Carbohydrates Metabolism

By: yohannis wondwosen

AAU
 Introduction
 CHO Metabolism includes:
 Digestion of CHO

 Absorption of digested

CHO
 Utilization of CHO which

includes:
 Anabolic
 Catabolic
 Amphibolic
pathways
 Excretion
 CHOs Digestion

 Digestion of the complex

carbohydrate
involves :
 Amylase produced
salivary gland and
pancreas
 Brush-boarder enzymes
in the small intestine
 CHOs Digestion
Sites of
Digestion
1.Buccalcavity(Mouth)

2. Stomach

 3. Small
Digestion intestine
in the buccal cavity:
 During the eating process & the homogenization occurs;
 with mastication in the mouth & the action of gastric folds
 Dietary polysaccharides become hydrated
 Salivary amylase (ptyalin)  -glycosidase
 On Starch & glycogen
 Specific for hydrolysis of -1,4 glucosidic linkage
 Producing maltose, -dextrins & Isomaltose…….Glc
 Its optimum pH is 6.7 - 6.8
 Activated by Chloride ions
 Starch digestion by salivary amylase is incomplete  Why?
 CHOs Digestion

 Digestion in the Stomach:

 Salivary amylase continues to act for
2 - 3 minutes
 acidic pH 1 - 2

 Digestion in the Small Intestine

 Two enzymes that digest CHO

1. Pancreatic juice
2. Intestinal mucosal brush border
enzymes
 CHOs Digestion

1. Pancreatic juice:
 Pancreatic amylase
 an -glycosidase
 has an optimum pH 7.1
 also activated by Cl-
 acts exactly as salivary A.
 The products of hydrolysis of
starch/Glycogen
 maltose
 maltotriose
 -limit dextrin:
 Branched & containing

 on average eight glycosyl

units
 CHOs Digestion
2. Intestinal mucosal brush
border:
 Disaccharidases 
 membrane-bound

 This final product of digestion of

starches is thus glucose ,
 but it is generated through a

complex series of enzyme

reactions
 Carbohydrates are digested
into:
 Glc, Gal, Man & Fru
 Lactose Intolerance
– more lactose is consumed than can be digested
– B/C Insufficient lactase production =
inability to digest lactose (milk sugar)
– lactose molecules attract water
• cause floating, abdominal discomfort, diarrhea
– intestinal bacteria feed on undigested lactose
• produce acid and gas

06/22/2025 8
 Lactose Intolerance
 Is the inability to digest lactose due the
deficiency of lactase enzymes
 Can be the result of:
 a primary deficiency of lactase

 an inherited or age-dependent decline

of enzyme expression
 it can be secondary to an injury to the

intestinal mucosa,
 an acquired medical problem due to
intestinal diseases:
 Tropical & non-tropical sprue, colitis,
kwashiorkor,
 gastroenteritis & excessive alcohol
consumption
 Monosaccharides Absorption
 Once the CHO split into monosaccharides
 Transported across the intestinal
epithelial cells &
 into the blood
 Absorption by the Intestinal Epithelium
 Glc/Gal is transported through the
absorptive cells of the intestine by
 Na-dependent facilitated
transport (SGLT)
 Facilitated diffusion
 It enters the absorptive cells by binding
to transport proteins,
 Two types of Glc/Gal transport proteins are
 Na+-dependent glucose
transporters
 Facilitative glucose transporters
Na+-Dependent Glucose Transporters
 SGLT1 & SGLT2  Fig-AB1
 Which are located on the luminal side of the absorptive
cells,
 enable these cells to concentrate glucose from the
intestinal lumen
 A low intracellular Na+ concentration is maintained
 by a Na+,K+-ATPase on the serosal (blood) side of the
cell
 that uses the energy from ATP cleavage to pump Na+
out of the cell into the blood
 The transport of Glc from a low conc. in the lumen to a high
conc. in the cell is promoted by
 Cotransport of Na+ from a high conc. in the lumen to
a low conc. in the cell
 Secondary active transport
Fig-AB1. Glucose transport in intestinal epithelial cells
15
 Facilitative Glucose Transporters
• Which do not bind Na+, are located on the serosal
side
– Glucose moves via the facilitative
transporters:
• From the high conc. inside the cell to the
lower conc. in the blood
– without the expenditure of energy
 Facilitative transporters for Glc also exist on the
luminal side (GLUT-5)
Jun 22, 2025 16
 Low affinity for glucose in contrast high
 Galactose & Fructose
 Galactose:
Absorption
 Absorbed through the
same mechanisms as
glucose
 Fructose:
 Both enters & leaves
absorptive epithelial cells
by:
 Facilitated diffusion
 GLUT-5( enter )
Transport of Monosaccharides into Tissues
 Liver:  GLUT-2
 Km for the glucose transporter is
 Relatively high compared with that of other tissues,
 probably 15 mM or above
 This is in keeping with the liver’s role
 as the organ that maintains blood glucose levels
 Muscle & Adipose tissue:  GLUT-4
 Transport of Glc is greatly stimulated by insulin
 The mechanism involves: Fig-Special
 Recruitment of GLUT-4 from IC vesicles into the plasma
membrane
 In adipose tissue  es Glc availability for the synthesis of:
 Fatty acids &
 glycerol  from the glycolytic pathway
 In skeletal muscle es Glc availability for:
 Glycolysis
 Glycogen synthesis
FIG-Special Regulation by insulin of glucose
transport by GLUT-4 into a myocyte
 Fates of the Body Carbohydrates
• Glucose
– The principal carbohydrate that is utilized by the cell
 Carbohydrate metabolism is the story of glucose
metabolism
• In the liver fructose and mannose are changed to glucose
• Glucose may undergo one of the following fates:
– Oxidative (catabolic) fates:
• Major pathways: A. Glycolysis** B. Krebs' cycle**
• Minor pathways: A. Pentose shunt B. Uronic acid pathway
– Anabolic fates:

