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1. CARBOHYDRATE METABOLISM
Ravish Yadav

2. Major Pathways
1. Glycolysis
2. Citric acid cycle
3. Gluconeogenesis
4. Glycogen metabolism
(a) Glycogenesis (b) Glycogenolysis
2

3. 3
Fate of glucose in the liver
GLUT2
Glucose
Glucose
Glucose-6-P
Glucokinase
Glycogen
synthesis
Pentose
phosphate
Glycolysis

4. 4
Fate of glucose in muscle
GLUT4
Glucose Glucose
Glucose-6-P
Hexokinase
Glycogen
synthesis
Glycolysis
Insulin
+

5. 5
Fate of glucose in adipocytes
GLUT4
Glucose Glucose
Insulin
+
Glucose-6-P
Hexokinase
LPL
Insulin+
Glycerol-3-P
Triglycerides
Fatty
acids
Insulin
-
Lipoproteins

6. glucose metabolism Summary
6
Glucose
Glycolysis
Cytoplasm
Pyruvic acid
Electrons carried in NADH
Krebs
Cycle
Electrons carried
in NADH and
FADH2
Electron
Transport Chain
Mitochondrion
Mitochondrion

7. Metabolism – the chemical
changes that take place in a cell that
produce energy and basic materials
needed for important life processes
-millions of cells
-Multiple organs (liver, adipose, heart, brain)
-Thousands of enzymes
-Various conditions (fed, fasted, exercise,
stress)

8. Glucose
Glucose-6-P
Pyruvate
Hexokinase
Pentose
Phosphate
Shunt
glycolysis
Carbohydrates
Serve as primary source of energy in the cell
Central to all metabolic processes
Glc-1- phosphate
glycogen
Cytosol - anaerobic

9. Pyruvate
cytosol
Aceytl CoA
mitochondria
(aerobic)
Krebs
cycle
Reducing
equivalents
Oxidative
Phosphorylatio
(ATP)
AMINO
ACIDS
FATTY ACIDS

10. No mitochondria
Glucose
Glucose
Glucose
The Full
Monty
Glucose
Glycogen
Lactate

11. Fasted State
Glucose
Glucose-6-P
Pyruvate
Hexokinase
Pentose
Phosphate
Shunt
glycolysis
Glc-1- phosphate
glycogen
Need 13.8 kJ/mol
ATP = -30 kJ/mol
-16.7 kJ/mol
GNG
G-6-Pase

12. Controlling Metabolic Flux
1. Control enzyme levels
2. Control of enzyme activity (activation or inhibition)

13. Control of enzyme activity
Rate limiting step

14. Glycogen synthase
(active)
OHP
Glycogen synthase
(inactive)
Glycogen formation
Glycogen synthase kinase
(active)
OH
IR
insulin
P
P
Protein Kinase B
(active)
Protein Kinase B
(inactive)
OH
PGlycogen synthase kinase
(inactive)

15. Controlling Metabolic Flux
1. Control enzyme levels
2. Control of enzyme activity (activation or inhibition)
3. Compartamentalization
Fatty acid oxidation occurs in mitochondrial matrix
Fatty acid synthesis occurs in endoplasmic reticulum membrane
exposed to the cytoplasm of the cell.
4. Hormonal control

16. I. Glycolysis (Embden Meyerhof
Pathway):
A. Definition:
1. Glycolysis means oxidation of glucose to give pyruvate (in the
presence of oxygen) or lactate (in the absence of oxygen).
B. Site:
cytoplasm of all tissue cells, but it is of physiological importance in:
1. Tissues with no mitochondria: mature RBCs, cornea and lens.
2. Tissues with few mitochondria: Testis, leucocytes, medulla of the
kidney, retina, skin and gastrointestinal tract.
3. Tissues undergo frequent oxygen lack: skeletal muscles especially
during exercise.
16

17. C. Steps:
Stages of glycolysis
1. Stage one (the energy requiring stage):
a) One molecule of glucose is converted into two molecules of
glycerosldhyde-3-phosphate.
b) These steps requires 2 molecules of ATP (energy loss)
2. Stage two (the energy producing stage(:
a) The 2 molecules of glyceroaldehyde-3-phosphate are converted into
pyruvate (aerobic glycolysis) or lactate (anaerobic glycolysis(.
b) These steps produce ATP molecules (energy production).
17

