino Acids
Pyruvate in tissues must go to liver
First converted to alanine
Cori cycle
Major source of C for Glc syn during fasting
Active muscle-- lactate
Amino arise from muscle protein breakdown
Lactate to pyruvate in liver
Provide temporary and readily available supply of Glc to muscle (exercise)

9. Gluconeogenesis Gluconeogenesis
-glucose biosynthesis found in all organisms
Some tissues require glucose
-brain, muscles
After hrs, glucose and glycogen reserves depleted
Some tissues synthesis glucose from non-carbohydrate precursor
-liver, kidney
-lactate, alanine
Easiest to start with pyruvate
-converted from lactate or a.a.

10. Gluconeogenesis: Regulation
Low [Glc]: glucagon increases protein kinase A (activates Fru-2,6-bisP phosphatase) lowering [Fru-2,6-bisP].
Activate Glc syn
and
Loss of glycolysis stim
neg reg pyruvate kinase
Substrate Cycle
Dec the net flux of a pathway
But allows a point for reg flux
Modulate one enzyme effect 2 opposing pathways
Inhibit PFK-1 ….. stim Glc syn

11. Regulation of Phosphofructokinase-1
Large oligomeric enzyme
bacteria/mammals - tetramer
yeast - octamer
ATP - product of pathway
- allosteric inhibitor
AMP - allosteric activator
- relieves inhibition by ATP
Citrate - feedback inhibitor
- regulates supply of pyruvate
- links Glycolysis and CAC
Fru-2,6-bisphosphate
- strong activator
- produced by PFK-2 when excess
fru-6-phosphate
- indirect means of substrate
stimulation or feed forward
activation

12. Regulation of Pyruvate Kinase
+ F 1,6 BP
Inactivation by covalent modification
-blood [Glc] drops, glucagon released
-liver protein kinase A (PKA) turned on
-PKA phosphorylates pyruvate kinase
Allosteric (feed-forward) activation
Fructose-1,6-bisphosphate
-allosterically activates
-produced in step three
-links control steps together
Allosteric inhibition by ATP
-product of pathway and CAC
High blood [Glc]
Low blood [Glc]

13. Regulation of Phosphofructokinase-1
Produced in pancreas in response to low [Glc]
Dual activities of PFK-2 reg
steady-state conc of Fru-2,6-bisP
Increased glycolysis
Fruc-6P inc….inc F-2,6-bisP
Stim PFK-1
Dec F-2,6-bisP
PFK-1 less active…..dec glycolysis
Activate Protein Kinase A
PFK-1 and
pyruvate kinase
Dec glycolysis
Inc glc syn
Stimulate glycogen breakdown
Figure 11-17

14. Pentose Phosphate Pathway
Shunt
glycogen
PPP
The pentose phosphate pathway (PPP) is the source of ribose (deoxyribose), and NADPH.
NADPH is required for biosynthesis.

15. Pentose Phosphate Pathway
Shunt
Synthesize 3 pentose phosphates
Ribulose 5-P
Xylulose 5-P
Ribose 5-P (DNA/RNA)
And NADPH
(for the reduction of RNA to DNA) Or
NADPH and glycolytic intermediates
Rapidly dividing cells need lots of NADPH and DNA
High PPP activity

16. The Oxidation Stage of PPP
Allosteric
- NADPH
Major reg step
Loss of Carbon

17. The Non-Oxidation Stage of PPP
All equilibruim rxns
When cells need lot of NADPH and nucleotides
- ribulose 5-phosphate  ribose 5-phosphate
- end of pathway

18. The Non-Oxidation Stage of PPP
Convert 5C sugars into glycolytic intermediates
Can be used in glycolysis of Gluconeogenesis

19. Pentose Phosphate Pathway
Thru PPP
3 Glc-6-P + 6 NADP+ + 3 H2O 
2 Fru-6-P + G3P + 6 NADPH + 3 CO2
Allow sub regeneration
via PPP and glyconeogenesis
Recycle 6C sugar
6 ribulose 5-P
5 Glc 5-P
6 Glc-6-P + 12 NADP+ 
5 Glc-6-P + 12 NADPH + 6 CO2 + Pi
Can be metabolized in
Glycolysis or Glcneogenesis

20. Glycogen Metabolism
Glycogen is the storage form of Glc found in muscles and liver (Plants: stored as Starch)
Glycogen complex: single glycogenin molecule (Tyr -OH) and >50,000 glucose residues
Stores of Glc in time of plenty and supplies it in times of need
Muscle: fuel for contraction
Liver: produce Glc…released to Bldstream to other tissues
All regulated by hormones: Glucagon, Epinephrin and Insulin

21. Glycogen Metabolism Synthesis: Different enzymes for
syn and degradation
Driven by PPi hydrolysis
Major regulatory step

22. UDP-Glc synthases in protists, animals, and fungi.
Key regulation
by phosphorylation
(hormonally regulated)
Pre-existing
Glycogenin primer
UDP-Glc synthases in protists, animals, and fungi.
ADP-Glc synthase in plants.
Primer of 4 to 8 Glc on a Tyr (-OH) of glycogenin. 1st Glc from UDP-Glc
via Glc transferase. Remaining Glc’s tranferred by glycogenin.
Amylo-(1,4 1,6)-transglycolase catalyzes the branch point. (Alpha 1-6 link)

23. Degradation: Primary regulation
Two subunits, two catalytic sites, allosteric sites.
AMP- activator; ATP & Glc-6-P – inhibitor.
Phosphorylation: active (phosphorylase a).
Dephosphorylated: less active (phosphorylase b).
Phosphorolysis rxn.
Generates phosph-sugar not free glc
Primary regulation

24. Energy yield from glycogen Higher than from glc
Branching inc speed of
syn and degradation
phosphorolytic
Reg by ATP and G-6-P
Sequential removal of Glc
From non-reducing end
Stops 4 Glc from branch pt
Primarily by phosphorylation
hydrolytic
Energy yield from glycogen
Higher than from glc

25. Regulation of Glycogen Metabolism
Hormonal Regulation:
Fed state
fasting
Via cAMP
phosphatase
Decrease
glycolysis
Via PIP3
Insulin: secreted by pancreas when Glc high inc rate of transport into cell and glycogen syn
GLUT4
Glucagon: secreted when Glc low
Epi: released by adrenal gland in response to neural signal (flight or flight)
Sudden energy response

26. Intracellular Regulation of Glycogen Metabolism by
Interconvertible Enzymes:
Low glc activate kinase and breakdown
AMP
phosphodiesterase
cAMP
Simultaneous
effect
Low [Glc]

27. Regulation of Phosphofructokinase-1
Produced in pancreas in response to low [Glc]
Dual activities of PFK-2 reg
steady-state conc of Fru-2,6-bisP
Increased glycolysis
Fruc-6P inc….inc F-2,6-bisP
Stim PFK-1
Dec F-2,6-bisP
PFK-1 less active…..dec glycolysis
Activate Protein Kinase A
PFK-1 and
pyruvate kinase
Dec glycolysis
Inc glc syn
Stimulate glycogen breakdown
Figure 11-17

28. High [Glc]