Download Bioenergetics, glycolysis, metabolism of monosaccharides and

Bioenergetics
Presented by
Dr. Mohammad Saadeh
The requirements for the Pharmaceutical Biochemistry II
Philadelphia University
Faculty of pharmacy
I. overview
Bioenergetics describes the transfer and utilization of energy in biologic
systems.
II. Free energy
∆G = ∆H-T∆S
 Enthalpy (ΔH, a measure of the
change in heat content of the
reactants and products)
 Entropy (ΔS, a measure of the
change in randomness or disorder
of reactants and products, Figure
6.1).
 Enthalpy and Entropy can be used
to define a third quantity, free
energy (G), which predicts the
direction in which a reaction will
spontaneously proceed.
III. Free energy change
ΔG and ΔGo.
 ΔG, represents the change in free energy and predict the direction
of a reaction.
 Standard free energy change, ΔGo, which is the energy change
when reactants and products are at a concentration of 1 mol/L.
A. Sign of ΔG predicts the direction of a reactions
1. If ΔG is negative (see figure A)
 The product has a lower free energy than the
substrate.
 The reaction goes spontaneously from A to B.
 The reaction is exergonic.
2. If ΔG is positive (see figure B)
 The product has a higher free energy than the
substrate.
 The reaction does not go spontaneously from
B to A.
 The reaction is endergonic.
3. If ΔG is zero
 The reactions are in equilibrium.
 The ΔG of the forward reaction (A → B ex:
ΔG= -5kcal/mol) is equal in magnitude but
opposite in sign to that of the back reaction
(B → A ex: ΔG = 5kcal/mol).
ΔG depends on the concentration of reactants and products
The ΔG of the reaction A → B depends on the concentration of the
reactant and product. At constant temperature and pressure.
Where: ΔGo is the standard free energy change, R is the gas constant (1.987
cal/mol . degree), T is the absolute temperature (K), [A] and [B] are the actual
concentrations of the reactant and product, ln represents the natural logarithm.
Example: for non-equilibirium conditions (see the
figure) glucose 6-phosphate, is high compared with the
concentration of product, fructose 6-phosphate.
• RT ln([fructose 6-phosphate] ⁄ [glucose 6phosphate]) is large and negative,
• causing ΔG to be negative despite ΔGo being
positive. Thus, the reaction can proceed in the
forward direction.
Standard free energy change, ΔGo
Under standard conditions, reactants and products are at 1 mol/L concentrations
(see the figure).
ln [A]/[B] = ln1 = 0, So:
Note: Under standard conditions, ΔGo
can be used to predict the direction a
reaction proceeds because ΔGo is equal
to ΔG.
Relationship between ΔGo and Keq
 In a reaction A → B
 point of equilibrium is when A is being converted to B as fast as B is
being converted to A (see the figure).
 At equilibrium point ∆G=zero
This equation allows some simple predictions:
equal
Forward reaction, exergonic
Back reaction, endergonic
ΔGo of two consecutive reactions are additive:
ΔGo are additive in any sequence of consecutive reactions, as are the
free energy changes (ΔG). For example:
ΔGs of a pathway are additive: in biochemical pathways (for example, A →
B → C → D → ...). As long as the sum of the ΔGs of the individual reactions
is negative the reaction can proceed.
Adenosine triphosphate (ATP) as an energy carrier
 reactions that have a large, positive ΔG are made possible by coupling
with cleavage of adenosine triphosphate (ATP).
 adenosine triphosphate (ATP) has a large, negative ΔG.
 ΔGo = –7.3 kcal/mol for each of the two terminal phosphate groups.
ATP
ADP
ADP+Pi
AMP+Pi
ΔGo = –7.3 kcal/mol
ΔGo = –7.3 kcal/mol
Structure of a mitochondrion
1. Membranes of the mitochondrion:
 Outer membrane is permeable to most
ions and small molecules.
 The inner mitochondrial membrane:
 It is impermeable to most small ions,
including H+, Na+, and K+, and small
molecules such as ATP, ADP, pyruvate.
 Specialized carriers are required to move
ions across this inner membrane.
