Upload
hussein-diab
View
223
Download
0
Embed Size (px)
Citation preview
7/29/2019 Chem 4311- Chapter20& 22
1/71
11/25/2012
1
Chapter 20
Electron Transport and
Oxidative Phosphorylation
Dr Khairul Ansari
20.1 Where in the Cell Do Electron Transport and Oxidative
Phosphorylation Occur?
Electron Transport: Electrons carried by reduced coenzymes (NADHand [FADH2] are passed through a chain of proteins and coenzymes todrive the generation of a proton gradient across the innermitochondrial membrane
Oxidative Phosphorylation: The proton gradient drives the synthesisof ATP
It all happens in or at the inner mitochondrial membrane
7/29/2019 Chem 4311- Chapter20& 22
2/71
11/25/2012
2
20.1 Where in the Cell Do Electron Transport and Oxidative
Phosphorylation Occur?
Figure 20.1 (a) A drawing of a mitochondrion. (b) Tomography of a rat
liver mitochondrion. The colors represent individual cristae.
20.2 How Is the Electron Transport Chain Organized?
Four protein complexes in the inner mitochondrial membrane
A lipid-soluble coenzyme (UQ, CoQ) and a water-soluble protein
(cytochrome c) shuttle between protein complexes
Electrons generally fall in energy through the chain - from
complexes I and II to complex IV
7/29/2019 Chem 4311- Chapter20& 22
3/71
11/25/2012
3
20.2 How Is the Electron Transport Chain Organized?
Figure 20.2 Reduction
potentials for the
components of the
mitochondrial electron-
transport chain. Values
indicated are consensus
values for animal
mitochondria. Black bars
represento'; red bars, .
20.2 How Is the Electron Transport Chain Organized?
Figure 20.3 An overview of the complexes and pathways in the
mitochondrial electron-transport chain.
7/29/2019 Chem 4311- Chapter20& 22
4/71
11/25/2012
4
20.2 How Is the Electron Transport Chain Organized?
Complex I Oxidizes NADH and Reduces Coenzyme Q
NADH-CoQ Reductase/NADH dehydrogenase
Complex I carries out electron transfer from NADH to
Coenzyme Q
The electron path:
NADH FMN Fe-S UQ FeS UQ
Four H+ transported out per 2 e-
7/29/2019 Chem 4311- Chapter20& 22
5/71
11/25/2012
5
Complex I Transports Protons From the Matrix to the Cytosol
Figure 20.5 (a) Structural
organization of mammalian
Complex I, based on electron
microscopy, showing functional
relationships within the L-
shaped complex. Electron flow
from NADH to UQH2 in themembrane pool is indicated.
Complex I Transports Protons From the Matrix to the Cytosol
Figure 20.5 (b) Structure of
the hydrophilic domain of
Complex I from Thermusthermophilus is shown on a
model of the membrane-
associated complex.
7/29/2019 Chem 4311- Chapter20& 22
6/71
11/25/2012
6
Complex I Transports Protons From the Matrix to the Cytosol
Figure 20.5 (c) Arrangement of the
redox centers in Complex I. The
various iron-sulfur centers of
Complex I are designated by capitalN.
Complex I Transports Protons From the Matrix to the Cytosol
Figure 20.5 (d) Blue arrows indicate the pathway of electron transfer
from NADH to coenzyme Q. The energy of electron transfer allows aproton to cross Complex I near the interface between its hydrophilic and
hydrophobic domains. Conformational changes accompanying these
events push the long helical rod (magenta), reorienting residues in the
associated subunits, so that protons bound there can cross into the
intermembrane space.
7/29/2019 Chem 4311- Chapter20& 22
7/71
11/25/2012
7
Solving a Medical Mystery Revolutionized Our Treatment of
Parkinsons Disease
Cases of paralysis among illegal drug users in 1982 was traced tosynthetic heroin that contained MPTP as a contaminant
MPTP is converted rapidly in the brain to MPP+
MPP+ is a potent inhibitor of mitochondrial Complex I
Such inhibition occurs especially in regions of the brain thatdeteriorate in Parkinsons disease
Treatment of the paralysis victims with L-Dopa restored normalmovement
Implantation of fetal brain tissue also worked
These treatments revolutionized the use of tissue implantation
to treat neurodegenerative diseases
Complex II Oxidizes Succinate and Reduces Coenzyme Q
Succinate-CoQ Reductase/succinate dehydrogenase (only TCAcycle enzyme that is an integral membrane protein in the innermitochondrial membrane)
Also known as flavoprotein 2 (FP2) - FAD covalently bound
four subunits, including 2 Fe-S proteins
Three types of Fe-S cluster:
4Fe-4S, 3Fe-4S, 2Fe-2S
Path: succinate FADH2 2Fe2+ UQH2
Net reaction:
succinate + UQ fumarate + UQH2
7/29/2019 Chem 4311- Chapter20& 22
8/71
11/25/2012
8
Complex II Oxidizes Succinate and Reduces Coenzyme Q
Figure 20.6 A scheme for electron
flow in Complex II. Oxidation ofsuccinate occurs with reduction of
[FAD]. Electrons are then passed
to Fe-S centers and then to CoQ.
Fatty-Acyl-CoA Dehydrogenases Also Supply Electrons to UQ
Figure 20.7 The fatty acyl-CoA dehydrogenase reaction, emphasizing
that the reaction involves reduction of enzyme-bound FAD (indicated
by brackets).
The fatty acyl-CoA dehydrogenases are three soluble matrix enzymes
involved in fatty acid oxidation (See also Chapter 23).
7/29/2019 Chem 4311- Chapter20& 22
9/71
11/25/2012
9
Complex III Mediates Electron Transport from Coenzyme Q
to Cytochrome c
UQ-Cytochrome c Reductase CoQ (UQ) passes electrons to cyt c (and pumps H+) in a unique redox
cycle known as the Q cycle
The principal transmembrane protein in complex III is the bcytochrome - with hemes bL and bH
Cytochromes, like Fe in Fe-S clusters, are one- electron transferagents
UQH2 is a lipid-soluble electron carrier
Cytochrome c is a water-soluble electron carrier
Complex III Mediates Electron Transport from Coenzyme Q
to Cytochrome c
Figure 20.9 The structures of iron
protoporphyrin IX, heme c, and heme
a.
