Download Figure 17-3 Degradation of glucose via the glycolytic pathway.

A stripped down Figure of Glycolysis
Fates of pyruvate
Other sugars (than glucose)
Energetics of glycolysis
Gluconeogenesis
Regulation of
glycolysis/gluconeogenesis
Fates of Pyruvate
Stage 2: x2
1 oxidation
2 substrate
level phos.
11
10
11a. Anaerobic Glycolysis – Reduction of Pyr to Lactate: Lactate DH
pyruvate + NADH + H+
lactate + NAD+
- Pyruvate is reduced to lactate to recover NAD+ needed for glycolysis
- This is a reversible reaction – several isoenzyme forms of LDH
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Figure 17-24 Reaction mechanism of lactate dehydrogenase.
Reduction of pyruvate to lactate: lactate dehydrogenase
pyruvate + NADH + H+
lactate + NAD+
•reduced at expense of electrons originally donated by 3-phosphoglyceraldehyde, carried
by NADH. Thus, no net oxidation occurs in glycolysis = fermentation; another organic
serving as electron acceptor.
•lactate, end-product under anaerobic conditions, diffuses thru cell membrane as waste
into blood - salvaged by liver and rebuilt to form glucose (gluconeogenesis). This occurs
in skeletal muscle during periods of strenuous exertion: Cells use O2 faster than can be
supplied by circulatory system; cells begin to function anaerobically, reducing pyruvate to
lactate rather than further oxidation. Causes soreness due to decreased pH.
Lactate fermentation also important commercially since bacteria capable are
responsible for production of cheeses, yogurts, and other foods obtained by
fermentation of lactose of milk.
Stage 2: x2
1 oxidation
2 substrate
level phos.
11
11b. Anaerobic Glycolysis – Reduction of Pyr to Ethanol: Pyr Carb. + ADH (in yeast,
not humans)
pyruvate Æ acetaldehyde
acetaldehyde + NADH + H+ Æ ethanol + NAD+
- Pyruvate is decarboxylated to form CO2 + acetaldehyde (TPP)
- Acetaldehyde is reduced to ethanol to recover NAD+ needed for glycolysis
Figure 17-25 The two reactions of alcoholic fermentation.
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Figure 17-26 Thiamine pyrophosphate.
Thiazole as an
electron sink
+
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Figure 17-27 Reaction mechanism of pyruvate
decarboxylase.
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Figure 17-30
The reaction mechanism of alcohol dehydrogenase
involves direct hydride transfer of the pro-R hydrogen of NADH to the re
face of acetaldehyde.
Reduction of pyruvate to ethanol: alcohol dehydrogenase
pyruvate + NADH + H+
ethanol + NAD+
In alcoholic fermentation, pyruvate is first decarboxylated to
acetaldehyde that then serves as electron acceptor, giving rise to
ethanol.
Commercially important in baking and brewing industries Other less common fermentation processes (bacteria) yield
propionic acid (swiss cheese); butyrate (rancid butter); acetone,
isopropanol.
Biochemical Regulation of
Glycolysis
Energetics of Glycolysis
The glycolytic pathway is
regulated at all three
irreversible steps. The
regulation is MOSTLY of a
straight forward biochemical
nature. We might consider it
a sort of “primitive”
regulation. The complete
discussion, however, will
require an integration of
systems as part of a
hormonal response. (More
later).
Fig. 17-33 PFK activity vs. [F-6-P].
The PFK
tetramer (only
dimer shown
here) is
allosterically
regulated. PFK
is in an R to T
equilibrium.
ATP stabilizes T
state and ADP
or AMP the R
state. Other
effectors include
F2,6BP and
citrate.
ATP
F6P
Regulator site:
ATP =I
ADP/AMP=Stim
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Figure 18-23 Comparison of the relative enzymatic activities
of hexokinase and glucokinase over the physiological blood
glucose range.
Liver contains many insulin
Independent GluT2
transporters. When blood
glucose is high, and insulin
is signaling glucose
reduction, sugar enters the
liver and glucokinase
generates G6P which
stimulates glycogen
synthesis
Other sugars feed into glycolysis
Lactase expression can be
repressed, depending on
environment. This is basis
for lactose intolerance.
Galactose
Galactosemia
Gluconeogenesis
1. What is the role of this pathway?
Convert 3-C lactate or pyruvate into 6-C glucose
2. What is the difference between glycolysis and gluconeogenesis?
Need to by-pass the three irreversible steps
3. Where is the pathway located?
Uses enzymes located in the cytosol and mito
The ability to synthesize glucose is important to mammals since certain
tissues, particularly brain and RBC, are almost solely dependent on
glucose as an energy source. In normal humans, under fasting conditions,
80% of glucose is consumed by brain. The glycogen reservoir in liver has
only 1/2 day supply for the brain. In periods of dietary glucose deprivation,
we must be able to make glucose from other sources.
Figure 23-9
The Cori cycle.
G-6-P
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G-6-P
Gluconeogenesis/
glycolysis
Figure 23-7
Pathways of
gluconeogenesis
and glycolysis.
3
HK
2
PFK
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Note that the ∆G
values are given in
the direction of
gluconeogenesis.
1
PK
Bypassing the PK step
The energy released from ATP hydrolysis is
“stored” in carboxylated intermediate. CO2 release
will help drive the next step.
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By-Passing “PK”: Two-phase reaction mechanism of
pyruvate carboxylase.
By-Passing “PK”: Conversion of pyruvate to oxaloacetate
and then to phosphoenolpyruvate.
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Step 2
GTP
The PK bypass uses OAA,
which must be generated in
the mitochondria. OAA
cannot be transported out so
it must be converted to PEP
or malate (or Asp but lets
ignore that).
Gluconeogenesis requires
NADH so reducing
equivalents must be
generated for that purpose;
cytoplasmic [NADH]/[NAD]
is very low.
Pathways converting lactate, pyruvate, and citric acid cycle
intermediates to oxaloacetate can all be used to generate glucose.
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The carbon skeletons
of certain amino acids
are readily made into
OAA (glycogenic
amino acids) and so
protein can be
sacrificed to make
glucose.
TCA
Regulation of glycolysis and gluconeogenesis
It is clear that these two paths must be coordinately regulated to
avoid wasteful futile cycles. When glycolysis is “on”,
gluconeogenesis should be “off”
Important regulatory enzymes of opposing pathways are located at
those steps where the two pathways are not identical.
SUMMARY: Pathways from glucose to pyruvate and pyruvate to glucose
are regulated by both the level of respiratory fuels and energy charge.
Thus, whenever cell has ample ATP and respiratory fuels such as acetylCoA, citrate, or NADH glycolysis is inhibited and gluconeogenesis
promoted.
These enzymes are
in different cell
compartments
3
3
2
2
In liver, PK
inhibited by
phosphorylation
1
1
Role of F2,6 BP in the Interconversion
of F-1,6-BP to F-6-P.
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Figure 18-24 Formation and degradation of β-D-fructose2,6-bisphosphate is catalyzed by PFK-2 and FBPase-2.