 It is rich in protein, involved in electron
transport and oxidative phosphorylation.
 The convolutions, called cristae, serve to
greatly increase the surface area of the
membrane.
Structure of a mitochondrion
Matrix of the mitochondrion:
 This gel-like solution in the interior of
mitochondria is 50% protein.
 include the enzymes responsible for the
oxidation of pyruvate, amino acids, fatty
acids (by β-oxidation), and those of the
tricarboxylic acid (TCA) cycle. The
synthesis of glucose, urea, and heme
occur partially in the matrix of
mitochondria.
 the matrix contains NAD+ and FAD (that
are required as hydrogen acceptors) and
ADP and Pi, which are used to produce
ATP.
 The matrix contains mitochondrial RNA
and DNA (mtRNA and mtDNA) and
mitochondrial ribosomes.
Introduction to Carbohydrates
Presented by
Dr. Mohammad Saadeh
The requirements for the Pharmaceutical Biochemistry II
Philadelphia University
Faculty of pharmacy
I. overview
Carbohydrates are the most abundant organic molecules in nature.
They have a wide range of functions:
1. Providing a dietary calories for most organisms.
2. Storage energy in the body,
3. Cell membrane components that mediate some forms of
intercellular communication.
4. Structural component of many organisms, including (the cell walls
of bacteria, exoskeleton of many insects, fibrous cellulose of
plants.
The empiric formula for many of the simpler carbohydrates is (CH2O)n,
where n ≥ 3 hence the name “hydrate of carbon.”
Classification and structure of carbohydrates
a. Monosaccharides classified according to
1. The number of carbon atoms they contain. Examples of some
monosaccharides commonly found in humans are listed in Figure 7.1.
2. Monosaccharides (Figure 7.12) containing an aldehyde group are called
aldoses and those with a keto group are called ketoses.
Figure 7.1. Examples of monosaccharides
found in humans, classified according to the
number of carbons they contain.
Figure 7.2. Examples of an aldose (A) and
a ketose (B) sugar.
Classification and structure of carbohydrates
Monosaccharides can be linked by glyosidic bonds to create larger structures.
A. Disaccharides contain two mono saccharide units.
B. Oligosaccharides contain from 3-10 monosaccharide units.
C. Polysaccharides contain > 10 monosaccharide units, and can be
hundreds of sugar units in length.
 Isomers: is a compounds with the same
chemical formula (figure 7.4).
 Epimers: two monosaccharide isomers
differ in configuration around one specific
carbon atom (with the exception of the
carbonyl carbon) (figure 7.4).
 Enantiomers: is a pair of sugars are
mirror images, the two members of the
pair are designated as D- and L-sugars
(figure 7.5).
Enzymes known as racemases are able to
interconvert D- and L-isomers.
Figure 7.5
vvi
Figure 7.4
Cyclization of monosaccharides
99% of monosaccharides are predominantly found in a ring (cyclic) form
in solution.
The aldehyde (or keto) group has reacted with an alcohol group on the
same sugar, making the carbonyl carbon (carbon 1 for an aldose or carbon
2 for a ketose) asymmetric. This a symmetric carbon is referred to as
anomeric carbon. This carbon can have two configurations, α or β which
is called anomers.
Fischer projection
Haworth projection
Figure 7.6
A. The α and β anomeric forms of glucose shown as modified Fischer projection formulas.
B. The interconversion shown as Haworth projection formulas. Carbon 1 is the anomeric carbon.
Reducing sugars:
In a chemical reaction, when the anomeric carbon of a carbohydrate
has a hydroxyl group available to participate, it is considered a
reducing sugar. Such sugars can react with chromogenic agents (for
example, Benedict’s reagent or Fehling’s solution) causing the reagent
to be reduced and colored.
All monosaccharides are reducing sugar
Example of non reducing sugars
Example of non reducing sugars
Example of disaccharides:
 Lactose (galactose + glucose)
 sucrose (glucose + fructose)
 Maltose ( glucose + glucose)
Example of polysaccharides:
 glycogen: animal branched poly glucose
 Starch: plant branched poly glucose
 Cellulose: plant unbranched poly glucose
Naming glyosidic bonds
Glucose-α(1
4) glucose
Complex carbohydrates
Complex carbohydrates attached by
glyosidic bonds to non- carbohydrates
such as: purines & pyrimidines (found
in nucleic acids), aromatic rings (such
as those found in steroids & bilirubin),
proteins (found in glycoproteins &
glycosaminoglycan), and lipids (found
in glycolipids).
