Carbohydrate Metabolism

SBP3201

Ts Dr. Sharifah Sakinah Syed Alwi

 Introduction to metabolism
• Complex substances are broken down for
energy, metabolites, structural components
etc
• Thousands of such reactions are occurring
simultaneously in a single cell
• The demand for energy and starting materials
varies in different biological process
• All of these rxns must be controlled or
regulated for optimum efficiency
 Intermediary metabolism
• Involved the synthesis and degradation of small
molecules in living cells

• Referred to as intermediary metabolism because they

focus on the small-molecule in metabolic pathways

• The synthesis and degradation of small molecules

serve 2 functions;
– Supplies energy needed for the synthesis of
macromolecules and other energy-requiring processes
– Furnishes these processes with the necessary starting
materials
 Definitions

• Catabolism
– breakdown of complex substances

• Anabolism
– the synthesis of complex substances from simpler
ones
 Free energy changes in
metabolism
• Overall ΔG is –ve for catabolic processes

Example: Example:
Higher energy A B C D E Lower energy
compound, G1 compound, G2

ΔG = G2 – G1 is a negative
• Overall ΔG is +ve for anabolic processes

W V U S P

• So, generally catabolic processes generate

energy for anabolic processes
 General pathway of metabolism
1. CATABOLISM
• Breakdown of macromolecules to building blocks –
generally hydrolytic
Protein Polysaccharide Lipid Nucleic acid

Amino Glucose & other Glycerol & fatty Ribose, het

acid sugars acids bases &
phosphates

• No useable energy yields here- only building blocks

obtained
• Breakdown of monomers to common intermediates
Glucose & other
sugars Glycerol & fatty
Amino acid
acids

PYRUVATE

ACETYL COA

TCA CYCLE ETS/OXIDATIVE ATP

PHOS

CO2

Oxidative processes-- produce ATP & NADH for energy

• Breakdown of intermediates to CO2 and electron is
accomplished through a central oxidative pathway:

• The Citric Acid Cycle (TCA) or the Krebs Cycle

• This cycle leads to the production of ATP by

processes called electron transport and oxidative
phosphorylation
2. ANABOLISM

• Utilization of critical common intermediates and

components of TCA cycle to make building blocks
• Making building block requires energy = ATP
• Synthesis of macromolecules requires energy = ATP
• CO2 not generally reused
• Some cells have specific nutrient requirements,
therefore cannot make some compounds:
• Vitamins

• Some amino acids (about ½) are required in the

diet by man

• Some microorganisms cannot make certain amino

acids and these must be supplied in nature or the
media
 General principles
• Processed of metabolism are highly
controlled:
– Anabolism and catabolism are not necessarily
balanced – one or the other may predominate in
certain cells or at different times depending on cell
needs
– The pathway to synthesize a complex substance is
not simply the reverse of the degradative pathway
Major pathways of carbohydrate met
 Carbohydrate digestion
• Glucose is the most important carbohydrate
• Glucose is the major metabolic fuel of mammals,
except ruminants
• Monosaccharide from diet:
– Glucose
– Fructose
– Galactose
• Fructose and galactose glucose at the
liver
• Blood glucose : carbohydrate met exist are:
– Glycolysis
– Glycogenesis
– HMP shunt
– Oxidation of pyruvate
– Kreb’s cycle
– Change to lipids
• Blood glucose : carbohydrate metabolism
(fasting)
– Glycogenolysis
– Gluconeogenesis
GLYCOLYSIS
 Glycolysis
• Is the breakdown of glucose into 2 molecules of pyruvic
acid, producing 2 ATP molecules
• Occur in the cytoplasm
• It can function either
– Aerobically – producing pyruvate
– Anaerobically – producing lactate
• All carbohydrates to be catabolized must enter glycolytic
pathway
• Glycolysis is central in generating both energy and
metabolic intermediaries
Aerobically glycolysis Anaerobically glycolysis

Pyruvate • The reoxidation of NADH through the

respiratory chain to oxygen is prevented
• Pyruvate is reduced by the NADH to
Mitochondria
lactate by lactate dehydrogenase enzyme
• Oxidation of 1 mol glucose via
Oxidized to Acetyl Co-A anaerobically glycolysis 2 mol ATP