7/29/2019 Chem 4311- Chapter20& 22
10/71
11/25/2012
10
Complex IV Transfers Electrons from Cytochrome cto
Reduce Oxygen on the Matrix Side
Cytochrome c Oxidase Electrons from cytochrome c are used in a four-electron reduction
of O2 to produce 2H2O
Oxygen is thus the terminal acceptor of electrons in the electrontransport pathway
Cytochrome c oxidase utilizes 2 hemes (a and a3) and 2 coppersites
Complex IV also transports H+ across the inner mitochondrialmembrane
Four H+ participate in O2 reduction and four H+ are transported in
each catalytic cycle
Complex IV Transfers Electrons from Cytochrome cto
Reduce Oxygen on the Matrix Side
Figure 20.13 Bovine cytochrome
c oxidase consists of 13 subunits.
The 3 largest subunits I
(purple), II (yellow), and III (blue)
contain the proton channels
and the redox centers.
Subunits I, II, and III are common
to most organisms. This minimal
complex is sufficient to carry outboth oxygen reduction and
proton transport.
7/29/2019 Chem 4311- Chapter20& 22
11/71
11/25/2012
11
Complex IV Transfers Electrons from Cytochrome cto
Reduce Oxygen on the Matrix Side
Figure 20.14 The
complete structure of
bovine cytochrome c
oxidase.
As in Figure 20.13,
subunit I is purple,
subunit II is yellow,
and subunit III is blue.
Complex IV Transfers Electrons from Cytochrome cto Reduce
Oxygen on the Matrix Side
Figure 20.15 The electron-
transfer pathway for
cytochrome c oxidase.
Cytochrome c binds on the
cytosolic face, transferring
electrons through the copper
and heme centers to reduce
O2 on the matrix side of the
membrane.
7/29/2019 Chem 4311- Chapter20& 22
12/71
11/25/2012
12
The Complexes of Electron Transport May Function as
Supercomplexes
For many years, the complexes of the electrontransport chain were thought to exist and functionindependently in the mitochondrial inner membrane
However, growing experimental evidence supports theexistence of multimeric supercomplexes of the fourelectron transport complexes
Also known as respirasomes, these complexes mayrepresent functional states
Association of two or more of the individual complexesmay be advantageous for the organism
A model for the electron-transport pathway in the
mitochondrial inner membrane.
Figure 20.18 (b) A model for the electron-transport pathway in the
mitochondrial inner membrane. UQ/UQH2 and cyt c are mobile
carriers and transfer electrons between the complexes.
7/29/2019 Chem 4311- Chapter20& 22
13/71
11/25/2012
13
Electron Transfer Energy Stored in a Proton Gradient: The
Mitchell Hypothesis
The coupling between oxidation and phosphorylation was a mysteryfor many years
Many biochemists squandered careers searching for the elusive"high energy intermediate"
Peter Mitchell proposed a novel idea - a proton gradient across theinner membrane could be used to drive ATP synthesis
The proton gradient is created by the proteins of the electron-transport pathway (Figure 20.19)
Mitchell was ridiculed, but the chemiosmotic hypothesis eventuallywon him a Nobel prize
Be able to calculate the
G for a proton gradient (Equation 20.23)
Electron Transfer Energy Stored in a Proton Gradient: The Mitchell
Hypothesis
Figure 20.19 The proton and electrochemical gradients existing
across the inner mitochondrial membrane.
7/29/2019 Chem 4311- Chapter20& 22
14/71
11/25/2012
14
20.3 What Are the Thermodynamic Implications of
Chemiosmotic Coupling?
How much energy can be stored in an electrochemical
gradient?
The free energy difference for protons across the inner
mitochondrial membrane includes a term for the
concentration difference and a term for the electrical
potential:
c1 and c2 are proton concentrations on the two sides of themembrane, Z is the proton charge, F is Faradays constant,
and is the potential difference across the membrane
G =RTln[c
2]
[c1]+ZY
20.4 How Does a Proton Gradient Drive the Synthesis of
ATP?
Proton diffusion through theATP synthase drives ATP synthesis
The ATP synthase consists of two parts: F1 and F0 (latter wasoriginally named "Fo" for its inhibition by oligomycin)
See Figure 20.20 and Table 20.2 for details
F1 consists of five polypeptides: , ,, , and
F0 includes three hydrophobic subunits denoted a, b and c
F0 forms the transmembrane pore or channel through whichprotons move to drive ATP synthesis
The a and b subunits comprise part of the stator and a ring ofcsubunits forms a rotor
7/29/2019 Chem 4311- Chapter20& 22
15/71
11/25/2012
15
ATP Synthase is Composed of F1 and F0
Figure 20.20 The ATP synthase, a
rotating molecular motor. The c,
and subunits constitute the
rotating portion (the rotor) of the
motor. The b, d and h subunits
form a long, slender stalk that
connects F0 in the membrane and
F1. Flow of protons from the a-
subunit through the c-subunits
turns the rotor and drives the
cycle of conformation changes in
the - and -subunits of F1 that
synthesize ATP.
ATP Synthase is Composed of F1 and F0
7/29/2019 Chem 4311- Chapter20& 22
16/71
11/25/2012
16
The Catalytic Sites of ATP Synthase Adopt Three Different
Conformations
Figure 20.21 (a) An axial view of the F1 unit
of the ATP synthase; (b) A side view of theF1 unit with one and one subunit
removed to show how the subunit (red)
extends through the center of the
hexamer.
John Walker Determined the Structure of the F1 Portion of
ATP Synthase
In Walkers crystal structure of F1, one of the subunits contains
AMP-PNP, one contains ADP, and the third site is empty the
three states of Boyers model!
7/29/2019 Chem 4311- Chapter20& 22
17/71
11/25/2012
17
Boyers 18O Exchange Experiment Identified the Energy-
Requiring Step
Figure 20.22 ATP-ADP exchange in the absence of a proton
gradient. Exchange leads to incorporation of18O in phosphate as
shown. Boyers experiments showed that 18O could be
incorporated into all four positions of phosphate, demonstrating
that the free energy change for ATP formation from enzyme-bound ADP + Pi is close to zero.
Boyers Binding Change Mechanism Describes Events of
Rotational Catalysis
Paul Boyer proposed that, at any instant:
the three -subunits of F1 exist in three different
conformations
these different states represent the three steps of ATP
synthesis
each site steps through the three conformations or states
to make ATP
In Boyers binding change mechanism, the three catalytic
sites thus cycle through the three intermediate states of ATP
synthesis
7/29/2019 Chem 4311- Chapter20& 22
18/71
11/25/2012
18
The Binding Change Mechanism
Figure 20.23 The binding change mechanism for
ATP synthesis by ATP synthase. This model
assumes that F1 has three interacting and
conformationally distinct active sites: an open
(O) conformation with almost no affinity for
ligands, a loose (L) conformation with low
affinity for ligands, and a tight (T) conformation
with high affinity for ligands.