N- & O-glycosides:
Sugars can be attached either to an –NH2,
producing N-glycosides or an –OH,
producing O-glycosides.
Digestion of dietary carbohydrates
Digestion of polysaccharide in mouth and intestinal lumen catalyzed by
glycoside hydrolases (glycosidases) that hydrolyze glycosidic bonds that
produced monosaccharides, glucose, galactose and fructose.
A. Salivary α-amylase:
1. Salivary α-amylase hydrolyzing random
glyosidic bond which is
found in starch and glycogen.
2. Salivary α-amylase can not hydrolyzing cellulose contain
,,
amylopectin and glycogen also contain
.
3. Carbohydrate digestion halts temporarily in the stomach, because
the high acidity inactivates salivary α-amylase.
4. Pancreatic α-amylase digestion starch in small intestinal because the
acidity of stomach neutralized by bicarbonate.
Digestion of dietary carbohydrates
B. Intestinal disaccharidases
 isomaltase cleaves the α(1→6) bond
in isomaltose.
 maltase cleaves maltose to producing
glucose.
 Sucrase cleaves sucrose producing
glucose and fructose.
 lactase (β-galactosidase) cleaves
lactose producing galactose and
glucose.
 Trehalase cleaves trehalose, an
α(1→1) disaccharide of glucose.
Intestinal absorption of monosaccharides
The duodenum and upper jejunum
absorb the bulk of the dietary sugars.
For example,
 galactose and glucose are transported
into the mucosal cells by an active,
energy-requiring process by sodiumdependent glucose cotransporter 1
(SGLT-1).
 Fructose uptake requires a sodiumindependent monosaccharide
transporter (GLUT-5) for its
absorption.
All three monosaccharides are
transported from the intestinal mucosal
cell into the portal circulation by GLUT-2.
Digestive enzyme deficiencies:
If carbohydrate degradation is
deficient (heredity, intestinal disease,
malnutrition, or drugs that injure the
mucosa of the small intestine),
undigested carbohydrate will pass
into the large intestine, where it can
cause:
1. osmotic diarrhea.
2. Bacterial fermentation of the
compounds produces large
volumes of CO2 and H2 gas,
causing abdominal cramps,
diarrhea, and flatulence.
 Lactose intolerance, caused by a
lack of lactase or age dependent
loss of lactase due to mutation in
chromosome 2 that control the
gene of lactase.
 Sucrase-isomaltase complex
deficiency This deficiency results
in an intolerance of ingested
sucrose.
Introduction to Metabolism and Glycolysis
Presented by
Dr. Mohammad Saadeh
The requirements for the Pharmaceutical Biochemistry II
Philadelphia University
Faculty of pharmacy
Introduction to Metabolism
Metabolism is a term that is used
to describe all chemical reactions
involved in maintaining the living
state of the cells and the organism.
Figure 8.1: Glycolysis, an example of a metabolic
pathway.
Metabolic map
Catabolic pathways Catabolic reactions serve to capture chemical energy
in the form of adenosine triphosphate (ATP) from the degradation of
energy-rich fuel molecules.
Figure 8.3: Three stages of catabolism.
Transport of glucose into cells
Glucose enters into cells by one of two transport mechanisms:
A. Sodium-independent facilitated diffusion transport
Glucose transport by GLUT-1 to GLUT-14 (glucose transporter isoforms 1–14). Glucose
movement is down c concentration gradient (no energy)
Isoforms of GLUT
Functions
GLUT-1
abundant in erythrocytes and blood brain barrier
GLUT-2
abundant in liver, kidney, and pancreatic β cells
GLUT-3
glucose transporter in neurons.
GLUT-4
abundant in adipose tissue and skeletal muscle.
(activated by increase the insulin).