• Gluconeogenesis & Glycogenesis/glycogenolysis

• Monosaccharides synthesis & Lactose synthesis

• Glycolipids, glycoproteins & Proteoglycans synthesis

Jun 22, 2025 25
 Cellular Respiration
Occurs in three series of reactions
1. Glycolysis
2. Citric acid cycle
3. Electron transport chain
Produces
• carbon dioxide
• water
• ATP (chemical energy)
• heat

Includes
• anaerobic reactions (without O2) - produce little ATP
• aerobic reactions (requires O2) - produce most ATP
 ATP Molecules
• each ATP molecule has three parts:
• an adenine molecule
• a ribose molecule
• three phosphate molecules in a chain
• Third phosphate attached by high-energy bond
• when the bond is broken, energy is transferred
• when the bond is broken, ATP becomes ADP
• ADP becomes ATP through phosphorylation
• phosphorylation requires energy released from cellular respiration
 ATP

•One of the common links between catabolism

and anabolism is ATP.
– ATP is used to shuttle chemical energy from
catabolism to anabolism.

28
 Glycolysis (Embden -Meyerhoff pathway)
 Oxidation of glucose or glycogen to pyruvate and
lactate is called glycolysis.
 This was described by Embeden, Meyerhoff and
Parnas. Hence it is also called as Embden -
Meyerhoff pathway.
 It occurs virtually in all tissues.
 Erythrocytes and nervous tissues derive its
energy mainly form glycolysis.
 This pathway is unique in the sense that it can
utilize O2 if available (‘aerobic’) and it can
function in absence of O2 also (‘anaerobic’)
 Glycolysis contain series of ten reactions
 breaks down glucose into 2 pyruvic acids
 occurs in cytosol
 anaerobic phase of cellular respiration
 yields two ATP molecules per glucose
 Aerobic phase of cellular respiration
 Yields 8 ATP molecules per glucose
 Glycolysis
Event 1 -
Phosphorylation
• two phosphates
Event 3 – Production of
NADH and ATP
added to glucose • hydrogen atoms are
• requires ATP
released
• hydrogen atoms bind to
NAD+ to produce NADH
• NADH delivers hydrogen
atoms to ETC if oxygen is
available
• ADP is phosphorylated to
become ATP
• two molecules of pyruvic
acid are produced

Event 2 – Splitting (cleavage)

•6-carbon glucose split into two 3-carbon
06/22/2025 30
molecules
Anaerobic Reactions (Absence of Oxygen)

If oxygen is not available -

 electron transport chain
cannot accept NADH
 pyruvic acid is
converted to lactic acid
 glycolysis is inhibited
 ATP production declines
 Aerobic Reactions (Presence of Oxygen)

If oxygen is available –
 pyruvic acid is used to
produce acetyl CoA
 citric acid cycle begins
 ETC functions
 CO2 and H2O are formed
 38 ATP / per glucose
 Differences between aerobic and anaerobic
glycolysis:
Anaerobic Aerobic

Lactate Pyruvate 1. End product

2 ATP 8 ATP 2 .energy

Through Lactate Through respiration 3.Regenerationof NAD+

formation chain in mitochondria

Not available as lactate Available and 2 Pyruvate 4. Availability to TCA

is cytoplasmic substrate can oxidize to give 30 in mitochondria
ATP
Substrate level phosphorylation:‫ڗ‬
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.
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
3. Provides important intermediates:
a) DHAP: can give glycerol-3phosphate,).(Rappaport path
way)
b) 3 Phosphoglycerate: used for synthesis of amino acid
serine.
c) Pyruvate: used in synthesis of amino acid alanine.
4. Aerobic glycolysis provides the mitochondria with pyruvate,
which gives acetyl CoA Krebs' cycle.
Comparison b/n glucokinase & hexokinase enzymes:
Hexokinase Glucokinaase

All tissue cells Liver only 1. Site

High affinity (low km) i.e. it acts Low affinity (high km) i.e. it 2. Affinity to glucose
even in the presence of low blood acts only in the presence of
glucose concentration. high blood glucose
concentration.

Glucose, galactose and fructose Glucose only 3. Substrate

No effect Induces synthesis of 4. Effect of insulin
glucokinase.

Allosterically inhibits hexokinase No effect 5. Effect of glucose-6-p

It phosphorylates glucose inside Acts in liver after meals. It 6. Function
the body cells. This makes glucose removes glucose coming in
concentration more in blood than portal circulation, converting
inside the cells. This leads to it into glucose -6-phosphate.
continuous supply of glucose for
the tissues even in the presence of
low blood glucose concentration.
Importance of lactate production in anaerobic glycolysis:
 In absence of oxygen, lactate is the end product of glycolysis:

Glucose  Pyruvate  Lactate

 In absence of oxygen, NADH + H+ is not oxidized by the

respiratory chain.
 The conversion of pyruvate to lactate is the mechanism for
regeneration of NAD+.
 This helps continuity of glycolysis, as the generated NAD+ will
be used once more for oxidation of another glucose
molecule.
 Entry of other mono saccharides in the
Glycolytic sequence

1. Fructose
Fructose enters the Glycolytic sequence by the
following steps.

Fructokinase
Fructose + ATP Fructose-1-P + ADP
 Entry of other mono saccharides in the Glycolytic sequence

Fructose -1-P aldolase ( aldolase B)

Fructose-1-P Dihydroxy acetone phosphate +
Glyceraldehyde

• Dihydroxy acetone phosphate is an intermediate in the

glycolytic pathway.
• It is then isomerizes in to Gyceraldehyde-3-P by an enzyme
called Triose phosphate isomerase (TPI).
TPI
Dihydroxy acetone –P Glyceraldehyde -3-P
 Entry of other mono saccharides in the
Glycolytic sequence
Glyceraldehyde is phosphorylated toGlyceraldehyde-3-P by
an enzyme called triose kinase.

