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Chapter 12:
Gluconeogenesis, Pentose Phosphate Pathway, &
Glycogen Metabolism
Glucose catabolism for the
production of energy
requires a source of Glc.
glycogen
Polysaccharides are
degraded and the resulting
Glc is stored as glycogen in
muscle and liver.
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.
PPP
Pathway
Glycolysis Net Reaction:
Glucose + 2 ADP + 2 NAD+ + 2 Pi
 2 Pyruvate + 2 ATP + 2 NADH + 2 H+ + 2 H2O
**Gluconeogenesis Net Reaction:**
2 Pyruvate + 4 ATP + 2 GTP + 2 NADH + 2 H+ + 6 H2O
 Glucose + 4 ADP + 2 GDP+ 2 NAD+ + 6 Pi
#1
#3
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
Gluconeogenesis
6 ATP needed total
4 needed to overcome
barrier of production of 2
mol of PEP
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)
Gluconeogenesis
No ATP needed since
Fru-1,6-bisP not high
energy intermediate
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)
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
Most cases Glc-6-P is end product---used in other pathways
Get to brain
And muscle
(glycogen syn)
Gluconeogenesis: Precursors
Major precurser in mammals: Lactate and Amino Acids,
Since the body does not transfer pyruvate
Lactate
Cori cycle
Amino Acids
Pyruvate in tissues must go to liver
First converted to alanine
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)
Gluconeogenesis
Gluconeogenesis
-glucose biosynthesis found in all
organisms
Some tissues require glucose
-brain, muscles
After 16-24 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.
Gluconeogenesis: Regulation
Low [Glc]:
glucagon
increases protein
kinase A (activates
Fru-2,6-bisP
phosphatase)
lowering [Fru-2,6bisP].
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
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
Regulation of Pyruvate Kinase
+ F 1,6 BP
Allosteric (feed-forward) activation
Fructose-1,6-bisphosphate
-allosterically activates
-produced in step three
-links control steps together
High blood [Glc]
Inactivation by covalent modification
-blood [Glc] drops, glucagon released
-liver protein kinase A (PKA) turned on
-PKA phosphorylates pyruvate kinase
Allosteric inhibition by ATP
-product of pathway and CAC
Low blood [Glc]
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
Dec glycolysis
Inc glc syn
Figure 11-17
PFK-1 and
pyruvate kinase
Stimulate glycogen breakdown
Pentose Phosphate Pathway
glycogen
The pentose phosphate pathway (PPP)
is the source of ribose (deoxyribose),
and NADPH.
NADPH is required for biosynthesis.
Shunt
PPP
Pentose Phosphate Pathway
Shunt
Synthesize 3 pentose phosphates
Ribulose 5-P
Xylulose 5-P
Ribose 5-P
And NADPH
(DNA/RNA)
(for the reduction of RNA to DNA)
Or
NADPH and glycolytic intermediates
Rapidly dividing cells need lots of NADPH and DNA
High PPP activity
The Oxidation Stage of PPP
Major reg step
Allosteric
- NADPH
Loss of Carbon
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
The Non-Oxidation Stage of PPP
Convert 5C sugars into glycolytic intermediates
Can be used in glycolysis of Gluconeogenesis
Pentose Phosphate Pathway
Thru PPP
3 Glc-6-P + 6 NADP+ + 3 H2O 
2 Fru-6-P + G3P + 6 NADPH + 3 CO2
Recycle 6C sugar
Allow sub regeneration
via PPP and glyconeogenesis
6 ribulose 5-P
Can be metabolized in
Glycolysis or Glcneogenesis
6 Glc-6-P + 12 NADP+ 
5 Glc-6-P + 12 NADPH + 6 CO2 + Pi
5 Glc 5-P
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
Glycogen Metabolism
Synthesis:
Different enzymes for
syn and degradation
Driven by PPi hydrolysis
Major regulatory step
(hormonally regulated)
Key regulation
by phosphorylation
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)
Degradation:
Two subunits, two catalytic sites, allosteric sites.
AMP- activator; ATP & Glc-6-P – inhibitor.
Phosphorolysis rxn.
Generates phosph-sugar not free glc
Phosphorylation: active (phosphorylase a).
Dephosphorylated: less active (phosphorylase b).
Primary regulation
Branching inc speed of
syn and degradation
phosphorolytic
Sequential removal of Glc
From non-reducing end
Reg by ATP and G-6-P
Primarily by phosphorylation
Stops 4 Glc from branch pt
hydrolytic
Energy yield from glycogen
Higher than from glc
Regulation of Glycogen Metabolism
Hormonal Regulation:
Fed state
fasting
phosphatase
Via cAMP
Via PIP3
Decrease
glycolysis
Insulin: secreted by pancreas when Glc high
inc rate of transport into cell and glycogen syn
Glucagon: secreted when Glc low
GLUT4
Epi: released by adrenal gland in response to neural signal (flight or flight)
Sudden energy response
Intracellular Regulation
of Glycogen Metabolism by
Interconvertible Enzymes:
Low glc activate kinase and breakdown
AMP
phosphodiesterase
cAMP
Low [Glc]
Simultaneous
effect
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
Dec glycolysis
Inc glc syn
Figure 11-17
PFK-1 and
pyruvate kinase
Stimulate glycogen breakdown
High [Glc]