GLUT-5
transporter for fructose in the small intestine and the
testes.
B. Sodium-monosaccharide cotransporter system
glucose is coupled to the concentration gradient
of Na+, The carrier is a sodium-dependent glucose
transporter or SGLT. This type of transport occurs
in the epithelial cells of the intestine, renal
tubules, and choroid plexus.
Glycolysis
Glycolysis occurs in cytosol is employed by all tissues for the breakdown
of glucose to pyruvate to provide energy (ATP) and intermediates for
other metabolic pathways.
1. Aerobic glycolysis (Figure B 8.9 in the next slide) :
 Pyruvate is the end product of glycolysis in cells with mitochondria
and an adequate supply of oxygen.
 Aerobic glycolysis sets the stage for the oxidative decarboxylation of
pyruvate to acetyl CoA, a major fuel of the TCA (or citric acid) cycle.
2. Anaerobic glycolysis (Figure C 8.9 in the next slide):
 pyruvate is reduced to lactate as NADH is oxidized to NAD+. it occur
without of oxygen.
 Anaerobic glycolysis produced ATP in tissues that lack mitochondria
(ex, RBCs) or in cells deprived of sufficient oxygen.
Glycolysis (Figure 8.9)
Reaction of Glycolysis from A to J
Glycolysis is oxidation of glucose to pyruvate
in ten reactions (from A toJ).
Glycolysis occurs in two stages (Figure 8.11).
1. Energy investment phase (from A-E):
phosphorylated forms of intermediates by
consuming 2 ATP.
2. Energy generation phase (from F-J): is
generated 4 ATP and 2NADH.
 Total energy produced from aerobic glycolysis (glucose to pyruvate) = (-2ATP +
4ATP + 2NADH) = 8 ATP
 NADH ≈ 3 ATP
Reaction of Glycolysis from A to J
A. Phosphorylation of glucose:
 Glucose move into the cell by protein
transport.
 After that hexokinase or Glucokinase catalyze
the phosphorylation of glucose to glucose 6phosphate (G-6-P).
 Used one ATP
Reaction of Glycolysis from A to J
Glucokinase differs from hexokinase in several properties:
Glucokinase:
Glucokinase has higher km and high Vmax.
Indirectly inhibited by F-6-P.
Activated by glucose.
Maintained of blood glucose level
Hexokinase:
hexokinase has lower km and low
Vmax.
Inhibited by G-6-P.
Note: glucokinase is translocated into the nucleus
and binds to glucokinase regulatory protein
(GKRP), glucokinase inactive (Figure 8.14)
stimulation
inhibition
Figure 8.14
Reaction of Glycolysis from A to J
B. Isomerization of glucose 6-phosphate
The isomerization of glucose 6-phosphate to fructose 6-phosphate is
catalyzed by phosphoglucose isomerase (Figure 8.15). The reaction is
readily reversible.
Reaction of Glycolysis from A to J
C. Phosphorylation of fructose 6-phosphate
The irreversible phosphorylation reaction catalyzed by phosphofructokinase-1 (PFK-1) is important control point and the rate-limiting and
committed step of glycolysis (Figure 8.16).
Regulation allosterically PFK-1 :
PFK-1 Activated by:
 AMP
 Fructose 1,6 bisphosphate
 Fructose 2,6 bisphosphate
and able to activated PFK-1
when ATP levels are high.
PFK-1 inhibited by:
 Elevated level of ATP.
 Elevated level of
citrate.
Phosphofructokinase-2 (PFK-2) is a bifunctional protein
that has:
1. kinase activity that produces fructose 2,6bisphosphate.
2. phosphatase activity that dephosphorylates fructose
2,6-bisphosphate back to fructose 6-phosphate.
3. Inhibitor of fructose 1,6-bisphosphatase
(gluconeogenesis).
During the well-fed state:






Decreased levels of glucagon.
elevated levels of insulin.
Elevated level of glucose.
increase in fructose 2,6-bisphosphate.
Increase rate of glycolysis.
Decrease in gluconeogenesis.
During fasting:
 Elevated levels of glucagon.
 low levels of insulin.
 Decrease fructose 2,6bisphosphate.