Kreb’s Cycle

CO2 + H2O + ATP Pyruvate + NADH + H+ Lactate

+ NAD+
Glycolysis pathway
 10 Steps in glycolysis
A. First Phase
1. Glucose in the cells phosphorylated by ATP in the presence of
gluco hexokinase to form glucose-6-phosphate
Hexokinase Glucokinase
Found in all cells of every organism Found in liver
Low specificity for monosaccharide Most effective when glucose level in
blood is high (right after meal
Relatively high affinity for glucose, Km High affinity for glucose, Km = ~10 mM
= 0.1 mM
Inhibited by its product, glucose-6- Not inhibited by glucose-6-phosphate
phosphate

2. G-6-P is then converted back into fructose-6-phosphate

3. Fructose-6-phophate is then phosphorylated by ATP in the
presence of phospho fructokinase to fructose 1,6 phosphate
1. Second phosphorylation
2. Commited step & irreversible
3. PFK is a tetrameric enzyme

Enzyme Activator Inhibitor

Hexokinase Glucose-6-phosphate, ATP

PFK-1 Fructose-2,6-bis Citrate, ATP
phosphate, AMP
Pyruvate Fructose-1,6-bis Acetyl-CoA, ATP
kinase phosphate, AMP
4. Fructose 1,6 diphosphate is split into 2 substances namely
glyceraldehydes-3-phosphate and dihydroxyacetane
phosphate.
- known as isomerization process; important in glucogenesis
- these 2 substances are inter convertible in the presence of triose
phosphate isomerase
- only glyceraldehyde phosphate can be used further in glycolysis
- aldose-ketose isomerization similar to phosphoglucoisomerase
rxn

**End of first phase

- production of 2 glyceraldehyde-3-phosphate molecules from 1
glucose molecule with the expenditure of 2 ATPs
- therefore, the energy yields of the following steps are multiplied by
two
B. Second Phase
5. The 2 molecules of glyceraldehyde phosphate and oxidised
into 2 molecules of 1,3-diphosphoglyceric acid catalysed by
the enzyme phosphoglyceraldehyde
- oxidation of glyceraldehyde-3-phosphate
- NAD and inorganic phosphates are required
- 1,3 - diphosphoglyceraldehyde is the possible intermediate product
6. Transfer of phosphate to make ATP
- first high energy compound generated = beginning of payoff
- product is acylphosphate, a fused carboxylic-phosphoric acid
anhydrate, which has a very high free energy of hydrolysis
- reversible rxn = +6.3 kJ/mole
** because this fused group retains some of the energy produced
by the oxidation of the aldehyde to the carboxylic acid

- first substrate level phosphorylation, yielding ATP

- 2 molecules of 1,3 bis PG yield 2 ATPs thus ATP yield = ATP input
- high free energy yield G°´ = -18.8 kJ/mole drives several of the previous
steps
7. Phosphate shift

8. Generation of second very high energy compound by a

dehydration
9. Final generation ATP

- rxn is so exergonic because the enol in PEP is transformed to a keto in

pyruvate.
- drives several previous reactions.
- pyruvate is the primary product of glycolysis
- pyruvate kinase is a highly regulated enzyme
- the energy is locked into high energy unfavorable enol configuration by
phosphoric acid ester
- upon later hydrolysis of phosphate:
high energy low energy
O O
-C=C-  -C-C-
Bookkeeping:
Bookkeeping

- 2 ATPs from each glyceraldehyde-3-phosphate = total of 4 per

original glucose in second phase.

- 2 molecules of NADH also produced.

- 2 ATPs were invested in the first

phase of glycolysis.

Glycolysis: Invest 2 ATP 4 ATP 

net 2 ATP and 2 NADH
Summary of Energy Relationship for
Glycolysis
Input = 2 ATP
1. glucose + ATP  glucose-6-P