Triose kinase
Glyceraldehyde + ATP Glyceraldehyde 3-P + ADP

• In this way 2 molecules of Glyceraldehyde -3-P are

formed from 1 molecule of Fructose.
• Glyceraldehyde -3-P is ultimately converted to
pyruvate by the remaining steps in the usual
glycolytic pathway.
Entry of other mono saccharides in the Glycolytic
sequence

II. Mannose

Mannose enters the glycolytic sequence in two steps.

HK
Mannose + ATP Mannose-6-P + ADP

Phospho manno isomerase(PMI)

Mannose -6-P Fructose-6-P

Fructose -6- P is an intermediate in the usual glycolytic pathway.

 Entry of other mono saccharides in the
Glycolytic sequence
III. Galactose
• Galactose enters the glycolytic pathway by the
following steps.
• Glucose-6-P is an intermediate in usual glycolytic
pathway and is converted to 2 molecules of
pyruvate by the remaining enzymes of the
pathway.
• The genetic absence of the enzyme UDP- Glucose
- Galactose-1-P Uridyl transferase enzyme lead to
the accumulation of Galactose in the blood , a
condition called galactosemia.
06/22/2025 45
 GLUCONEOGENESIS
• Gluconeogenesis is a biochemical pathway in
which D-Glucose is synthesized from non-
carbohydarte precussors such as pyruvate ,
Lactate , Oxaloacetate , , certain amino acid etc.
• Gluconeogenesis is an anabolic pathway .
• takes place mainly in the liver and to a lesser
extent in the renal cortex.
• This pathway is operated partially in the
mitochondria and partially in the cytosol.
• Gluconeogenesis takes place when there is a lack
of sufficient glucose in the body and during
starvation.
 GLUCONEOGENESIS
• Most of the enzymes involved in gluconeogenesis are
the same as that involved in Glycolysis (Reversal of
Glycolysis)
• The three irreversible steps in glycolysis are bypassed in
gluconeogenesis with the help of 4 additional enzymes
which are designated as the key enzymes of
gluconeogenesis.

They are
• Pyruvate carboxylase
• Phospho-enol pyruvate carboxykinase
• Fructose 1,6-bisphosphatase &
• Glucose -6-phosphatase.
 GLUCONEOGENESIS
Substrate for Gluconeogenessis.
1. Pyruvate
2. Lactate-
3. Glucogenic amino acids –
Examples include alanine , aspartic acid , glutamic acid, etc.
• These amino acids are either deaminated or transaminated to
form corresponding keto acids (carbon skeleton).
• These keto acids enters the Citric acid cycle and are converted to
oxalo acetate which is a substrate for Gluconeogenesis.
4. Glycerol–liberated during lipid mobilization (associated with
fasting and hypoglycemia).
5.Propionyl COA -activated propionic acid- an odd chain fatty acid
 GLUCONEOGENESIS
Glucose – Alanine cycle The cyclic pathway
involved in the interconvertion between
Alnine and Glucose in the body is called
Glucose –Alanine cycle.
 GLUCONEOGENESIS

Significance of Gluconeogenesis

• maintenance of blood glucose level during

starvation/ hypoglycemia.
• D- Glucose is the only source of energy for NS.
• Re-utilize the lactate formed during anaerobic
glycolysis and glycerol produced in adipose tissue.
• Only liver can replenish D- Glucose - Glucose-6-
Phosphatase enzyme is present only in liver.
• Propionic acid -is the only glucogenic fatty acid.
 GLUCONEOGENESIS

Regulation
• Glycolysis and gluconeogenesis are
reciprocally regulated.
• Glucagon enhances gluconeogenesis by
inducing the synthesis of key enzymes.
• Glucocorticoids enhances gluconeogenesis.
• ATP enhances gluconeogenesis.
• AMP inhibit gluconeogenesis.
• Insulin inhibit gluconeogenesis.
Glycolysis vs. Gyconeogenesis regulation
Glycolysis vs. Gyconeogenesis regulation
 Maintaining glucose homeostasis
• Blood glucose homeostasis is regulated mainly
by two hormones:
Insulin
 secreted when blood glucose is high.
 Controls transport of glucose from blood to
muscle and fat cells
Glucagon
 secreted when blood glucose is low.
 Helps in release of glucose from storage.
06/22/2025 55
• Glucose homeostasis
Body
cells
Insulin take up more
glucose

Beta cells
of pancreas stimulated
to release insulin into
the blood Liver takes Blood glucose level
up glucose declines to a set point;
High blood and stores it as stimulus for insulin
glucose level glycogen release diminishes

STIMULUS:
Rising blood glucose
level (e.g., after eating
a carbohydrate-rich
meal) Homeostasis: Normal blood glucose level
(about 90 mg/100 mL) STIMULUS:
Declining blood
glucose level
(e.g., after
skipping a meal)