 Decrease rate of glycolysis.
 Increase in gluconeogenesis.
Figure 8.17 Effect of elevated insulin concentration on the intracellular concentration of fructose 2,6-bisphosphate in liver.
PFK-2 = phosphofructokinase-2; FBP-2 = fructose bisphosphatase-2.
Reaction of Glycolysis from A to J
D. Cleavage of fructose 1,6-bisphosphate
 Aldolase cleaves fructose 1,6-bisphosphate
to dihydroxyacetone phosphate and
glyceraldehyde 3-phosphate.
 The reaction is reversible and not
regulated.
 Used one ATP
Reaction of Glycolysis from A to J
E. Isomerization of dihydroxyacetone
phosphate
Triose phosphate isomerase interconverts
dihydroxyacetone phosphate and
glyceraldehyde 3-phosphate.
Reaction of Glycolysis from A to J
F. Oxidation of glyceraldehyde 3-phosphate
 The oxidation aldehyde group of
glyceraldehyde 3-phosphate to a carboxyl
group which attached to Pi to form 1,3bisphosphoglycerate by glyceraldehyde 3phosphate dehydrogenase is the first
oxidation-reduction reaction of glycolysis
(Figure 8.18).
 Produced 2NADH.
• Synthesis of of 2,3-bisphosphoglycerate (2,3BPG) in red blood from 1,3bisphosphoglycerate by mutase.
NOTE:
1) NADH-linked conversion of pyruvate to
lactate (anaerobic glycolysis).
2) oxidation of NADH to NAD+ Electron
transport chain (aerobic glycolysis).
Reaction of Glycolysis from A to J
G. Synthesis of 3-phosphoglycerate
producing ATP
When 1,3-BPG is converted to 3phosphoglycerate by phosphoglycerate
kinase.
Synthesize 2 ATP from ADP.
Example of substrate-level phosphorylation,
energy phosphate comes from a substrate.
Reaction of Glycolysis from A to J
H. Shift of the phosphate group from carbon
3 to carbon 2
The shift of the phosphate group from carbon
3 to carbon 2 of phosphoglycerate by
phosphoglycerate mutase is freely reversible.
I. Dehydration of 2-phosphoglycerate
Dehydration of 2-phosphoglycerate by
enolase to form phosphoenolpyruvate (PEP).
The reaction is reversible.
H
Reaction of Glycolysis from A to J
J. Formation of pyruvate producing ATP
 The conversion of phosphoenolpyruvate
(PEP) to pyruvate catalyzed by pyruvate
kinase.
 2 molecule of PEP Produced 2 ATP.
 example of substrate-level phosphorylation.
(PEP)
The conversion of phosphoenolpyruvate (PEP) to pyruvate catalyzed by
pyruvate kinase and produced 2ATP.
Regulation of pyruvate kinase (allosteric enzyme):
1. Feedforward regulation: In liver, Elevated level of
fructose 1,6-bisphosphate effect of two kinase
activities :
 Increase activity of phosphofructokinase-1.
 Increase activity of pyruvate kinase.
2. Covalent modulation of pyruvate kinase (PK):
 Phosphorylation by a cAMP-dependent protein
kinase leads to inactivation of PK in the liver (Figure 8.19).
When glucose levels are low:
 Elevated level of glucagon and decrease level of
insulin.
 Increases level of cAMP that is cause inactivation
of pyruvate kinase.
 Therefore, PEP is unable to continue in glycolysis,
but instead enters the gluconeogenesis.
Figure 8.19.
Pyruvate kinase deficiency:
 RBCs lacks mitochondria and depend
on glycolysis for production of ATP and
maintain biconcave shape of RBCS.
 Inherited defects or deficiency in
glycolytic enzyme effects on
erythrocytes and present as mild to
sever chronic, nonspherocytic anemia
(change in RBCs shape)
K. Reduction of pyruvate to lactate
(anaerobic glycolysis)
 In anaerobic glycolysis, NADH is
reoxidized to NAD+ by the conversion of
pyruvate to lactate.
 Anaerobic glycolysis produced 2ATP and
two molecules of lactate.