Proton Flow Through F0 Drives Rotation of the Motor and
Synthesis of ATP
Figure 20.24 (a) Protons
entering the inlet half-
channel in the -subunit are
transferred to binding sites
on c-subunits. Rotation of the
c-ring delivers protons to the
outlet half-channel in the -
subunit. Flow of protons
through the structure turns
the rotor and drives the cycle
of conformational changes in that synthesize ATP.
7/29/2019 Chem 4311- Chapter20& 22
19/71
11/25/2012
19
Figure 20.25 The reconstituted vesicles
containing ATP synthase and
bacteriorhodopsin used by Stoeckenius
and Racker to confirm the Mitchell
chemiosmotic hypothesis.
Upon illumination, bacteriorhodopsin
pumped protons into these vesicles,
and the resulting proton gradient was
sufficient to drive ATP synthesis by theATP synthase.
Racker and Stoeckenius Confirmed the Mitchell Model in a
Reconstitution Experiment
Inhibitors of Oxidative Phosphorylation Reveal Insights About the
Mechanism
Many details of electron transport and oxidative phosphorylationhave been learned from studying the effects of inhibitors
Rotenone inhibits Complex I - and helps natives of the Amazon rainforest catch fish
(Natives have learned to beat the roots of certain trees along riverbanks, releasing rotenone, which paralyzes the fish, making themeasy prey)
Cyanide, azide and CO inhibit Complex IV, binding tightly to the ferricform (Fe3+) ofa3
Oligomycin is an ATP synthase inhibitor
7/29/2019 Chem 4311- Chapter20& 22
20/71
11/25/2012
20
Inhibitors of Oxidative Phosphorylation Reveal Insights About
the Mechanism
Figure 20.27 The sites of action ofseveral inhibitors of electron
transport and oxidative
phosphorylation.
Uncouplers Disrupt the Coupling of Electron Transport and
ATP Synthase
Uncoupling e- transport and oxidative phosphorylation
Uncouplers disrupt the tight coupling between electron transportand oxidative phosphorylation by dissipating the proton gradient
Uncouplers are hydrophobic molecules with a dissociable proton
They shuttle back and forth across the membrane, carryingprotons to dissipate the gradient
7/29/2019 Chem 4311- Chapter20& 22
21/71
11/25/2012
21
Uncouplers Disrupt the Coupling of Electron Transport and ATP
Synthase
Figure 20.28 Structures of several
uncouplers, molecules that dissipate
the proton gradient across the inner
mitochondrial membrane and
thereby destroy the tight coupling
between electron transport and the
ATP synthase reaction.
Hibernating Animals Generate Heat by Uncoupling Oxidative
Phosphorylation
Grizzly Bear
7/29/2019 Chem 4311- Chapter20& 22
22/71
11/25/2012
22
Some Plants Use Uncoupled Proton Transport to Raise the
Temperature of Floral Spikes
Skunk Cabbage
Hibernating Animals Generate Heat by Uncoupling Oxidative
Phosphorylation
Chipmunk
7/29/2019 Chem 4311- Chapter20& 22
23/71
11/25/2012
23
Some Plants Use Uncoupled Proton Transport to Raise the
Temperature of Floral Spikes
Philodendron
ATP-ADP Translocase Mediates the Movement of ATP &
ADP Across the Mitochondrial Membrane
ATP must be transported out of the mitochondria
ATP out, ADP in - through a "translocase"
ATP movement out is favored because the cytosol is "+" relativeto the "-" matrix
But ATP out and ADP in is net movement of a negative chargeout - equivalent to a H+ going in
So every ATP transported out costs one H+
One ATP synthesis costs about 3 H+
Thus, making and exporting 1 ATP = 4H+
7/29/2019 Chem 4311- Chapter20& 22
24/71
11/25/2012
24
ATP-ADP Translocase Mediates the Movement of ATP
& ADP Across the Mitochondrial Membrane
Figure 20.29 (a) The bovine ATP-ADP translocase.
ATP-ADP Translocase Mediates the Movement of ATP
& ADP Across the Mitochondrial Membrane
Figure 20.29 (b) Outward transport of ATP (via the ATP-
ADP translocase) is favored by the membrane
electrochemical potential.
7/29/2019 Chem 4311- Chapter20& 22
25/71
11/25/2012
25
20.5 - What Is the P/O Ratio for Mitochondrial Electron
Transport and Oxidative Phosphorylation?
How many ATP can be made per electron pair sent through the chain?
The e- transport chain yields 10 H+ pumped out per electron pairfrom NADH to oxygen
8 H+ per turn of c8 F0 rotor 3 ATP
3.7 H+ flow back into matrix per ATP to cytosol
10/3.7 = 2.7 ATP for electrons entering as NADH
For electrons entering as succinate (FADH2), about 6 H+ pumped per
electron pair to oxygen
6/3.7 = 1.6 ATP for electrons entering as succinate
20.6 How Are the Electrons of Cytosolic NADH Fed into
Electron Transport?
Most NADH used in electron transport is cytosolic and NADHdoesn't cross the inner mitochondrial membrane
What to do?
"Shuttle systems" effect electron movement without actuallycarrying NADH
Glycerophosphate shuttle stores electrons in glycerol-3-P,which transfers electrons to FAD
Malate-aspartate shuttle uses malate to carry electrons acrossthe membrane
7/29/2019 Chem 4311- Chapter20& 22
26/71
11/25/2012
26
The Glycerophosphate Shuttle Ensures Efficient Use of
Cytosolic NADH
Figure 20.30 The glycerophosphate shuttle couples cytosolic
oxidation of NADH with mitochondrial reduction of [FAD].
The Malate-Aspartate Shuttle is Reversible
Figure 20.31 Themalate-aspartate
shuttle.