Blood glucose level

rises to set point; Alpha
stimulus for glucagon cells of
release diminishes pancreas stimulated
to release glucagon
into the blood
Liver
breaks down
glycogen and Glucagon
releases glucose
Figure 26.8 to the blood
 Fate of pyruvate
2 Ethyl alcohol (in yeast)

Glucose 2,pyruvate 2-AcetylCOA (under aerobic

condition)

2 Lactate (in muscles & RBC

under anaerobic condition)
 Fate of pyruvate
1. Oxidative decarboxylation of pyruvate to acetyl COA
(under aerobic condition)
• Pyruvate is transported to the mit.matrix with the
help of a transport protein called pyruvate transporter
which is present in the inner mit. membrane.
• In the mit. matrix pyruvate is oxidatively
decarboxylated to acetyl COA.
• This process takes place with the help of an enzyme
complex called Pyruvate Dehydrogenase Complex
(PDC).
• PDC is a multienzyme complex consisting of 3 enzymes
and 5 co-enzymes.
 Fate of pyruvate
Enzymes
1. Pyruvate dehydrogenase
2. Dihydrolipoyil trans acetylase
3. Dihydrolipoyil dehydrogenase
Co-enzymes
1. Thiamine pyrophosphate(TPP)
2. COASH
3. FAD
4. NAD+
5. Lipoic acid
The five reactions of the
Pyruvate dehydrogenase
multi enzyme complex
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.
 Fate of pyruvate

• Oxidative decarboxylation is an irreversible

reaction.
• It yields 2 NADH (for 2 molecules of pyruvate
formed from 1 molecule of Glucose) which
on oxidation yield a total of 6 molecules of
ATP .
 Fate of pyruvate

Anaerobic glycolysis ( under anaerobic condition)

• In the absence of sufficient oxygen pyruvate is reduced to

lactate.
• This process is called anaerobic glycolysis.
• It takes place in the cytosol of skeletal muscle cells.
• The reaction is catalyzed by an enzyme called Lactate
dehydrogenase (LDH) which requires NADH+H+ as a co-enzyme.
• The net energy production in anaerobic glycolysis is only 2
molecules of ATP per molecule of Glucose.
•
 Coris Cycle or Lactic Acid Cycle
 In an actively contracting muscle, only about 8% of the pyruvate is
utilized by TCA cycle and
 The remaining reduced to lactate.
 The lactic acid thus generated
accumulate in the muscle tissues.
Causes the muscle cramps, often associated with strenuous
muscular exercise
 During exercise, blood lactate level increases considerably
 Lactate diffuse into blood
 then reaches liver where it is oxidized to pyruvate.
 It is then taken up through gluconeogenesis pathway and becomes
glucose
 The glucose enter into blood and then taken to muscle.
 This cycle is called cori's cycle,
 Significance of the cycle

 by which the lactate is

efficiently reutilized by the
body

 Muscle cannot form glucose

by gluconeogenesis process
because
 glucose 6 phosphatase
is absent.
 Unlike Liver, muscle cannot
supply Glucose to other
organs in spite of having
Glycogen
FIg . The Cori cycle.
 CITRIC ACID CYCLE
• Under aerobic condition pyruvate formed by glycolysis
enters the mitochondria and undergo oxidative
decarboxylation to form acetyl COA.
• Acetyl COA is completely oxidized in the mitochondrial
matrix in to CO2 and H2O in a cyclic pathway known as
Citric acid cycle.
• Citric acid cycle is also known as Krebs cycle because it
was elucidated by a scientist named Hans Krebs.
• It is also called as tricarboxylic acid cycle because;
citrate the first intermediate in this cycle is a
tricarboxylic acid.
 CITRIC ACID CYCLE
• Citric acid cycle consists of 8 steps and 8
enzymes and all these reactions are taking
place in the mitochondrial matrix.
• All enzymes except one are present in the
matrix in a soluble form and are called soluble
enzymes.
• But succinate dehydrogenase(SDH) is present
bound to the inner membrane and is called a
membrane bound enzyme.
 CITRIC ACID CYCLE
• There are three irreversible steps in citric acid
cycle which are called rate limiting steps or key
enzyme steps.
• The steps are step I (Citrate synthase), step III
(ICDH) and step IV (alpha ketoglutarate
dehydrogenase).
• The citric acid cycle can be represented as
follows.
 CITRIC ACID CYCLE
• During each turn of the cycle 1 molecule of Acetyl
COA enters the cycle and 3 NADH, 1 FADH2 , 1
GTP , 2 CO2 and 1 COASH are produced in the cycle.
• Citric acid cycle is considered as an amphibolic cycle
because it is having both catabolic and anabolic
roles.
• Catabolic role- It is a pathway for the complete
oxidation of carbohydrates amino acids and fatty
acids.
• Anabolic role – The intermediates of this cycle form
the precursors of several amino acids, steroids,
cholesterol etc.
 steps Enzyme ATP /NADH (produced or utilized)

Step III ICDH + 2 NADH + 2H+ ( =+ 6 ATP)

StepIV Alpha KGDH + 2 NADH + 2H+ ( =+ 6 ATP)

StepV Succynyl COA synthetase + 2 GTP (=+ 2 ATP)

StepVI SDH + 2 FADH2 (=+ 4 ATP)

Step VIII MDH + 2 NADH + 2H+ (= +6 ATP)

Energy yield of Citric acid cycle( 2 turns of the cycle / 2 acetyl COA /1 Glucose)