 It occurs in lens and cornea of the eye,
kidney medulla, testes, leukocytes and red
blood cells, because these are all poorly
vascularized and/or lack mitochondria.
Reduction of pyruvate to lactate (anaerobic
glycolysis)
anaerobic glycolysis occurs in cells, don’t have
mitochondria such as erythrocytes.
 Lactate formation in exercising muscle, where
production of NADH exceeds the oxidative
capacity of the respiratory chain causing drop
intracellular pH and cramps.
 The liver oxidize lactate to pyruvate is either
converted to glucose by gluconeogenesis or
oxidized to TCA cycle.
 Heart oxidizes lactate to pyruvate then to CO2 and
H2O via TCA cycle.
 Elevated level of lactate in the plasma , termed
lactic acidosis occur when there is a collapse of
the circulatory system, or when an individual is in
shock.
Energy yield from glycolysis
aerobic glycolysis (8 ATP + 2 pyruvate):
 Total energy produced from aerobic glycolysis (glucose to
pyruvate) = (-2ATP + 4ATP + 2NADH+ 2 pyruvate) = 8 ATP + 2
pyruvate
 NADH ≈ 3 ATP
Anaerobic glycolysis (2 ATP + 2 Lactate):
 Total energy produced from Anaerobic glycolysis (glucose to
pyruvate) = (2ATP + 2 lactate)
Hormonal regulation of glycolysis (figure 8.23)
During the well-fed state:




During fasting:
Elevated level of glucose.

Decreased levels of glucagon.

elevated levels of insulin.

Increase amount of glucokinase,
phosphofructkinase, and pyruvate
kinase.

 increase in fructose 2,6-bisphosphate.

 Increase rate of glycolysis.

 Decrease in gluconeogenesis.
Elevated levels of glucagon.
low levels of insulin.
Decrease amount of glucokinase,
phosphofructkinase, and
pyruvate kinase.
Decrease fructose 2,6bisphosphate.
Decrease rate of glycolysis.
Increase in gluconeogenesis.
Figure 8.23: Hormonal regulation
of glycolysis
Fates of Pyruvate
1. Pyruvate converted to lactate.
2. Oxidatively decarboxylated by pyruvate
dehydrogenase, producing acetyl CoA.
3. Carboxylated to oxaloacetate (a TCA
cycle intermediate) by pyruvate
carboxylase.
4. Reduced by microorganisms to ethanol
by pyruvate decarboxylase.
Metabolism of Monosaccharides and
Disaccharides
Presented by
Dr. Mohammad Saadeh
The requirements for the Pharmaceutical Biochemistry II
Philadelphia University
Faculty of pharmacy
Glucose, fructose, and galactose are important in energy metabolism.
Fructose Metabolism:
 Fructose is a monosaccharide in fruits and honey.
 10% of the calories are supplied by fructose (approximately 55 g/day).
 The sucrose combination of the glucose and fructose.
 Entry of fructose into cells is not insulin dependent.
 fructose does not promote the secretion of insulin.
A. Phosphorylation of fructose
in liver, kidney, and small intestinal mucosa, phosphorylated fructose to
fructose 1-phosphate, using ATP as the phosphate donor and by either
hexokinase (low affinity, high Km) or fructokinase (high affinity, low Km).
Fructose Metabolism
Cleavage of fructose 1-phosphate
Fructose 1-phosphate is cleaved by aldolase B (called
fructose 1-phosphate aldolase) to dihydroxyacetone
phosphate (DHAP) and glyceraldehyde.
 Humans express three aldolases, A, B and C, all
cleave fructose 1,6-bisphosphate produced during
glycolysis to DHAP and glyceraldehyde 3phosphate
 only aldolase B cleaves fructose 1-phosphate.
 DHAP can directly enter glycolysis or
gluconeogenesis.
 Glyceraldehyde can be metabolized by a number
of pathways, (Figure 12.3 in the next slide).
 Synthesis of phosphoglyceride and
triacylglycerol.