7/29/2019 Chem 4311- Chapter20& 22
27/71
11/25/2012
27
The Net Yield of ATP from Glucose Oxidation Depends on
the Shuttle Used
See Table 20.3
32.0 ATP per glucose if glycerol-3-P shuttle used
34.2 ATP per glucose if malate-Asp shuttle used
In bacteria - no mitochondria - no extra H+ used to export ATP to
cytosol. Assuming 10 c-subunits per F0 rotor (as in E. coli):
10 H+/NADH and 10 H+/3 ATP = 3 ATP/NADH
6 H+/succ and 10 H+/3ATP = ~ 1.8ATP/FADH2
(10 NADH + 2 [FADH2])/glucose 33.6 ATP
The Net Yield of ATP from Glucose Oxidation Depends on
the Shuttle Used
7/29/2019 Chem 4311- Chapter20& 22
28/71
11/25/2012
28
20.7 How Do Mitochondria Mediate Apoptosis?
Mitochondria play a significant role in apoptosis, the programmeddeath of cells
Mitochondria do this in part, by partitioning some of the apoptotic
activator molecules, e.g., cytochrome c
Oxidation of bound cardiolipins releases cytochrome c from the
inner membrane
Opening of pores in the outer membrane releases cytochrome c
from the mitochondria
Binding of cytochrome c to Apaf-1 in the cytosol leads to assembly
of apoptosomes, thus triggering the events of apoptosis
20.7 How Do Mitochondria Mediate Apoptosis?
Figure 20.32 (a) Cytochrome c is anchored at the inner mitochondrial
membrane by association with cardiolipin. The peroxidase activity ofcytochrome c oxidizes a cardiolipin lipid chain, releasing cytochrome
c from the membrane.
7/29/2019 Chem 4311- Chapter20& 22
29/71
11/25/2012
29
20.7 How Do Mitochondria Mediate Apoptosis?
Figure 20.32 (b) The opening of pores
in the outer membrane, induced by a
variety of triggering agents, releases
cytochrome c to the cytosol, where it
initiates the events of apoptosis.
Figure 20.32 (b, top)
7/29/2019 Chem 4311- Chapter20& 22
30/71
11/25/2012
30
Figure 20.32 (b bottom)
20.7 How Do Mitochondria Mediate Apoptosis?
Figure 20.33 Apaf-1 is a multidomain protein, consisting of an N-
terminal CARD, a nucleotide-binding and oligomerization domain
(NOD), and several WD40 domains.
7/29/2019 Chem 4311- Chapter20& 22
31/71
11/25/2012
31
20.7 How Do Mitochondria Mediate Apoptosis?
Figure 20.33 Binding of cytochrome c to the WD40 domains and
ATP hydrolysis unlocks Apaf-1 to form the semi-open
conformation. Nucleotide exchange leads to oligomerization and
apoptosome formation.
20.7 How Do Mitochondria Mediate Apoptosis?
Figure 20.33 A model of
the apoptosome, a
wheel-like structure
with molecules of
cytochrome c bound to
the WD40 domains,
which extend outward
like spokes.
7/29/2019 Chem 4311- Chapter20& 22
32/71
11/25/2012
32
Chapter 22
Gluconeogenesis, Glycogen Metabolism,
and the Pentose Phosphate Pathway
Dr Khairul Ansari
7/29/2019 Chem 4311- Chapter20& 22
33/71
11/25/2012
33
22.1 What Is Gluconeogenesis, and How Does It Operate?
Gluconeogenesis is the generation (genesis) of "new (neo) glucose"from common metabolites
Humans consume 160 g of glucose per day
75% of that is in the brain
Body fluids contain only 20 g of glucose
Glycogen stores yield 180-200 g of glucose
Glycogen stores are at least partially depleted in strenuous exercise
So the body must be able to make its own glucose
To restore the amount stored in glycogen and to sustain normalactivity
The Chemistry of Glucose Monitoring Devices
Individuals with diabetes must measure their serum glucose
concentration, often several times a day
Computerized automated devices have made this task much
easier
These devices rely on the oxidation of glucose to gluconic acid
by glucose oxidase
A colored dye produced in this reaction is directly
proportional to the amount of glucose in the sample
The patient typically applies a drop of blood to a plastic test
strip that is then inserted into the meter
7/29/2019 Chem 4311- Chapter20& 22
34/71
11/25/2012
34
The Gluconeogenesis Pathway
The Gluconeogenesis Pathway
7/29/2019 Chem 4311- Chapter20& 22
35/71
11/25/2012
35
The Gluconeogenesis Pathway
The Substrates for Gluconeogenesis Include Pyruvate,
Lactate, and Amino Acids
Pyruvate, lactate, glycerol, amino acids and all TCA
intermediates can be utilized
Fatty acids cannot
Why?
Most fatty acids yield only acetyl-CoA
Acetyl-CoA (through TCA cycle) cannot provide for net
synthesis of sugars
7/29/2019 Chem 4311- Chapter20& 22
36/71
11/25/2012
36
Features of Gluconeogenesis
Occurs mainly in liver and kidneys
Not the mere reversal of glycolysis for 2 reasons:
1) The G of glycolysis is -74 kJ/mol
If gluconeogenesis were just the reverse of glycolysis, its Gwould be positive
Energetics must change to make gluconeogenesis favorable
2) Reciprocal regulation of glycolysis and gluconeogenesis:
When glycolysis is active, gluconeogenesis is turned off, andwhen gluconeogenesis is proceeding, glycolysis is turned off.
Gluconeogenesis - Something Borrowed, Something New
Gluconeogenesis retains seven steps of glycolysis:
Steps 2 and 4-9
Three steps are replaced:
Pyruvate carboxylase and PEP carboxykinase replace the pyruvatekinase reaction of glycolysis
Fructose-1,6-bisphosphatase replaces the phosphofructokinasereaction of glycolysis
Glucose-6-phosphatase replaces the hexokinase reaction ofglycolysis
The new reactions provide for a spontaneous pathway (G negativein the direction of sugar synthesis), and they provide new
mechanisms of regulation
7/29/2019 Chem 4311- Chapter20& 22
37/71
11/25/2012
37
Pyruvate Carboxylase is a Biotin-Dependent Enzyme
Pyruvate is converted to oxaloacetate The reaction requires ATP and bicarbonate as substrates
This is a hint that biotin is required
Biotin is covalently linked to an active-site lysine
Acetyl-CoA is an allosteric activator
The mechanism (Figure 22.3) is typical of biotin chemistry
Regulation: when ATP or acetyl-CoA are high, pyruvate entersgluconeogenesis
Note the "conversion problem" in mitochondria
Pyruvate Carboxylase is a Biotin-Dependent Enzyme
The pyruvate carboxylase reaction is the initiation of the
gluconeogenesis pathway
Carboxylations that use bicarbonate as the carbon source require
biotin as a coenzyme
7/29/2019 Chem 4311- Chapter20& 22
38/71
11/25/2012
38
Pyruvate carboxylase is a
compartmentalized reaction.