2. fructose-6-P + ATP  fructose 1,6 bisphosphate

Output = 4 ATP + 2 NADH

1. 2 glyceraldehyde 3-P + 2 Pi + 2 NAD+
2 (1,3 bisphosphoglycerate) + 2 NADH

2. 2 (1,3 bisphosphoglycerate) + 2 ADP

2 (3-P-glycerate) + 2 ATP

3. 2 PEP + 2 ADP  2 pyruvate + 2 ATP

Net = 2 ATP and 2 NADH
 Energy Yield From Glycolysis

Glucose + 2 Pi + 2 ADP + 2 NAD+ → 2 pyruvate + 2 ATP + 2 NADH + 2 H +

glucose 6 CO2 = -2840 kJ/mole

2 ATPs produced = 2 x 30.5 = 61 kJ/mole glucose
Energy yield = 61/2840 = 2% recovered as ATP

*** subsequent oxidation of pyruvate and NADH can recover more of the
free energy from glucose

Three irreversible kinase reactions primarily drive glycolysis forward.

 hexokinase or glucokinase
 phosphofructokinase
 pyruvate kinase
Diverse fate of pyruvate

To citric acid cycle

Under anaerobic conditions pyruvate is
converted to lactate.
Exercising muscle is an
example

The NAD+ that is consumed in

the glyceraldehyde 3-phosphate
reaction is produced in the
lactate DH reaction.

The redox balance is

maintained. The activities of
glyceraldehyde 3-phosphate DH
and Lactate DH are linked
metabolically.

What happens to the lactate

after a run?
1. Helps drive glycolysis by using up NADH
2. Reversible so pyruvate can be regenerated in alternative metabolism
3. Lactate fermentation important in red blood cells, parts of the retina and in
skeletal muscle cells during strenuous exercise
4. Lactate dehydrogenase
- Has multiple form.
- An isoenzyme
- Consist of 2 polypeptides M and H come together to form LDH
- A tetramer so a mixture is formed
- M4
- M3H
- M3H2
- MH3
- H4
 5. Skeletal muscle and liver contain predominantly the ‘M’
forms; heart the ‘H’ form
6. During and after myocardial infarction (heart attack), heart
cells die releasing LDH into the circulation

Remember!
The NAD+ that is consumed in the glyceraldehyde 3-phosphate reaction is
produced in the lactate DH reaction. Thus, redox balance is maintained.

The NADH that is produced in the glyceraldehyde 3-phosphate reaction is

consumed in the lactate DH reaction. Thus, redox balance is maintained.

Glucose + 2 Pi +2 ADP → 2 lactate + 2 ATP + 2 H2O

 In anaerobic yeast, pyruvate→ethanol

Pyruvate is decarboxylated.

Acetaldehyde is reduced.
The Citric Acid Cycle
Aerobic metabolism in the
mitochondria
 The citric acid cycle
• Series of biochemical reactions aerobic organisms use to
release energy stored in the 2 acetyl group in acetyl-CoA
• Aacetyl CoA is composed of an acetyl group derived from
the breakdown of CHO, lipids and some amino acid that is
linked to the acyl carrier molecule co-enzyme A
 Function of TCA cycle
1. Involved in both anabolic and catabolic processes
a. Anabolic reactions
- The intermediates of the citric acid are used as precursors in the
biosynthesis of many compounds
b. Catabolic reactions
- The cycle provides a mean for the degradation of 2 carbon acetyl
residues, which are derived from CHO, fatty acid and amino acids
2. The citric acid cycle provides much of the energy
respiration.
- Electron that are generated from the action are transferred to the ETC
and used the process of oxidative phosphorylation to generate ATP
 Stoichiometric reaction of TCA
cycle

Acetyl CoA + 3 NAD+ + FAD + GDP + Pi + 2H2O

2 CO2 + 3 NADH + FADH2 + CoASH + GTP + 3H+

Occurs in the mitochondrial matrix.

Preparatory Step
Pyruvic acid is converted to acetyl CoA in three main steps:
 Decarboxylation

 Carbon is removed from pyruvic acid

 Carbon dioxide is released

An example of a biological redox system

O O
CH3 C C O + NADH + H+
pyruvate is HO O
reduced
CH3 C C O + NAD+
H
H+ comes from NADH supplies H:-
the solvent (two electrons as “hydride”)
Oxidation
 Hydrogen atoms are removed from pyruvic acid
 NAD+ is reduced to NADH + H+

Formation of acetyl CoA – the resulting acetic acid

is combined with coenzyme A, a sulfur-containing
coenzyme, to form acetyl CoA
 Pyruvate decarboxylate complex
pyruvate dehydrogenase
complex