 Glycolysis, by phosphorylated to
glyceraldehyde 3-P
 Gluconeogenesis, by converted to
dihydroxyacetone phosphate
Figure 12.3
Fructose Metabolism
C. Kinetics of fructose metabolism
The rate of fructose metabolism is more rapid than that of glucose because the
trioses formed from fructose 1-phosphate bypass phosphofructokinase-1 the
major rate-limiting step in glycolysis.
D. Disorders of fructose metabolism
 fructokinase deficiency, or aldolase B deficiency cause hereditary fructose
intolerance (HFI) lead to liver failure and death and appear when feed food
containing sucrose or fructose.
 Therefore, Fructose 1-phosphate accumulates, resulting decrease level of
inorganic phosphate (Pi) and ATP, AMP rises.
 affects gluconeogenesis, and protein synthesis (causing a decrease in blood
clotting factors and other essential proteins), and Kidney function may also
be affected.
E. Conversion of mannose to fructose 6-phosphate
Mannose, the C-2 epimer of glucose.
phosphorylates mannose, producing mannose 6-phosphate by Hexokinase,
which isomerized to fructose 6-phosphate by phosphomannose isomerase.
phosphomannose isomerase
Hexokinase
Mannose
mannose 6-phosphate
fructose 6-phosphate
Fructose Metabolism
F. Conversion of glucose to fructose
via sorbitol
Sugars are phosphorylated following
their entry into cells because trapped
within the cells. (organic phosphates
cannot cross membranes).
Synthesis of sorbitol:
 Aldose reductase reduces glucose
to sorbitol.
 Aldose reductase included in lens,
retina, Schwann cells of peripheral
nerves, liver, kidney, placenta, RBCs,
and in cells of the ovaries and
seminal vesicles).
 sorbitol dehydrogenase, which can
oxidize the sorbitol to produce
fructose.
Fructose Metabolism
The effect of hyperglycemia on sorbitol metabolism:
 Elevated intracellular glucose due to hyperglycemia and an adequate
supply of NADPH cause aldose reductase to produce sorbitol.
 Sorbitol accumulate in cells causing strong osmotic effects, swelling ,
water retention. peripheral neuropathy, and microvascular problems
leading to nephropathy and retinopathy.
Galactose Metabolism
 The source of galactose is lactose (galactosyl β-1,4-glucose) obtained
from milk.
 Entry of galactose into cells is not insulin dependent.
A. galactose phosphorylated by galactokinase to galactose 1-phosphate
(ATP is the phosphate donor) (Figure 12.5).
B. Galactose 1-phosphate. This compound is converted to UDPgalactose by galactose 1-phosphate uridyltransferase (GALT).
C. UDP-galactose converted to UDP-glucose by UDP-hexose 4epimerase to enter the mainstream of glucose metabolism
(glycolysis and gluconeogenesis).
D. UDP-galactose including synthesis of lactose, glycoproteins
glycolipids and glycosaminoglycan.
See figure 12.5 in the next slide
and GALT
Figure 12.5: Metabolism of galactose. GALT=galactose 1-phosphate uridyltransferase (GALT).
Figure 12.6
Structure of UDP-galactose.
UDP = uridine diphosphate.
Lactose Synthesis
 Lactose is a disaccharide that consists of
galactose and glucose (galactosyl β(1→4)glucose).
 Milk are the dietary sources of lactose.
 Lactose is synthesized by lactose synthase (UDPgalactose:glucose galactosyltransferase), from
UDP-galactose and glucose in the lactating
mammary gland.
lactose synthase (occurs in Golgi) has two subunits:
protein A (galactosyl transferase) transfers
galactose from UDP-galactose to N-acetyl-Dglucosamine, forming β(1→4) linkage found in
lactose, and producing N-acetyllactosamine
protein B (α-lactalbumin), found only in the
lactating mammary glands, and whose synthesis
is stimulated by the peptide hormone, prolactin).
Note: When both subunits are present, the
galactosyl transferase produces lactose.
Science Should be as simple as possible, but not simpler.
Albert Einstein
References:
Biochemistry. Lippincott's Illustrated Reviews. 6th Edition by, Richard A Harvey,
Denise R. Ferrier. Lippincott Williams and Wilkins, a Wolters kluwer business. 2014.