Total no. of ATP utilized =0

Net yield of ATP= 2 4ATP/ Glucose molecule
Total energy yield during the complete oxidation of one molecule of
Glucose via. glycolysis, PDC and Citric acid cycle
Total energy yield = 38 molecules of ATP / Glucose molecule

Pathway Energy yield

Glycolysis 8 ATP

Oxidative decarboxylation of 6 ATP

pyruvate to acetyl COA ( PDC)

Citric acid cycle 24 ATP

 CITRIC ACID CYCLE
Regulation of citric acid cycle
• Key enzymes are the regulatory points in citric acid
cycle.
• The key enzymes are stimulated by Ca++ ions which
are liberated during increased muscular work /
energy demand.
• The key enzymes are activated by NAD + and ADP.
• The key enzymes are inhibited by NADH + H+ and ATP.
• Citric acid cycle is activated when there is an
increased energy demand and inhibited when the
energy level is sufficient in the body.
 ELECTRON TRANSPORT AND
OXIDATIVE PHOSPHORYLATION

Electron Transport Chain (ETC)

• The reducing equivalents such as NADH and FADH2
formed during Citric acid cycle donate its electron to
a series of electron carriers present in the inner
membrane of the mitochondria.
• The electrons are finally accepted by molecular
oxygen and oxygen gets reduced to water (metabolic
water).
• This flow of electron from reduced substrate to
molecular oxygen is termed electron transport.
 ELECTRON TRANSPORT AND
OXIDATIVE PHOSPHORYLATION
• A series of electro carriers present in the inner
mitochondrial membrane which are involved in the
process of electrons transport from reduced substrate
to molecular oxygen are collectively called electron
transport chain (ETC).
• Since this electron transport is the final event in cell
respiration, this chain is also known as respiratory
chain.
• Electron transport takes place by a series of oxidation-
reduction reactions involving different electron
carriers.
 ELECTRON TRANSPORT AND
OXIDATIVE PHOSPHORYLATION
• Electron carriers of ETC are arranged in to four major
complexes and a mobile electron carrier.
• Complex –I

• Complex –II

• Complex –III

• Complex- IV
&
• Ubiquinone or Coenzyme Q, the mobile electro carrier.
 ELECTRON TRANSPORT AND
OXIDATIVE PHOSPHORYLATION

Oxidative phosphorylation
During the process of electron transport from reduced substrate
to molecular oxygen along the electron carriers (ETC), there is a
large decrease in the free energy.
• The free energy which gets liberated is used for the
phosphorylation of ADP to form ATP.
• This type of coupled formation of ATP which is associated with
the electron transport (oxidative process) is called as oxidative
phosphorylation.
• Oxidative phosphorylation is always coupled to electron
transport. The enzyme involved in the process of ATP synthesis is
called ATP Synthase .
• ATP Synthase is located in the inner mitochondrial membrane.
 ELECTRON TRANSPORT AND
OXIDATIVE PHOSPHORYLATION
• There are three sites of oxidative phosphorylation in
the electron transport chain.
• Site I – associated with complex I
• Site II – associated with complex II
• Site II – associated with complex IV

• The electrons from NADH pass through all the three

ATP forming sites and produce 3 molecules of ATP.
• Whereas, the electrons from FADH2 by passes the site I
of ATP formation and produce 2 molecules of ATP.
ETC
 ELECTRON TRANSPORT AND
OXIDATIVE PHOSPHORYLATION
Substrate level phosphorylation –
• The formation of ATP by the phosphorylation of ADP, which takes place at the
level of substrate is termed substrate level phosphorylation.
• Here the phosphate group is directly transferred from substrate to ADP.
Examples.
• 1) The formation of ATP during the conversion of 1,3 Diphospho glycerate to 3-
phospho glycerate( 7th step in Glycolysis).
&
• 2) The formation of ATP during the conversion of phosphoenol pyruvate to
pyruvate (10th step in Glycolysis).

• Ox. Phosphorylation is the major mechanism and sub.

Phosphorylation is the minor mechanism of ATP
formation inside the cells.
 ELECTRON TRANSPORT AND
OXIDATIVE PHOSPHORYLATION
Inhibitors of electron transport
Substances that block or prevent the transport of electrons along
the electro transport chain.
Inhibitors act at different complexes.
Examples
• Complex I to Ubiquinone - Rotenone
• Complex II to ubiquinone -Carboxin
• Complex III -Antimycin A
• Complex IV -hydrogen sulphide,
carbon monoxide, Cyanide etc.
 ELECTRON TRANSPORT AND
OXIDATIVE PHOSPHORYLATION

Uncouplers of Electron Transport

• Uncouplers are substances that allow electron transport to takes
place, but prevents oxidative phosphorylation i.e. the synthesis of
ATP is inhibited .
• They uncouple electron transport and oxidative phosphorylation.
Eg. Oligomycin, --antibiotic
2,4 dinitrophenol-lipophilic molecule that perforate membrane
causing leakage of protons in to the matrix, prevents the
formation of a proton gradient etc.

• Thermogenin is a natural uncoupler protein present in the brown

adipose tissue of new born babies.
 Electron Transport
High-energy electrons from NADH and FADH2 are passed
along the electron transport chain from one carrier protein
to the next.

Copyr
ight
Pears
on
 Electron Transport
At the end of the chain, an enzyme combines these
electrons with hydrogen ions and oxygen to form water.

Copyr
ight
Pears
on
 Electron Transport
As the final electron acceptor of the electron transport chain,
oxygen gets rid of the low-energy electrons and hydrogen ions.