Figure 22.4 Pyruvate is converted to
oxaloacetate in the mitochondria. Because
oxaloacetate cannot be transported across
the mitochondrial membrane, it must be
reduced to malate, which is then
transported to the cytosol and oxidized back
to oxaloacetate before gluconeogenesis can
continue.
PEP Carboxykinase Uses GTP and a Decarboxylation to Drive
PEP Synthesis
PEP carboxykinase catalyzes the conversion of oxaloacetate to PEP
Lots of energy is needed to drive this reaction
Energy is provided in 2 ways:
Decarboxylation is a favorable reaction
GTP is hydrolyzed
The GTP used here is equivalent to an ATP
7/29/2019 Chem 4311- Chapter20& 22
39/71
11/25/2012
39
PEP Carboxykinase Uses GTP and a Decarboxylation to Drive PEP
Synthesis
The CO2 added to pyruvate in the pyruvate carboxylase reaction is
removed in the PEP carboxykinase reaction.
The use of GTP here (by mammals and several other organisms) is
equivalent to the consumption of an ATP, due to the activity of the
nucleoside diphosphate kinase (see Figure 19.2).
Fructose-1,6-bisphosphatase
Hydrolysis of F-1,6-bisPase to F-6-P
Thermodynamically favorable the G in liver is -8.6 kJ/mol
This is an allosterically regulated enzyme:
citrate stimulates
fructose-2,6-bisphosphate inhibits
AMP inhibits
The inhibition by AMP is enhanced by fructose-2,6-
bisphosphate
7/29/2019 Chem 4311- Chapter20& 22
40/71
11/25/2012
40
Fructose-1,6-bisphosphatase
The fructose-1,6-bisphosphatase reaction
The value ofG in the liver is -8.6 kJ/mol
Glucose-6-Phosphatase Converts Glucose-6-P to Glucose in
the Endoplasmic Reticulum
Presence of G-6-Pase in ER ofliver and kidney cells makesgluconeogenesis possible
Muscle and brain do not do gluconeogenesis
G-6-P is hydrolyzed after uptake into the ER
The glucose-6-phosphatase system includes the phosphatase itselfand three transport proteins, T1, T2, and T3.
T1 takes glucose-6-P into the ER, where it is hydrolyzed by thephosphatase
T2 and T3 export glucose and Pi, respectively, to the cytosol
Glucose is exported to the circulation by GLUT2
7/29/2019 Chem 4311- Chapter20& 22
41/71
11/25/2012
41
Glucose-6-Phosphatase Converts Glucose-6-P to Glucose in
the Endoplasmic Reticulum
Figure 22.5 Glucose-6-phosphatase is localized in the ER.
Coupling with hydrolysis of ATP and GTP drives
gluconeogenesis
The net reaction of conversion of pyruvate to glucose in
gluconeogenesis is:
2 pyruvate + 4 ATP + 2 GTP + 2 NADH + 2 H+ + 6 H2O glucose +
4ADP + 2 GDP + 6Pi + 2 NAD+
Net energy
G = - 37.7 KJ/mol
7/29/2019 Chem 4311- Chapter20& 22
42/71
11/25/2012
42
Gluconeogenesis Inhibitors and Other Diabetes Therapy Strategies
Diabetes is the inability to assimilate and metabolize blood glucose
(Type I-unable to synthesize and secrete insulin and type II- producesufficient insulin but the metabolic pathway that response to insulin
are defective)
Metformin improves sensitivity to insulin by stimulating glucose
uptake by glucose transporters
Gluconeogenesis inhibitors may be the next wave of diabetes
therapy
3-Mercaptopicolinate and hydrazine inhibit PEP carboxykinase
Chlorogenic acid inhibits transport activity by the glucose-6-
phosphatase system
S-3483 does the same, but binds a thousand times more tightly to
the transporter
Lactate Formed in Muscles is Recycled to Glucose in the
Liver
How your liver helps you during exercise:
Recall that vigorous exercise can lead to a buildup of lactate andNADH, due to oxygen shortage and the need for more glycolysis
NADH can be reoxidized during the reduction of pyruvate to lactate
Lactate is then returned to the liver, where it can be reoxidized topyruvate by liver LDH
Liver provides glucose to muscle for exercise and then reprocesseslactate into new glucose
7/29/2019 Chem 4311- Chapter20& 22
43/71
11/25/2012
43
22.2 How Is Gluconeogenesis Regulated?
Reciprocal control with glycolysis When glycolysis is turned on, gluconeogenesis should be turned off
When energy status of cell is high, glycolysis should be off andpyruvate, etc., should be used for synthesis and storage of glucose
When energy status is low, glucose should be rapidly degraded toprovide energy
The regulated steps of glycolysis are the very steps that areregulated in the reverse direction!
Figure 22.8 The
principal regulatory
mechanisms in
glycolysis and
gluconeogenesis.
Allosteric activators are
indicated by plus signs
and allosteric inhibitors
by minus signs.
7/29/2019 Chem 4311- Chapter20& 22
44/71
11/25/2012
44
22.2 How Is Gluconeogenesis Regulated?
Allosteric and Substrate-Level Control
Glucose-6-phosphatase is under substrate-level control, notallosteric control
The fate of pyruvate depends on acetyl-CoA
Fructose-1,6-bisphosphatase is inhibited by AMP, activated bycitrate - the reverse of glycolysis
Fructose-2,6-bisphosphate is an allosteric inhibitor of fructose-1,6-bisphosphatase
Fructose-2,6-bisphosphate is apowerful inhibitor of fructose-
1,6-bisphosphatase
22.3 How Are Glycogen and Starch Catabolized in Animals?
Obtaining glucose from storage (or diet)
-Amylase is an endoglycosidase
It cleaves dietary amylopectin or glycogen to maltose, maltotrioseand other small oligosaccharides
It is active on either side of a branch point, but activity is reducednear the branch points
Debranching enzyme cleaves "limit dextrins"
Note the 2 activities of the debranching enzyme
It transfers trisaccharide groups
And cleaves the remaining single glucose units from the mainchain
7/29/2019 Chem 4311- Chapter20& 22
45/71
11/25/2012
45
22.3 How Are Glycogen and Starch Catabolized in Animals?
Figure 22.11 (a) The sites of
hydrolysis of starch by - and -
amylases are indicated.