CoA-SH TPP, FAD

O Mg 2+ , lipoic acid
-
CH3 C C O O
pyruvate
+
NAD + NADH + H
CO 2

O
CH3 C S CoA
Acetyl CoA
• An eight-step cycle in which each acetic acid is
decarboxylated and oxidized, generating:
– 3 molecules of NADH + H+
– 1 molecule of FADH2
– 2 molecules of CO2
– 1 molecule of ATP

• For each molecule of glucose entering

glycolysis, 2 molecules of acetyl CoA enter the
Krebs cycle
TCA Cycle
 Reactions of TCA cycle
A) Acetyl CoA plus oxaloacetate to citrate and coenzyme A
1) this initial condensation reaction is catalysed by citrate synthase.
2) the reaction is stimulated by AMP.

B) Citrate to isocitrate. This isomerization reaction is catalysed by aconitase.

C) Isocitrate to a-ketoglutarate and CO2

1) this reaction is catalysed by isocitrate dehydrogenase
2) in this oxidative decarboxylation reaction, NAD+ is reduced to NADH.
3) Regulation
a) this reaction is inhibited by ATP and NADH.
b) this reaction is stimulated by ADP.

D) a-ketoglutarate and CoA to succinyl CoA

1) this reaction is catalysed by a-ketoglutarate deHase.
• TCA- step 1

- -
COO O COO
CH3 C S CoA CH2
C O acetyl-CoA -
HO C COO
CH2 CH2
Citrate synthase
- -
COO COO
Oxaloacetate Citrate

CoA-SH + H+
A. Acetyl CoA plus oxaloacetate to citrate and
coenzyme A
1. This initial condensation reaction is catalysed by
citrate synthase
2. The reaction is stimulated by AMP
• TCA- step 2
- -
COO COO
CH2 CH2
- -
HO C COO aconitase CH COO
CH2 HO C H
- -
COO COO
Citrate Isocitrate

B. Citrate to isocitrate.
-This isomerization reaction is catalysed by aconitase.
• TCA- step 3

-
COO -
NAD+ NADH + H+ COO
CH2
CH2
-
CH COO CH2
HO C H C O
- H+ CO2
COO isocitrate dehydrogenase COO
-

Isocitrate -ketoglutarate
C. Isocitrate to ketoglutarate and CO2
1. This reaction is catalysed by isocitrate
dehydrogenase
2. In this oxidative decarboxylation reaction, NAD+ is
reduced to NADH
3. Regulation:
a. This reaction is inhibited by ATP and NADH
b. This reaction is stimulated by ADP
• TCA- step 4

+ CoA-SH + CO2
NAD+ NADH + H +
-
- Mg2+ COO
COO
CH2
CH 2
CH2
CH 2 TTP, FAD, lipoic acid
C O
C O -ketoglutarate dehydrogenase complex
- S CoA
COO
-ketoglutarate Succinyl-CoA
D. α- ketoglutarate and CoA to succinyl CoA
1. This reaction is catalysed by α-ketoglutarate deHase that
contains tightly bound TPP, lipoamide and FAD
2. In this oxidative decarboxylase reaction, NAD+ is reduced to
NADH and H+ and CO2 is released
3. The product, succinyl CoA is an energy-rich thioester like
acetyl CoA
4. The reaction is inhibited by ATP, NADH and succinyl CoA
• TCA- step 5

CoA-SH +
GDP GTP
- -
COO COO
CH2 CH2
CH2 CH2
succinyl-CoA synthetase
C O Pi -
COO
S CoA
Succinate
Succinyl-CoA
E. Succinyl CoA and GDP and Pi to succinate and
GTP and CoA

1. This reaction is catalyzed by succinyl CoA synthetase

2. This is a substrate level phosphorylation with energy
being conserved in the form of GTP
• TCA- step 6

- FAD FADH2 -
COO OOC H
C
CH2
CH2 succinate dehydrogenase C
H -
-
COO
COO
Fumarate
Succinate
F. Succinate to fumarate

1. This reaction is catalysed by succinate deHase (SDH)

a. Prosthetic groups; SDH possesses three different types of iron-sulfur
centers and covalently bound FAD.
b. SDH is tightly associated with the inner mitochondrial membrane.