Copyr
ight
Pears
on
 Electron Transport
When 2 high-energy electrons move down the electron
transport chain, their energy is used to move hydrogen ions (H+)
across the membrane.

Copyr
ight
Pears
on
 Electron Transport
During electron transport, H+ ions build up in the intermembrane
space, so it is positively charged.

Copyr
ight
Pears
on
 Electron Transport
The other side of the membrane, from which those H+ ions are
taken, is now negatively charged.

Copyr
ight
Pears
on
 Electron Transport
The inner membranes of the mitochondria contain protein
spheres called ATP synthases.

ATP
synthase

Copyr
ight
Pears
on
 Electron Transport

As H+ ions escape through channels into these proteins, the ATP

synthase spins.

Channel

ATP
synthase

Copyr
ight
Pears
on
 Electron Transport

As it rotates, the enzyme grabs a low-energy ADP, attaching a

phosphate, forming high-energy ATP.

Channel

ATP
synthase

ATP

Copyr
ight
Pears
on
 Electron Transport Chain

Electron Transport
Hydrogen Ion
Movement Channel Mitochondrion

Intermembrane
Space
ATP synthase

Inner
Membrane

Matrix
ATP
Production

94
 Electron Transport

• As it rotates, the enzyme grabs a low-energy ADP, attaching a

phosphate, forming high-energy ATP.

Channel

ATP
synthase

ATP

95
 ELECTRON TRANSPORT CHAIN

INTERMEMBRANE
SPACE CRISTAE

MATRIX

96
 Pentose Phosphate Pathway
 Also known as:
 Pentose shunt
 Hexose monophosphate shunt
 Phosphogluconate pathway
 HMP-alternative pathway for oxidation of Glucose-not for
Energy
 It occurs in the cytosol.
Major differences with glycolysis path way
1.Occurs in certain specialized tissues
Liver,adipose, RB cells,testes,ovary,aderenal cortex and
lactating mammary gland
2.It is a multicyclic process
3.Oxidation by dehydrogenation but NADP+
4. Neither uses nor produces ATP
5. Produces CO2
 Pentose Phosphate Pathway

 The pathway begins with the

glycolytic intermediate
glucose 6-P.
 It reconnects with
glycolysis because
 glyceraldehyde 3-P and
fructose 6-P
 two intermediates
further down in
the glycolytic
pathway.
 It is for this reason that the
pentose pathway is often
referred to as a shunt
 Moderate glucose flux

Glycolysis
only
 Large glucose flux

Pentose
Phosphate
Pathway
Glycolysis
 There are two main stage
in HMP
1. Oxidative stage
2. Non-oxidative stage
 Irreversible
 1st NADPH is produced
 primarily regulated at
G6PD Regulatory
 NADPH-comp inhibitor of enzyme
G6PD
 Hydrolysis
 hydrolase or lactonase
 irreversible

 Oxidative
decarboxylation
 Irreversible
 2nd NADPH is produced 5 carbon atoms
 The reactions are readily
reversible
 Interconversion of pentoses is
achieved by two peculiar reactions
depends on two enzymes.
1.Transketolase:
it transfers a two carbon unit ,a “ketol group
“of a keto pentose to an aldose to form
another aldose and ketose
2.Transaldolase :
it transfers a 3-carbon moity
“dihyderoxyacetone” from the ketose to
the aldose to form again aldose and ketose
 Biomedical importance
• It does not generate ATP but has two major
function :
1. The formation of NADPH
 used for reductive syntheses
 fatty acid
 steroids
 Cholesterol
 Sphingolipides
 conversion of oxidized glutathione G-S-S-G to reduced G-SH
2. Provision of pentose
 Nucleotide biosynthesis leading to:
• DNA
• RNA
• Various cofactors (CoA, FAD, SAM, NAD+/NADP+).
 Detoxification of Superoxide Anion and Hydrogen Peroxide

In erythrocytes :
• Antioxidant enzymes
• HMP Shunt provides NADPH Superoxide dismutase
for the reduction of oxidized
glutathione
Glutathione peroxidase
• This reaction is important b/c Glutathione reductase
 accumulation of H2O2
may decrease the life
span of the erythrocyte
 damage to the
membrane cell
hemolysis
 Regulation of the Pentose Pathway
 Glucose 6-phosphate DH is the regulatory enzyme
 It is primarily regulated by
 cytoplasmic levels of NADP+ and NADPH
 NADPH is a potent competitive inhibitor of the enzyme
 the ratio NADPH/NADP+ is ↑ , the enzyme is inhibited.
 But the ratio NADPH/NADP+ decreases and enzyme
stimulated.
 Again rate of the path ways are enhanced
on feeding high carbohydrate diets
But reduce in
 starvation and DM
 G-6-PD deficiency
 Inherited disease
 most common disease producing enzyme abnormality in humans- X-linked
 Most G6PD-deficient individuals are
asymptomatic
 But factors-
 Oxidant drugs
antibiotics (sulfamethoxazole)
antimalarial (primaquin)
antipyritics (acetanilid)
 ingest Fava beans [favism]
 severe infection
 These all factors make to be symptomatic

106
 G-6-PD deficiency
 Because ↓activity of G6-PD→↓NADPH [HMP]
→↓detoxification of FR & peroxides
 Hemolytic anemia resulted
 Shortened life span due to complications
 RBC- most vulnerable
 Because HMP is only means for NADPH production. (other tissues NADP-
dependent malate dehydrogenase also]
 But in contrary ,Increased resistance to falciparum malaria in
female carriers of mutation G-6-P dehydrogenase
• The basis for this resistance is
 the weakening of the red cell membrane (the
erythrocyte is the host cell for the parasite) such
that
 it cannot sustain the parasitic life cycle long
enough for productive growth

107
 Pathway Questions

1. What does the pentose phosphate pathway accomplish for the cell?

– The oxidative phase generates NADPH which is required

for many biosynthetic pathways and for detoxification of
reactive oxygen species.