Metabolism of Tissue Glycogen is Regulated
Digestive breakdown of starch is unregulated - nearly 100% of ingestedfood is absorbed and metabolized
But tissue glycogen is an important energy reservoir - its breakdownis carefully controlled
Glycogen consists of "granules" of high MW
Glycogen phosphorylase cleaves glucose from the nonreducing endsof glycogen molecules
This is a phosphorolysis, not a hydrolysis
Metabolic advantage: product is a sugar-P - a potential glycolysissubstrate
7/29/2019 Chem 4311- Chapter20& 22
46/71
11/25/2012
46
Metabolism of Tissue Glycogen is Regulated
Figure 22.13 The glycogen phosphorylase reaction. Phosphate is the
attacking nucleophile, so this reaction is a phosphorolysis.
22.4 How Is Glycogen Synthesized?
Glucose units are activated for transfer by formation of sugarnucleotides
What are other examples of "activation"?
acetyl-CoA, biotin, THF
Luis Leloir showed in the 1950s that glycogen synthesis dependson sugar nucleotides
UDP-glucose pyrophosphorylase catalyzes a phosphoanhydrideexchange (Figure 22.14)
driven by pyrophosphate hydrolysis
7/29/2019 Chem 4311- Chapter20& 22
47/71
11/25/2012
47
22.4 How Is Glycogen Synthesized?
UDP-glucose is one of the sugar nucleotides. Discovered by Luis
Leloir in the 1950s, they are activated forms of sugar.
The mechanism of the UDP-
glucose pyrophosphorylase
reaction. Attack by a phosphate
oxygen of glucose-1-P on the -
phosphorus of UTP is followed
by departure of the
pyrophosphate anion.
7/29/2019 Chem 4311- Chapter20& 22
48/71
11/25/2012
48
Glycogen Synthase Catalyzes Formation of(14)
Glycosidic Bonds in Glycogen
Forms (14) glycosidic bonds in glycogen
The very large glycogen particle is built around a single protein,glycogenin, at the core
The first glucose is linked to a tyrosine -OH on the protein
Sugar units are then added by the action of glycogen synthase
Glycogen synthase transfers glucosyl units from UDP-glucose toC-4 hydroxyl at a nonreducing end of a glycogen strand.
Note the oxonium ion intermediate (Fig. 22.15)
Figure 22.15
The glycogen
synthase
reaction.
7/29/2019 Chem 4311- Chapter20& 22
49/71
11/25/2012
49
Figure 22.16 Formation of glycogen
branches by the branching enzyme.
Six- or seven-residue segments of a
growing glycogen chain are transferred
to the C-6 hydroxyl group of a glucose
residue on the same or a nearby chain.
Advanced Glycation End Products A Serious Complication
of Diabetes
Sugars can react nonenzymatically with proteins
The C-1 carbonyl groups of glucose form Schiff bases linkages
with lysine side chains of proteins
These Schiff base adducts undergo Amadori rearrangements
and subsequent oxidations to form irreversible glycation end
products (AGEs)
AGEs are implicated in circulation, joint, and vision problems
in diabetics
Measurement of glycated hemoglobin is a better diagnostic
yardstick for type-2 diabetes than serum glucose levels
7/29/2019 Chem 4311- Chapter20& 22
50/71
11/25/2012
50
RAGE
Receptor for Advanced Glycation End-Products
RAGE is a multifunctional protein of the innate immune system that
plays pivotal roles in diabetes, chronic inflammation,
neurodegenerative diseases, T-lymphocyte proliferation, and cancer
It is a 1-TMS protein with 3 extracellular domains
The first two extracellular domains contain a basic patch and a
hydrophobic patch
Binding of its ligands depends on interactions with these surfaces,
particularly the large basic patch comprised of Arg and Lys side
chains
Binding of ligands induces dimerization of RAGE and triggers
intracellular responses related to inflammation and tumorigenesis
22.5 How Is Glycogen Metabolism Controlled?
A highly regulated process, involving reciprocal control of glycogen
phosphorylase and glycogen synthase
GP allosterically activated by AMP and inhibited by ATP, glucose-6-P
and caffeine
GS is stimulated by glucose-6-P
Both enzymes are regulated by covalent modification -
phosphorylation
7/29/2019 Chem 4311- Chapter20& 22
51/71
11/25/2012
51
Glycogen Synthase is Regulated by Covalent Modification
Glycogen synthase exists in two distinct forms Active, dephosphorylated GS-I
Less active, phosphorylated GS-D
The phosphorylated form is allosterically activated by glucose-6-P
At least 9 serine residues are phosphorylated
Four different protein kinases are involved
Dephosphorylation is carried out by phosphoprotein phosphatase-1 (PP1)
PP1 inactivates glycogen phosphorylase and activates glycogensynthase
Insulin Modulates the Action of Glycogen Synthase in
Several Ways
Binding of insulin to plasma membrane receptors in the liver
and muscles triggers protein kinase cascades that stimulate
glycogen synthesis
Insulins effect include stimulation of lipid synthesis, glycogen
synthesis, protein synthesis, glycolysis, and active transport,
and inhibition of gluconeogenesis and lipid breakdown
Glucose uptake provides substrate for glycogen synthesis and
glucose-6-P, which allosterically activates the otherwise
inactive form of glycogen synthase
7/29/2019 Chem 4311- Chapter20& 22
52/71
11/25/2012
52
Insulin Modulates the Action of Glycogen Synthase in
Several Ways
Figure 22.17
Insulin triggers
protein kinases
that stimulate
glycogen
synthesis.
The Actions of Insulin on Metabolism
Figure 22.17b The metabolic effects of insulin are mediated
through protein phosphorylation and second messenger
modulation.
7/29/2019 Chem 4311- Chapter20& 22
53/71
11/25/2012
53
Hormones Regulate Glycogen Synthesis and Degradation
Storage and utilization of tissue glycogen and other aspects ofmetabolism are regulated by hormones, including glucagon,epinephrine, and the glucocorticoids
Insulin is a response to increased blood glucose
Insulin triggers glycogen synthesis when blood glucose rises
Between meals, blood glucose is 70-90 mg/dL
Glucose rises to 150 m/dL after a meal and then returns tonormal within 2-3 hours
Glucagon and epinephrine stimulate glycogen breakdown
Hormones Regulate Glycogen Synthesis and Degradation
Insulin is secreted from the pancreas (to liver) in response toan increase in blood glucose
Note that the portal vein is the only vein in the body thatfeeds an organ
Insulin acts to lower blood glucose rapidly in several ways,stimulating glycogen synthesis and inhibiting glycogenbreakdown
7/29/2019 Chem 4311- Chapter20& 22
54/71
11/25/2012
54
Hormones Regulate Glycogen Synthesis and Degradation
Figure 22.18 The
portal vein system
carries pancreatic
secretions such as
insulin and
glucagon to the
liver.