18. Energy Investment Phase (steps 1-5)
18

19. Energy-Payoff Phase (Steps 6-10) 19

20. Energy production of glycolysis:
Net energyATP utilizedATP produced
2 ATP2ATP
From glucose to
glucose -6-p.
From fructose -6-p to
fructose 1,6 p.
4 ATP
(Substrate level
phosphorylation)
2ATP from 1,3 DPG.
2ATP from
phosphoenol
pyruvate
In absence of oxygen
(anaerobic
glycolysis)
6 ATP
Or
8 ATP
2ATP
-From glucose to
glucose -6-p.
From fructose -6-p to
fructose 1,6 p.
4 ATP
(substrate level
phosphorylation)
2ATP from 1,3 BPG.
2ATP from
phosphoenol
pyruvate.
In presence of
oxygen (aerobic
glycolysis)
+ 4ATP or 6ATP
(from oxidation of 2
NADH + H in
mitochondria).
20

21. E. oxidation of extramitochondrial NADH+H+:
1. cytoplasmic NADH+H+ cannot penetrate
mitochondrial membrane, however, it can be used to
produce energy (4 or 6 ATP) by respiratory
chain phosphorylation in the mitochondria.
2. This can be done by using special carriers for
hydrogen of NADH+H+
These carriers are either
dihydroxyacetone phosphate (Glycerophosphate
shuttle) or
oxaloacetate (aspartate malate shuttle).
21

22. a) Glycerophosphate shuttle:
1) It is important in certain muscle and nerve cells.
2) The final energy produced is 4 ATP.
3) Mechanism:
- The coenzyme of cytoplasmic glycerol-3- phosphate dehydrogenase
is NAD+.
- The coenzyme of mitochodrial glycerol-3-phosphate dehydogenase is
FAD.
- Oxidation of FADH, in respiratory chain gives 2 ATP.
As glycolysis gives 2 cytoplasmic NADH + H+  2 mitochondrial FADH, 2
x 2 ATP  = 4 ATP.
b) Malate – aspartate shuttle:
1) It is important in other tissues patriculary liver and heart.
2) The final energy produced is 6 ATP.
22

23. Differences between aerobic and
anaerobic glycolysis:
AnaerobicAerobic
LactatePyruvate1. End product
2 ATP6 or 8 ATP2 .energy
Through Lactate
formation
Through respiration
chain in mitochondria
3. Regeneration of
NAD+
Not available as lactate
is cytoplasmic substrate
Available and 2 Pyruvate
can oxidize to give 30
ATP
4. Availability to TCA in
mitochondria
23

24. Importance of lactate production in anerobic
glycolysis:
1. In absence of oxygen, lactate is the end product of glycolysis:
2. In absence of oxygen, NADH + H+ is not oxidized by the
respiratory chain.
3. The conversion of pyruvate to lactate is the mechanism for
regeneration of NAD+.
4. This helps continuity of glycolysis, as the generated NAD+ will be
used once more for oxidation of another glucose molecule.
Glucose  Pyruvate  Lactate
24

25. Substrate level phosphorylation:
This means phosphorylation of ADP to ATP at the reaction itself .in
glycolysis there are 2 examples:
- 1.3 Bisphosphoglycerate + ADP 3 Phosphoglycerate + ATP
- Phospho-enol pyruvate + ADP Enolpyruvate + ATP
I. Special features of glycolysis in RBCs:
1. Mature RBCs contain no mitochondria, thus:
a) They depend only upon glycolysis for energy production (=2 ATP).
b) Lactate is always the end product.
2. Glucose uptake by RBCs is independent on insulin hormone.
3. Reduction of met-hemoglobin: Glycolysis produces NADH+H+, which
used for reduction of met-hemoglobin in red cells.
25