– The nonoxidative phase interconverts C3, C4, C5, C6 and C7

monosaccharides to produce ribose-5P for nucleotide
synthesis, and also to regenerate glucose-6P to maintain
NADPH production by the oxidative phase.
 Pathway Questions
2. What are the key enzymes in the pentose phosphate pathway?

Glucose-6P dehydrogenase (G6PD)–This reaction is the commitment step in

the pathway and is feedback-inhibited by NADPH.

Transketolase and Transaldolase - together these two enzyme catalyze the

reversible "carbon shuffle" reactions of the nonoxidative phase of the
pathway.
Glycogen Metabolism
 Glycogen Metabolism cont

Carbohydrates are stored mainly in the form of

glycogen for the following reasons:
Dietary intake of glucose and glucose precursors
are sporadic.
Storage of glucose in the form of fat is not
suitable because:
 Fat cannot be mobilized as rapidly in
muscles as glycogen.
 Fat cannot be used as a source of energy
in the absence of oxygen.
 Unlike glycogen fat cannot be transformed
directly to glucose
 Glycogen Metabolism cont
Glycogen Function
 In liver
 The synthesis and breakdown of glycogen regulated
 To maintain blood glucose levels
 In muscle
 The synthesis and breakdown of glycogen regulated
 To meet the energy requirements of the
muscle cell.
 Glycogen Metabolism cont
Glycogen Synthesis (or Glycogenesis)
 Takes place in virtually all animal tissues
 But is especially prominent in
 The liver
 Skeletal muscles
 Very small amount of glycogen synthesis & storage in the
CNS.
 This is why it is completely dependent on blood glucose
as a source of energy.
Sources of Glucose
1. For liver glycogen:
 Blood glucose; Other hexose’s: fructose & galactose
 Non-carbohydrate sources: “gluconeogenesis”,
e.g., amino acids, glycerol and lactate during fed
state.
2. For muscle glycogen:
 Glycogen Metabolism cont.
 Site: cytoplasm of all cells particularly liver and
muscles.
 Steps:

1. The starting point for synthesis of glycogen

 glucose 6-phosphate
 By phosphoglucomutase

2. Glu-1-p The active nucleotide UDP-glc

by reaction
 with UTP catalyzed by UDP-glucose
pyrophosphorylase:
The sugar nucleotide UDP-Glucose donates glucose for
glycogen synthesis
3. Synthesis of Glycogen primer with the help of a protein
called Glycogenin:
 A glycogen primer containing 8 glucose units is first
synthesized on the glycogenin protein
• with the help of an enzyme called glycosyl
transferase.
• achieved by the successive addition of glucose
units from UDP glucose to the non reducing end
• The primer remains attached to the glycogenin
protein at its Tyrosine residue.
 Glycogen Metabolism cont
4. Extension by Glycogen synthase
 connects C1 of glucose units of UDP-
glucose with C4 of a terminal glucose
residue in a pre-existing glycogen chain
(glycogen primer)
 Glycogen Metabolism cont.
5. Branching
 The glycogen-branching enzyme, also called
 amylo (14) to (16) transglycosylase or

 Glycosyl-(4:6)-Transferase:
 transfer of 6 or 7 glucose residues from the
non- reducing end of a glycogen branch having at
least 11 residues to the C6 hydroxyl group of a
glucose residue
Glycogen Metabolism cont.
 The key regulatory enzyme of
glycogenesis
 glycogen synthase.
 exists in 2 forms:
 Inactive form
 glycogen synthase b
 This form is phosphorylated, i.e.,
phospho-synthase.
 By protein kinase
 Active form
 glycogen synthase a
 Dephospho-synthase results
from dephosphorylation of
synthase
 by phosphatase.
 Glycogen Metabolism cont.

Glycogen Breakdown ( Glycogenolysis)

 process of glycogen catabolism into:
 Glucose  to blood, in the liver Or
 Glucose-6-phosphate  Lactic acid, in the skeletal
muscles.
 through the action of three enzymes:
 Glycogen phosphorylase,
 Glycogen debranching enzyme, &
 Phosphoglucomutase.
Site
 Cytoplasm of all cells
 Glycogen Metabolism cont.
 Steps:

1. Glycogen phosphorylase
catalyzes the reaction (14) glycosidic linkage
removing the terminal glucose residue as
 -D-glucose 1-phosphate
Pyridoxal phosphate (PLP) is an essential cofactor
in the reaction
 its phosphate group acts on the glycosidic bond.
acts repetitively on the non reducing ends
 until it reaches a point four glucose residues away from an
(16) branch point
 Glycogen Metabolism cont.

2. Further degradation by glycogen phosphorylase

 can occur only after the debranching enzyme
 also known as oligo (16) to (14)
glucantransferase
 catalyzes two successive reactions
 First, the transferase activity
 the enzyme shifts three glucose residues
from the branch to a near by nonreducing end
 Second ,cutting the glucose remaining at the
branch point (16)
o then released as free glucose by
o the enzyme’s (16) glucosidase activity.
o Then glycogen phosphorylase activity
continue.
 Glycogen Metabolism cont.