2. This is a dehydrogenation reaction during which FAD is reduced to

FADH2. FADH2 is reoxidised by transfering e-directly to the electron
transport chain of the mitochondrial membrane.
• TCA- step 7

H2O
-
- COO
OOC H
C CH2
fumarase
C H C OH
H -
COO -
Fumarate
COO
L-Malate

G. Fumarate to malate:
- this hydration reaction is catalysed by fumarase
• TCA- step 8

NAD+ NADH + H+ -
- COO
COO
CH2
CH2
H C OH malate dehydrogenase C O
-
COO
- COO
L-Malate Oxaloacetate
H. Malate to oxaloacetate

1. This reaction is catalysed by malate dehydrogenase

2. This is a dehydrogenation reaction during which
NAD+ is reduced to NADH
Gluconeogenesis
 Gluconeogenesis
• It is the biosynthesis of glucose from simpler
molecules, primarily pyruvate and its precursors
• This pathway is similar to the reverse of
glycolysis but differs at critical sites
• General principles of metabolic control
– Pathways are not simple reversals of each other
– Under reciprocal control
 Why do we produce glucose?
• Need to maintain glucose levels in a narrow
range in blood
• Some tissue- brain, erythrocytes and muscles in
exertion use glucose at rapid rate
• Sometimes require glucose in addition to dietary
glucose
• The brain and erythrocytes can use only glucose
as a source of energy
 Where is glucose synthesized?
• Liver is the major location for gluconeogenesis
• Under normal circumstances:
– the liver is responsible for 85%-95% of the glucose that is made
• During starvation @ metabolic acidosis:
– the kidney is capable of making glucose and may contribute up to
50% of the glucose formed
– Because the amount contributed by the liver is decreased
considerably
– The only other tissue capable of gluconeogenesis is the epithelial
cell of the small intestine , which contributes not more that 5% of
the total glucose formation
 Functions of gluconeogenesis
1. During starvation or periods of limited carbohydrate intake, when
the levels of liver glycogen are low (liver glycogen supplies are
adequate for 10-24 hours), gluconeogenesis is important in
maintaining adequate blood sugar concentrations.
2. During extended exercise, when CHO and lipid reserves are
mobilised, gluconeogenesis allows the use of lactate from
glycolysis and glycerol from fat breakdown.
3. During metabolic acidosis, gluconeogenesis in the kidney allows
the excretion of an increased number of protons.
4. Gluconeogenesis allows the use of dietary protein in CHO pathway.
Precursors/ substrates for gluconeogenesis

 pyruvate- major precursor

 lactate–from muscle, forms pyruvate
 some amino acid carbon skeletons- from diet or breakdown of muscle
protein during starvation- most important is alanine
 TCA cycle intermediates
 propionate from breakdown of fatty acids and amino acids
 glycerol from certain lipids.
Adipose Liver Muscle

Glucose Glucose Glucose

3-phosphoglycerate
TAG

glycerol glycerol pyruvate pyruvate

alanine lactate lactate alanine

Interplay between metabolic pathways in different tissues

Interconversion of lactate and pyruvate

1. Catalysed by lactate deHase (LDH) and oxidised (NAD+) dependent

enzyme.
• Lactate + NAD+ pyruvate + NADH + H+
• In gluconeogenic tissues (ie, liver), LDH usually runs this
reaction in the direction of pyruvate formation.

2) In muscle cells and RBC, LDH usually runs this reaction in the
direction of lactate formation.

3) The direction in which the reaction proceeds depend on the

following factors:
• the ratio of NAD+/NADH and Lactate/pyruvate
• the isozyme of LDH that is present.
Cori cycle

1. Pyruvate formed from glucose by glycolysis in the muscle cells and

RBC is converted to lactate by LDH.

2. Lactate is released into the blood, taken up by the liver, and

converted to pyruvate by LDH.

3. Pyruvate is converted to glucose via gluconeogenesis in the liver

and is released into the blood where it can be used as an energy
source for muscle as well as other tissues.
 The Cori Cycle

Lactate produced from pyruvate passes via the blood to the liver, where it may
be converted to glucose.
The glucose may travel back to the muscle to fuel glycolysis.
Alanine
• Pyruvate formed from glycolysis in the muscle may be
converted to alanine by a transamination reaction.

• Alanine also may be formed in muscle during degradation of

protein which occurs during starvation.

• Alanine is released by the muscle into the blood, taken up by

the liver, and converted back to pyruvate by the reverse of the
transamination reaction that occurred in the muscle.