26. Biological importance (functions) of glycolysis:
1. Energy production:
a) anaerobic glycolysis gives 2 ATP.
b) aerobic glycolysis gives 8 ATP.
2. Oxygenation of tissues:
Through formation of 2,3 bisphosphoglycerate, which decreases the
affinity of Hemoglobin to O2.
3. Provides important intermediates:
a) Dihydroxyacetone phosphate: can give glycerol-3phosphate, which is
used for synthesis of triacylglycerols and phospholipids (lipogenesis).
b) 3 Phosphoglycerate: which can be used for synthesis of amino acid
serine.
c) Pyruvate: which can be used in synthesis of amino acid alanine.
4. Aerobic glycolysis provides the mitochondria with pyruvate, which gives
acetyl CoA Krebs' cycle.
26

27. Reversibility of glycolysis (Gluconeogenesis):
1. Reversible reaction means that the same enzyme can catalyzes the
reaction in both directions.
2. all reactions of glycolysis -except 3- are reversible.
3. The 3 irreversible reactions (those catalyzed by kinase enzymes) can be
reversed by using other enzymes.
Glucose-6-p  Glucose
F1, 6 Bisphosphate  Fructose-6-p
Pyruvate  Phosphoenol pyruvate
4. During fasting, glycolysis is reversed for synthesis of glucose from non-
carbohydrate sources e.g. lactate. This mechanism is called:
gluconeogenesis.
27

28. • As pyruvate enters the mitochondrion, a
multienzyme complex modifies pyruvate to
acetyl CoA which enters the Krebs cycle in the
matrix.
– A carboxyl group is removed as CO2.
– A pair of electrons is transferred from the
remaining two-carbon fragment to NAD+ to
form NADH.
– The oxidized
fragment, acetate,
combines with
coenzyme A to
form acetyl CoA.
28

29. Kreb Cycle
29

30. Electron Transport Chain
30

31. Total energy yield
• Glycolysis 2 ATP
• Krebs Cycle 2 ATP
• ETC  32 ATP
• Total 36 ATP
31

32. 32
Overview of glucose metabolic pathways
Glycolysis:
from G6P to pyruvate
Gluconeogenesis:
from oxaloacetate to G6P
Glycogen synthesis:
from G6P to glycogen
Glycogenolysis:
from glycogen to G6P
TCA cycle
The pathways must be carefully
regulated to keep pathways going in
opposite directions from proceeding
simultaneously.

33. 33
Regulation of glycolysis
Glycolytic flux is controlled by need for ATP and/or for intermediates formed
by the pathway (e.g., for fatty acid synthesis).
Control occurs at sites of irreversible reactions
Phosphofructokinase- major control point; first enzyme “unique” to
glycolysis
Hexokinase or glucokinase
Pyruvate kinase
Phosphofructokinase responds to changes in:
Energy state of the cell (high ATP levels inhibit)
H+ concentration (high lactate levels inhibit)
Availability of alternate fuels such as fatty acids, ketone bodies (high
citrate levels inhibit)
Insulin/glucagon ratio in blood (high fructose 2,6-bisphosphate levels
activate)

34. 34
Control points in glycolysis
hexokinaseGlucose-6-P -
*

35. 35
Why is phosphofructokinase, rather
than hexokinase, the key control point
of glycolysis?
Because glucose-6-phosphate is not only an intermediate in glycolysis. It
is also involved in glycogen synthesis and the pentose phosphate
pathway.
PFK catalyzes the first unique and irreversible reaction in glycolysis.

36. 36
Phosphofructokinase (PFK-1) as a regulator
of glycolysis
fructose-6-phosphate fructose-1,6-bisphosphate
PFK-1
PFK allosterically inhibited by:
High ATP lower affinity for fructose-
6-phosphate by binding to a regulatory
site distinct from catalytic site.
High H+ reduced activity to prevent
excessive lactic acid formation and drop
in blood pH (acidosis).
Citrate prevents glycolysis by
accumulation of this citric acid cycle
intermediate to signal ample
biosynthetic precursors and availability
of fatty acids or ketone bodies for
oxidation.