Figure-G3 Removal of a terminal

Figure-G4 Glycogen breakdown
glucose residue from the
near an (16) branch point
nonreducing end of a glycogen
chain by glycogen phosphorylase
 
Glycogen Metabolism
Regulation cont.
of Glycogenolysis

Regulation of Glycogenolysis
 The key regulatory enzyme
 phosphorylase.
 present in 2 forms:
o Active
 Phosphorylase a
 phosphorylase form.
o Inactive
phosphorylase b
dephosphorylase
form.
 Glycogen Metabolism cont.
Glycogen synthesis and breakdown are reciprocally regulated

Glycogen synthesis and breakdown are reciprocally regulated

Red=inactive forms, green = active forms.

Inactive
Active
Protein phosphatase 1 (PP1) regulates glycogen metabolism.
 CLINICAL CORRELATES OF CHO
GLYCOGEN STORAGE DISEASE
a group of inherited disorders characterized by
deposition of an abnormal type or quantity of
glycogen, or
failure of storage or mobilization of glycogen
into/from tissues
1. Type 0:
Is due to the deficiency of liver glycogen synthase
It leads to fasting hypoglycemia, ketosis& early
death
2.Type I (Von Gierk’s disease)
due to glucose 6-phosphatase deficiency in the liver
cell and intestinal mucosal cell
Hypoglycemia is major problems
 CLINICAL CORRELATES OF CHO …………….

3.Type II (pomp's disease)

Due to deficiency of lysosomal α-1,4-and α-1,6-
glycosidase which act on glycogen to hydrolyze it.
Glycogen accumulate in lysosomes of all tissue,
mainly skeletal and cardiac muscles
It disrupts the function of muscles cells causing
cardiomegaly, heart failure and death
4.Type III (Limit Dextrinosis,Cori’s or Forbe’s disease )
Due to disorder concern debranching enzymes
5. Type IV (Andersone’s Disease,amylopectinosis)
Deficiency of the glycogen branching enzyme
Cirrhosis of the liver with the storage of abnormal
glycogen
 CLINICAL CORRELATES OF CHO …………….

6.Type V: McArdle Disease;

Skeletal Muscle Glycogen Phosphorylase Defect
 Skeletal muscle is affected, whereas the
liver enzyme is normal.
 Exercise capacity is greatly reduced,
hypoglycemia during exercise
 There is no rise in blood lactate during
strenuous exercise.
 Muscle contains a high level of glycogen
with normal structure
 CLINICAL CORRELATES OF CHO …………….

7. Type VI: Hers Disease

Liver Glycogen Phosphorylase Defect
 Liver is affected, whereas the skeletal
muscle enzyme is normal.
 Marked hepatomegaly occurs due to a
high level of glycogen with normal
structure.
 Following administration of glucagon,
there is no increase in blood glucose
Metabolic blocks causing glycogen storage diseases
 CLINICAL CORRELATES OF CHO …………….

hypoglycemia (<90mg%)

( -)
alpha cells secrete
glucagon

liver cells:
negative increase glycogenolysis
feedback increased gluconeogenesis

increased blood
glucose

normoglycemia (>90mg
%)
 CLINICAL CORRELATES OF CHO …………….

hyperglycemia (>110mg%)

beta cells secrete insulin

( -)

 increased glucose uptake into body cells increase

negative feedback
glycogenesis (skeletal muscle, liver)
 increased lipogenesis

decreased blood glucose

normoglycemia (<110mg%)
 Diabetes
•Diabetes
– Inability to regulate blood glucose levels
– Three types:
• Type 1 diabetes
• Type 2 diabetes
• Gestational diabetes
– Untreated diabetes can cause nerve damage,
kidney damage, blindness, and death
– retinopathy, nephropathy, and neuropathy.
 Diabetes
• Type 1 diabetes
– Accounts for 10% of all cases
– Patients do not produce enough insulin
– Causes hyperglycemia – high blood sugar
(glucose)
– Requires insulin injections
– May be an autoimmune disease
 Diabetes
• Type 2 diabetes
– Most diabetics have Type 2 diabetes
– Body cells are insensitive or unresponsive to insulin
– Excess insulin is often produced
– Causes hyperglycemia
– because cells cannot remove glucose from the
blood
 Diabetes
• Type 2 diabetes
– Causes include genetic predisposition, obesity,
and physical inactivity
– Treated with diet, exercise, and possibly oral
medications
– Healthy lifestyle choices may prevent or delay
onset of type 2 diabetes
Main symptomes and signs of DM and mechanisms
of their onset
1. Hyperglycemia:
· relative or absolute deficiency of insulin effect  
transport of
glucose to muscle and fat cells  glycemia
·  insulin effect  gluconeogenesis in liver  blood level

of
glucose

Three p’s symptoms

Polyuria:  blood level of glucose  ed amount of glucose
filtered by the glomeruli of the kidney
absorbtion
capacity of renal tubules for glucose is
exceeded
 Hypoglycemia
• Hypoglycemia
– Low blood sugar (glucose)
– Reactive hypoglycemia results when too much
insulin is produced after a meal
• Causes shakiness, sweating, anxiety
– Fasting hypoglycemia results when too much insulin
is produced even when the patient has not eaten
06/22/2025 141
Galactosemia
 Galactocemia: How does it
happen?

Dietary Lactose Galactose Galactose 1-Phosphate Glucose

LIVER EYES
BRAIN  Jaundice
 Hetaptomegaly cataracts
Mental retardation
 Cirrhosis

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