• Pyruvate is then used to produce glucose via gluconeogenesis.

Glycerol
•Glycerol is formed in adipose tissue by lipolysis and triacylglycerols.
•Glycerol is released into the blood and taken up by the liver where it

is phosphorylated to 3-phosphoglycerate, which is an intermediate

in gluconeogenesis.

Amino acid
Glucogenic amino acids other than alanine may be converted to TCA
intermediates that are metabolised to oxaloacetate, an intermediate
in gluconeogenesis.
 glyceraldehyde-3-phosphate
NAD+ + Pi Glyceraldehyde-3-phosphate
NADH + H+ Dehydrogenase
1,3-bisphosphoglycerate
ADP
Summary of ATP
Phosphoglycerate Kinase
Gluconeogenesis 3-phosphoglycerate
Pathway: Phosphoglycerate Mutase
2-phosphoglycerate
Gluconeogenesis
enzyme names in H2O Enolase

red. phosphoenolpyruvate
CO2 + GDP
PEP Carboxykinase
Glycolysis enzyme GTP
names in blue. oxaloacetate
Pi + ADP
Pyruvate Carboxylase
HCO3 + ATP
pyruvate Gluconeogenesis
 glucose Gluconeogenesis
Pi
Glucose-6-phosphatase
H2O
glucose-6-phosphate
Phosphoglucose Isomerase
fructose-6-phosphate
Pi
Fructose-1,6-bisphosphatase
H2O
fructose-1,6-bisphosphate
Aldolase

glyceraldehyde-3-phosphate + dihydroxyacetone-phosphate
Triosephosphate
Isomerase
(continued)
Reaction of gluconeogenesis

A. Pyruvate to oxaloacetate

1. The hydrolysis of ATP provides energy for the carboxylation of

pyruvate.
2. Pyruvate carboxylase catalyses this reaction. The prosthetic group
of the enzyme is biotin. Mg2+ and Mn2+ is required. Acetyl CoA is
required as an activator and regulates activity in a concentration-
dependent manner.
3. This reaction occurs in mitochondrial matrix.
Pyruvate to Oxaloacetate

Acetyl-CoA
Biotin, Mg2+

pyruvate carboxylase

Pyruvate Oxaloacetate
+ ATP + ADP
+ CO2 + H2O + Pi + H +
B. Interconversion of OAA and malate

•OAA cannot permeate the mitochondrial membrane wall, and it

must be transported across the membrane in a form of malate.
• Malate deHase catalyses the reversible reaction

OAA + NADH + H+ malate + NAD+ (occurs in mitochondria)

•In the cytosol, a cytosolic malate deHase catalyses the reverse

reaction, which generates OAA.
C. OAA to PEP

1. Hydrolysis of GTP provides the energy for the

carboxylation of OAA.
2. PEP carboxykinase (PEPCK) catalyses this reaction, which
requires Mn2+ for activation.
3. Occurs in cytosol.
4. The two reactions catalysed by pyruvate carboxylase and
PEPCK convert pyruvate to PEP, thus bypassing the
irreversible reaction catalysed by pyruvate kinase during
glycolysis.
D. PEP to F-1,6-BP

•This conversion occurs by six sequential reactions that are simply the
reverse of those occur in glycolysis, and they are catalysed by the
same enzymes.

E. F-1,6-BP to F-6-P and Pi

•This reaction is the reverse of the reaction catalysed by
phosphofructokinase during glycolysis.
•Fructose-1,6-bisphosphatase catalyses this reaction- major
regulatory enzyme in gluconeogenesis.
•Allosteric enzyme- citrate as activator
- AMP and F-2,6-BP is the inhibitor
F. F6P to G-6-P
•This reaction, the reverse of the conversion of G6P to F6P in
glycolysis, is catalysed by the same enzyme, phosphoglucose
isomerase.

G6P to glucose and Pi

•This is the reverse of the reaction catalysed by glucokinase and
hexokinase during glycolysis. However, in gluconeogenesis this
reaction is catalysed by glucose-6-phosphatase, which is present only
in gluconeogenic tissues.
Glycolysis and gluconeogenesis are
reciprocally regulated

Insulin stimulates Glucagon stimulates

A high [AMP] indicates

that the energy charge
is low and signals the
need for ATP.