37. 37
Phosphofructokinase (PFK-1) as a
regulator of glycolysis
PFK-1 activated by:
Fructose-2,6-bisphosphate (F-2,6-P2)
F-6-P
F-1,6-P2
F-2,6-P2
glycolysis
+
PFK-2
PFK-1
Activates PFK-1 by increasing its affinity
for fructose-6-phosphate and
diminishing the inhibitory effect of ATP.
F-2,6-P2

38. 38
Phosphofructokinase-2 (PFK-2) is also a
phosphatase (bifunctional enzyme)
Bifunctional enzyme has two activities:
6-phosphofructo-2-kinase activity, decreased by phosphorylation
Fructose-2,6-bisphosphatase activity, increased by phosphorylation
fructose-6-phosphate fructose-2,6-bisphosphate
phosphatase
kinase
ATP ADP
Pi

39. 39
Hormonal control of F-2,6-P2 levels and glycolysis
Hormonal regulation of
bifunctional enzyme
Glucagon (liver) or
epinephrine (muscle) increase
cAMP levels, activate cAMP-
dependent protein kinase. In
liver, this leads to decreased
F-2,6-P and inhibits glycolysis.
The effect is opposite in
muscle; epinephrine
stimulates glycolysis.
Insulin decreases cAMP,
increases F-2,6-P stimulates
glycolysis. Phosphorylation of PFK2 by protein kinase
activates its phosphatase activity on F2,6P in liver.

40. Glycogen Metabolism
PPi
UTP
UDP
Glycogen (Glucose)n+1
UDP-Glucose
Glucose-1-P
Pi
Glucose-6-P
2 Pi
Glycogen
(Glucose)n
Glycogen
(Glucose)n
Glycogen
Synthase
Glycogen
Phosphorylase
Phosphoglucomutase
UDP-Glucose
Pyrophosphorylase
Pyrophosphatase
40

41. Glycogenesis:
• Glycogenesis is the formation of glycogen from glucose.
Glycogen is synthesized depending on the demand for
glucose and ATP (energy). If both are present in relatively
high amounts, then the excess of insulin promotes the
glucose conversion into glycogen for storage in liver and
muscle cells.
• In the synthesis of glycogen, one ATP is required per glucose
incorporated into the polymeric branched structure of
glycogen. actually, glucose-6-phosphate is the cross-roads
compound. Glucose-6-phosphate is synthesized directly
from glucose or as the end product of gluconeogenesis.
41

42. Glycogenolysis
In glycogenolysis, glycogen stored in the liver and muscles, is
converted first to glucose-1- phosphate and then into
glucose-6-phosphate. Two hormones which control
glycogenolysis are a peptide, glucagon from the pancreas
and epinephrine from the adrenal glands.
Glucagon is released from the pancreas in response to low
blood glucose and epinephrine is released in response to a
threat or stress. Both hormones act upon enzymes to
stimulate glycogen phosphorylase to begin glycogenolysis
and inhibit glycogen synthetase (to stop glycogenesis).
42

43. .
• Glycogen is a highly branched polymeric structure
containing glucose as the basic monomer. First individual
glucose molecules are hydrolyzed from the chain, followed
by the addition of a phosphate group at C-1. In the next
step the phosphate is moved to the C-6 position to give
glucose 6-phosphate, a cross road compound.
• Glucose-6-phosphate is the first step of the glycolysis
pathway if glycogen is the carbohydrate source and
further energy is needed. If energy is not immediately
needed, the glucose-6-phosphate is converted to glucose
for distribution in the blood to various cells such as brain
cells.
43

44. 44
GLUCOSE
G-6-Pase GK
G-6-P
F-6-P
P-ENOLPYRUVATE
PEPCK
PK
PYRUVATEOXALOACETATE
FBPase 1 PFK 1
F-1,6-P2
GlycolysisGluconeogenesis

45. 45
GLUCOSE
G-6-Pase GK
G-6-P
F-6-P
P-ENOLPYRUVATE
PEPCK
PK
PYRUVATEOXALOACETATE
FBPase 1 PFK 1
F-1,6-P2
GlycolysisGluconeogenesis
Increase
Hepatic Glucose Utilization
Decrease
Hepatic Glucose Output

46. 46
GLUCOSE
G-6-Pase GK
G-6-P
F-6-P
P-ENOLPYRUVATE
PEPCK
PK
PYRUVATEOXALOACETATE
FBPase 1 PFK 1
F-1,6-P2
GlycolysisGluconeogenesis
Decrease
Hepatic Glucose Utilization
Increase
Hepatic Glucose Output