Glucagon and Epinephrine Stimulate Glycogen Breakdown
and Inhibit Glycogen Synthesis
Glucagon and epinephrine stimulate glycogen breakdown theopposite effect of insulin
Glucagon (a 29-residue peptide) is also secreted by pancreas
Glucagon acts in liver and adipose tissue only
Epinephrine (adrenaline) is released from adrenal glands
Epinephrine acts on liver and muscles
When either hormone binds to its receptor on the outside surfaceof the cell membrane, a phosphorylase cascade amplifies the signal
7/29/2019 Chem 4311- Chapter20& 22
55/71
11/25/2012
55
Figure 22.20 Glucagon
and epinephrine
activate a cascade of
reactions that
stimulate glycogen
breakdown and inhibit
glycogen synthesis in
liver and muscles,
respectively.
Glucagon and Epinephrine Actions in Liver and Muscle
Figure 22.20 Glucagon and epinephrine each
activate glycogen breakdown and inhibit
glycogen synthesis in liver and muscles,
respectively. In both tissues, binding of glucagon
or epinephrine activates adenylyl cyclase,
initiating the cascade.
7/29/2019 Chem 4311- Chapter20& 22
56/71
11/25/2012
56
Glucagon and Epinephrine Actions in Liver and Muscle
Figure 22.20. In liver, glucagon inhibits glycolysis and
stimulates gluconeogenesis. In muscles, epinephrine
stimulates glycolysis to provide energy for contraction.
Epinephrine and Glucagon
The difference:
Both are glycogenolytic in liver, but for different reasons
Epinephrine is the fight-or-flight hormone
It rapidly mobilizes large amounts of energy
Glucagon is for long-term maintenance of steady-state levels ofglucose in the blood
It activates glycogen breakdown
It activates liver gluconeogenesis
7/29/2019 Chem 4311- Chapter20& 22
57/71
11/25/2012
57
Cortisol and Glucocorticoids Exert a Variety of Effects on
Glycogen Metabolism
Glucocorticoids are steroid hormones that exert distinct
effects on liver, skeletal muscle, and adipose tissue
Cortisol is primarily catabolic it promotes protein
breakdown and decreases protein synthesis in skeletal muscle
In liver, however, it stimulates gluconeogenesis and increases
glycogen synthesis, by
Stimulating expression of genes for gluconeogenic
enzymes
Activating enzymes of amino acid metabolism
Stimulating the urea cycle (see Chapter 25)
Cortisol and Glucocorticoids Exert a Variety of Effects on
Glycogen Metabolism
Figure 22.21 The effects of cortisol on carbohydrate and protein
metabolism in the liver.
7/29/2019 Chem 4311- Chapter20& 22
58/71
11/25/2012
58
22.6 Can Glucose Provide Electrons for Biosynthesis?
Cells are provided with a constant supply of NADPH for biosynthesisby the pentose phosphate pathway
Also called the hexose monophosphate shunt
This pathway also produces ribose-5-P
This pathway consists of two oxidative processes followed by fivenon-oxidative steps
It operates mostly in the cytosol of liver and adipose cells
NADPH is used in cytosol for fatty acid synthesis
22.6 Can Glucose Provide Electrons for Biosynthesis?
Figure 22.22 The pentose
phosphate pathway. The
numerals in the blue circles
indicate the steps discussed in
the text.
7/29/2019 Chem 4311- Chapter20& 22
59/71
11/25/2012
59
22.6 Can Glucose Provide Electrons for Biosynthesis?
Figure 22.22 The pentose phosphate pathway. The numerals in the
blue circles indicate the steps discussed in the text.
Figure 22.22 The
pentose phosphate
pathway.
7/29/2019 Chem 4311- Chapter20& 22
60/71
11/25/2012
60
The Oxidative Steps of the Pentose Phosphate Pathway
Glucose-6-P Dehydrogenase Irreversible 1st step - highly regulated!
Gluconolactonase
The uncatalyzed reaction happens, too
6-Phosphogluconate Dehydrogenase
An oxidative decarboxylation (in that order)
The Oxidative Steps of the Pentose Phosphate Pathway
Figure 22.23 The glucose-6-phosphate dehydrogenase reaction is the
committed step in the pentose phosphate pathway.
7/29/2019 Chem 4311- Chapter20& 22
61/71
11/25/2012
61
Figure 22.24 The Gluconolactonase Reaction
Figure 22.24 The gluconolactonase reaction. The uncatalyzed
reaction also occurs.
The Oxidative Steps of the Pentose Phosphate Pathway
Figure 22.25 The 6-phosphogluconate dehydrogenase reaction.Initial NADP+-dependent dehydrogenation yields a -keto acid, 3-
keto-6-phosphogluconate, which is very susceptible to
decarboxyation (the second step). The resulting product, D-ribulose-
5-P, is the substrate for the nonoxidative reactions of the pentose
phosphate pathway.
7/29/2019 Chem 4311- Chapter20& 22
62/71
11/25/2012
62
The Nonoxidative Steps of the Pentose Phosphate Pathway
Five steps, but only 4 types of reaction... Phosphopentose isomerase
converts ketose to aldose
Phosphopentose epimerase
epimerizes at C-3
Transketolase ( a TPP-dependent reaction)
transfer of two-carbon units
Transaldolase (uses a Schiff base mechanism)
transfers a three-carbon unit
The Nonoxidative Steps of the Pentose Phosphate Pathway
Figure 22.26 The phosphopentose isomerase reaction converts aketose to an aldose. The reaction involves an enediol
intermediate.
7/29/2019 Chem 4311- Chapter20& 22
63/71
11/25/2012
63
The Nonoxidative Steps of the Pentose Phosphate Pathway
Figure 22.27 The phosphopentose epimerase reaction interconverts
ribulose-5-P and xylulose-5-phosphate. The mechanism involves an
enediol intermediate and occurs with inversion at C-3.
The Nonoxidative Steps of the Pentose Phosphate Pathway
Figure 22.28 The transketolase reaction of step 6 in the pentosephosphate pathway. This is a two-carbon transfer reaction that
requires thiamine pyrophosphate as a coenzyme. TPP chemistry
was discussed in Chapter 19 (see the pyruvate dehydrogenase
reaction).