High [ATP] and [citrate]

indicate the energy
charge is high and
intermediates are
abundant.
Gluconeogenesis Stoichiometry

2pyruvate + 4ATP + 2GTP + 2NADH + 6H2O  glucose + 4ADP + 2GDP

+6Pi +2NAD+ + 2H+

G°’ = -9kcal mol-1.

Just the reverse of glycolysis, G°’ = 20kcal mol-1.

PENTOSE PHOSPHATE
PATHWAY
Functions:
• Provides a source of reduced NADPH for reductive biosynthesis.
• Provides a source of ribose-5-phosphate for nucleic acid
biosynthesis.
• Provides a route for the conversion of pentoses to fructose-6-
phosphate.
• Erythrocytes depend on the pentose phosphate pathway for
NADPH, which is required to maintain glutathione in the reduced
state. Reduced glutathione is needed to maintain the integrity of
the RBC membrane.
Location
• The pentose phosphate pathway is most active in the
erythrocyte, liver, mammary gland, adipose tissue, and
the adrenal cortex.
• Within the cell, the enzymes of this pathway are located
in the cytoplasm.
Oxidative phase
(irreversible)
Regulation:

•Glucose-6-phosphate deHase (G6PD) is inhibited by NADPH and

activated by glucose-6-phosphate and GSSG, which indicates
oxidative damage and a need for NADPH.

•A high CHO diet triggers the synthesis of the enzyme G6PD and
phosphogluconate deHase.
Non-oxidative phase

•All reactions are reversible.

•What happens to ribulose-5-phosphate depends on
the metabolic needs of the cells.
Non-oxidative phase
CHO metabolism;
glycolysis and pentose
phosphate pathway
•If the cells requires more NADPH than ribose molecules, it can
channel the products of the nonoxidative phase of the pentose
phosphate pathway into glycolysis.
•Excess ribose-5-phosphate can be converted into the glycolytic
intermediates fructose-6-phosphate and glyceraldehyde-3-
phosphate.

Overall Oxidation:
6 G-6-P + 12 NADP+ + 6 H2O 
6 R-5-P + 6 CO2 + 12 NADPH + 12 H+
 Metabolism of other important sugars
 In the liver, fructose is converted to fructose-1-phosphate and
then split into DHAP and glyceraldehyde.
 Glyceraldehyde is then converted to glyceraldehyde-3-
phosphate by glyceraldehyde kinase.
 In muscle and fat tissue fructose is converted to F-6-P.
Glycogen Metabolism

 Glycogen metabolism is carefully regulated so that sufficient

glucose is available for the body’s energy needs.
 Insulin, glucagon, and epinephrine control glycogenesis and
glycogenolysis.
 Glycogenesis
•Muscle: excess glucose is stored as glycogen: energy storage

•Liver: glucose is removed from the blood in response to insulin,

which signals high blood glucose levels.

•Glycogen synthase, and thus glycogenesis, is activated by

glucose-6-phosphate an indicator of excess of glycose. High levels
of ATP (as well as glucose-6-phosphate) inhibit the glycogenolysis
by inhibiting glycogen phosphorylase.
 (amylo-(1,4 1,6)-glucosyl transferase

Glycogenesis
Formation of amylose chains
•The synthesis of new glycogen requires the presence of existing
glycogen chains and glucosyl residues from UDP-glucose.
•The residues are successively transferred to the C-4 terminus of an
existing glycogen chain in a-1,4-glycosidic linkages.
•Glycogen synthase –rate limiting step in glycogen synthesis.

Formation of branch chains and further growth

•Segments of the amylose chain are transferred to a C-6 hydroxyl
group of a glucosyl residue that is four residues away length before
a segment is transferred from it.
 Glycogenolysis

Phosphorolytic cleavage of the terminal a-1,4-glycosidic bond.

Glycogen phosphorylase
Glycogen (n residues) + Pi glycogen(n-1 residues) + G1P
-Is a rate limiting step in glycogenolysis.

Removal of branch chains

Debranching enzyme catalyses the removal of branches;
-1,4 1,4-glucan transferase
-a-1,6-glucosidase (amylo-6-glucosidase)-a single residue on c-6 is
removed to yield a free glucose molecule
glycogenolysis