47. 47
+
F-6-P / F-1,6-P2SUBCYCLE
FBPase 1 PFK 1
F-1,6-P 2
FBPase 2 PFK 2
PK
-
+
F-6-P
G-6-P
F-2,6-P2

48. 48
The bifunctional enzyme
FBPase 2 PFK 2
Fructose-6-P
Fructose-2,6-bis-P
Fructose-2,6-bis-P
Fructose-6-P P

49. 49
The bifunctional enzyme
FBPase 2 PFK 2
Fructose-6-P
Fructose-2,6-bis-P
Fructose-2,6-bis-P
Fructose-6-P P
Phosphorylation of PFK2 by PKA
promotes gluconeogenesis

50. 50
The bifunctional enzyme
FBPase 2 PFK 2
Fructose-6-P
Fructose-2,6-bis-P
Fructose-2,6-bis-P
Fructose-6-P
Double mutant, blocks phosphorylation
of PFK2 and phosphatase activity of FBPase2

51. 51
The bifunctional enzyme
FBPase 2 PFK 2
Fructose-6-P
Fructose-2,6-bis-P
Fructose-2,6-bis-P
Fructose-6-P
Increased PFK1,
Increased glycolysis,
Fed State
Hepatic overexpression
of the double mutant results
in a gene expression profile
consistent with the fed state,
and protection from
Type I and II diabetes

52. 52
Gluconeogenesis
• Mechanism to maintain adequate glucose levels in tissues,
especially in brain (brain uses 120 g of the 160g of glucose needed
daily). Erythrocytes also require glucose.
• Occurs exclusively in liver (90%) and kidney (10%)
• Glucose is synthesized from non-carbohydrate precursors
derived from muscle, adipose tissue: pyruvate and lactate (60%),
amino acids (20%), glycerol (20%)

53. 53
Gluconeogenesis takes energy and is regulated
Converts pyruvate to
glucose
Gluconeogenesis is not
simply the reverse of
glycolysis; it utilizes
unique enzymes
(pyruvate carboxylase,
PEPCK, fructose-1,6-
bisphosphatase, and
glucose-6-phosphatase)
for irreversible
reactions.
6 ATP equivalents are
consumed in
synthesizing 1 glucose
from pyruvate in this
pathway
hexokinaseGlucose-6-P - Glucose 6-phosphatase

54. 54
Irreversible steps in gluconeogenesis
• First step by a gluconeogenic-specific
enzyme occurs in the mitochondria
pyruvate oxaloacetate
Pyruvate
Carboxylase
• Once oxaloacetate is produced, it is
reduced to malate so that it can be
transported to the cytosol. In the
cytosol, oxaloacetate is subsequently
dexcarboxylated/phosphorylated by
PEPCK (phosphoenolpyruvate
carboxykinase), a second enzyme
unique to gluconeogenesis.
The resulting phosphoenol pyruvate is
metabolized by glycolysis enzymes in
reverse, until the next irreversible step

55. 55
Irreversible steps in gluconeogenesis (continued)
• Fructose 1,6-bisphosphate + H2O
fructose-6-phosphate + Pi
Fructose 1,6-
Bisphosphatase
(FBPase)
• In liver, glucose-6-phosphate can be dephosphorylated to
glucose, which is released and transported to other tissues. This
reaction occurs in the lumen of the endoplasmic reticulum.
Requires 5 proteins!
2) Ca-binding stabilizing
protein (SP)
1) G-6-P transporter
3) G-6-Pase
4) Glucose transporter
5) Pi transporter

56. 56
Gluconeogenesis and Glycolysis are reciprocally regulated
• Fructose 1,6-bisphosphatase is main regulatory step in
gluconeogenesis.
• Corresponding step in glycolysis is 6-phosphofructo-1-kinase (PFK-1).
• These two enzymes are regulated in a reciprocal manner by several
metabolites.
Fructose-6-phosphate
Fructose 1,6-bisphosphate
6-phosphofructo
-1-kinase
Fructose
1,6-bisphosphatase
+ Citrate
- AMP
- F 2,6-BP
Citrate -
AMP +
F 2,6-BP +
Reciprocal control—prevents simultaneous reactions in same cell.