7/29/2019 Chem 4311- Chapter20& 22
64/71
11/25/2012
64
The Nonoxidative Steps of the Pentose Phosphate Pathway
Figure 22.29 The transketolase reaction of step 8 in the pentose
phosphate pathway. This is another two-carbon transfer, and italso requires TPP as a coenzyme.
The Nonoxidative Steps of the Pentose Phosphate Pathway
Figure 22.30 The mechanism of the TPP-dependent transketolase
reaction. The group transferred is really an aldol. Despite this, the
name transketolase persists.
7/29/2019 Chem 4311- Chapter20& 22
65/71
11/25/2012
65
Figure 22.30 Themechanism of the
TPP-dependent
transketolase
reaction. The group
transferred is really
an aldol. Despite
this, the name
transketolase
persists.
The Nonoxidative Steps of the Pentose Phosphate Pathway
Figure 22.31 The transaldolase reaction. In this reaction, a 3-
carbon unit is transferred, first to an active-site lysine, and
then to the acceptor molecule.
7/29/2019 Chem 4311- Chapter20& 22
66/71
11/25/2012
66
Figure 22.32 The
transaldolase
mechanism
involves attack on
the substrate by an
active-site lysine.
Departure of
erythrose-4-P
leaves the reactive
enamine, which
attacks the
aldehyde carbon ofGly-3-P.
Utilization of Glucose-6-P Depends on the Cells Need
for ATP, NADPH, and Rib-5-P
Glucose can be a substrate either for glycolysis or forthe pentose phosphate pathway
The choice depends on the relative needs of the cell forbiosynthesis and for energy from metabolism
ATP can be made if G-6-P is sent to glycolysis
Or, if NADPH or ribose-5-P are needed for biosynthesis,G-6-P can be directed to the pentose phosphatepathway
Depending on these relative needs, the reactions ofglycolysis and the pentose phosphate pathway can becombined in four principal ways
7/29/2019 Chem 4311- Chapter20& 22
67/71
11/25/2012
67
Four Ways to Combine the Reactions of Glycolysis and Pentose
Phosphate
1) Both ribose-5-P and NADPH are needed by the cell
In this case, the first four reactions of the pentosephosphate pathway predominate
NADPH is produced and ribose-5-P is the principalproduct of carbon metabolism
2) More ribose-5-P than NADPH is needed by the cell
Synthesis of ribose-5-P can be accomplished withoutmaking NADPH, by bypassing the oxidative reactions
of the pentose phosphate pathway
Four Ways to Combine the Reactions of Glycolysis and
Pentose Phosphate
Case 1: Both ribose-5-P and NADPH are needed
Figure 22.33 When biosynthetic demands dictate, the first four
reactions of the pentose phosphate pathway predominate and
the principal products are ribose-5-P and NADPH.
7/29/2019 Chem 4311- Chapter20& 22
68/71
11/25/2012
68
Four Ways to Combine the Reactions of Glycolysis and
Pentose Phosphate
3) More NADPH than ribose-5-P is needed by the cell This can be accomplished if ribose-5-P produced in
the pentose phosphate pathway is redirected toproduce glycolytic intermediates
4) Both NADPH and ATP are needed by the cell, butribose-5-P is not
This can be done by redirecting ribose-5-P, as incase 3 above, if fructose-6-P and glyceraldehyde-3-
P made in this way proceed through glycolysis toproduce ATP and pyruvate, and pyruvate continuesthrough the TCA cycle to make more ATP
Integrating the Warburg Effect ATP consumption promotes cancer metabolism Cancer cells use glycolytic intermediates for the
synthesis of macromolecules and must balance theirATP requirements and biosynthetic needs
Xiaodong Wang has shown that EMTPD5, a UDPase inthe ER is associated with ATP consumption in tumorcells
UMP made in this reaction is transported into thecytosol, where it is converted back to UDP, then UTP,and then to UDP-glucose
Ensuing reactions send glycolytic intermediates to thepentose phosphate pathway, helping cancer cells tofine-tune production of NADPH, ribose-5-P, and ATP
7/29/2019 Chem 4311- Chapter20& 22
69/71
11/25/2012
69
Cellular Signals Modulate Production of NADPH, ribose-
5-P, and ATP
ENTPD5 expression is enhanced in tumors and promotes ATP consumption,
stimulating aerobic glycolysis. PI3K and AKT stimulate glucose uptake, as well
as hexokinase and PFK. AMP kinase inhibits PFK, whereas p53 blocks synthesis
of NADPH by inhibition of G6P dehydrogenase.
Xylulose-5-Phosphate is a Metabolic Regulator
In addition to its role in the pentose phosphatepathway, xylulose-5-P is also a signaling molecule
When blood glucose rises, glycolysis and the pentosephosphate pathways are activated in the liver
The latter pathway makes xylulose-5-P, whichstimulates protein phosphatase 2A (PP2A)
PP2A dephosphorylates PFK-2/F-2,6-BPase and alsocarbohydrate-responsive element-binding protein
(ChREBP)
Glycolysis and lipid biosynthesis are both activated as aresult
7/29/2019 Chem 4311- Chapter20& 22
70/71
11/25/2012
70
Activation of PP2A triggers dephosphorylation of PFK-2/F2,6-BPase,which raises F-2,6-BP levels, activating glycolysis and inhibiting
gluconeogenesis.
Figure 22.34 Dephosphorylation of ChREBP elevates
expression of genes for lipogenesis.
Xylulose-5-Phosphate is a Metabolic Regulator
Aldose Reductase and Diabetic Cataract Formation
The complications of diabetes include a highpropensity for cataract formation in later life
Hyperglycemia is the cause, but why?
Evidence points to the polyol pathway, in whichglucose and other simple sugars are reduced inNADPH-dependent reactions
Glucose is reduced by aldose reductase to sorbitol,which accumulates in lens fiber cells, increasing
pressure and eventually rupturing the cells
Aldose reductase inhibitors such as tolrestat andepalrestat suppress cataract formation
7/29/2019 Chem 4311- Chapter20& 22
71/71
11/25/2012
Aldose Reductase and Diabetic Cataract Formation
Glucose is reduced by aldose reductase to sorbitol, which
accumulates in lens fiber cells, increasing pressure and eventually
rupturing the cells
Aldose reductase inhibitors such as tolrestat and epalrestat suppress
cataract formation
Aldose Reductase and Diabetic Cataract Formation