ELECTRON TRANSPORT
CHAIN
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DR. S. SHEKHARASSOC. PROFESSOR
DEPT. OF
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BIOCHEMISTRY
SYNTHESIS OF ATP
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ATP can be synthesized in two
ways
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1. Oxidative phosphorylation:Major source of ATP in aerobic
organisms.
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It is linked with mitochondrialETC.
2.
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Substrate
level
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phosphorylation:When the energy of high energy
compound
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is
directly
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transferred
to
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nucleoside
diphosphate
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toform
a
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triphosphate without the help
from ETC.
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The high-energy compounds such as? PEP
? 1,3-bisphosphoglycerate
? Succinyl CoA
can transfer high-energy phosphate to ultimately
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produce ATP.
STORAGE FORMS
? Phosphocreatine ( creatine phosphate)
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? Provides high energy reservoir of ATP to regenerateATP rapidly, catalyzed by creatine kinase.
? Stored mainly in Muscle, Heart & Brain.
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BIOLOGICAL OXIDATIONThe transfer of electrons from the reduced
coenzymes through the respiratory chain to
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oxygen is known as biological oxidation.Energy released during this process is trapped
as ATP.
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This
coupling
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ofoxidation
with
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phosphorylation
is
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calledoxidative
phosphorylation.
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TRANSPORT OF REDUCING EQUIVALENT:SHUTTLE PATHWAY
? The inner mitochondrial is impermeable to
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NADH.
? Therefore, the NADH produced in the cytosol
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cannot directly enter the mitochondria.? Two pathways
A. Glycerol-phosphate shuttle- In muscle and
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brainB. Malate-aspartate shuttle - In liver and heart
GLYCEROL-PHOSPHATE SHUTTLE
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? Cytosolic glycerol 3-phosphate dehydrogenaseoxidizes NADH to NAD+
? The reducing equivalents are transported
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through glycerol 3-phosphate into the
mitochondria.
? Glycerol 3-phosphate dehydrogenase-present
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on outer surface of inner mitochondrial
membrane ? reduces FAD to FADH2.
.
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? Dihydroxyacetone phosphate (DHAP) escapesinto the cytosol & the shuttling continues.
? FADH2 gets oxidized via ETC to generate
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1.5ATP
GLYCEROL PHOSPHATE SHUTTLE
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MALATE-ASPARTATE SHUTTLE? In the cytosol, oxaloacetate accepts the
reducing equivalents (NADH) & becomes
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malate.
? Malate enters the mitochondria where it is
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oxidized by mitochondrial MDH? In this reaction, NADH & oxaloacetate are
regenerated.
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? NADH gets oxidized via ETC & 2.5 ATP are
produced.
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MALATE-ASPARTATE SHUTTLE .
? In the mitochondria, oxaloacetate participates
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in transamination reaction with glutamate to
produce aspartate & ketoglutarate.
? The aspartate enters the cytosol &
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transaminates with -ketoglutarate to give
oxaloacetate & glutamate.
REDOX POTENTIAL
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Oxidation:? Oxidation is defined as the loss of electrons
and reduction as the gain in electrons.
? When a substance exists both in the reduced
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state & in the oxidized state, the pair is called a
redox couple.
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Redox potential(E0):? The oxidation-reduction potential or redox
potential, is a quantitative measure of the
tendency of a redox pair to lose or gain
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electrons.? The redox pairs are assigned specific standard
redox potential at pH 7.0 & 250C
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? The more negative redox potential represents a
greater tendency to lose electrons.
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? A more positive redox potential indicates a
greater tendency to accept electrons
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? The electrons flow from a redox pair with morenegative E0 to another redox pair with more
positive E0
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? The redox potential (E0) is directly related to
the change in the free energy (G0)
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ELECTRON TRANSFER CHAIN
? The flow of electrons occurs through
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successive
dehydrogenase
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enzymesin
mitochondria , together known as the ETC.
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(the electrons are transferred from higher tolower potential.)
Significance:
? The free energy released during the transport
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of electrons is utilized for the formation of ATPMITOCHONDRIAL ORGANIZATION
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? Mitochondria consists of five distinct parts? Outer membrane, inner membrane, intermembrane
space, cristae & matrix
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Inner mitochondrial membrane:
? The ETC & ATP synthesizing system are located on
inner mitochondrial membrane, which is specialized
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structure, rich in proteins? Inner membrane is highly folded to form cristae.
? Surface area of inner mitochondrial membrane is
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increased due to cristae.? The inner surface of inner mitochondrial membrane
possesses specialized particles, the phosphorylating
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subunits which are centres for ATP production.2H+
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4H+Organisation of electron transport chain and route-
map of electron flow through ETC.
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ETC consists of four enzymes complexes & two
free electron carriers
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Complex I: NADH-ubiquinone oxidoreductaseComplex II: Succinate dehydrogenase
Complex III: Ubiquinol cytochrome oxidoreductase
Complex IV: Cytochrome oxidase
? Two free electron carriers are coenzyme Q &
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Cytochrome C.
? Complex V: It is ATP synthase.
? The complexes I-IV are carriers of electrons while
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complex V is responsible for ATP synthesis.
? The enzyme complexes & mobile carriers are
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collectively involved in the transport of
electrons which, ultimately, combine with
oxygen to produce water.
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? Largest proportion of O2 supplied to body isutilized by mitochondria for the operation of
ETC.
Complex I
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? Of the two coenzymes NAD+& NADP+, NAD+
is more actively involved in ETC.
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? Tightly bound to the inner membrane? NAD+ is reduced to NADH + H+ by
dehydrogenases with the removal of two
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hydrogen atoms from the substrates, thesubstrates includes pyruvate, gly-3-P. etc.
? NADPH is more effectively utilized for
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anabolic reactions - fatty acid synthesis,
cholesterol synthesis.
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? The enzyme NADH dehydrogenase (NADH
coenzyme Q reductase) is a flavoprotein with FMN as
the prosthetic group.
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? The coenzyme FMN accepts two electrons & a proton
to form FMNH2.
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? NADH dehydrogenase is a complex enzyme closelyassociated with non- heme iron proteins or iron-sulfur
proteins.
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? In this, 4 protons are pumped out from mitochondria.? NADH + H+ + FMN NAD+ + FMNH2
Complex II ? Succinate - Co Q- Reductase
? The electrons from FADH2 enter ETC at the level of
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Co Q.
? Succinate DH is an enzyme found in inner
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mitochondrial membrane.? It is also a flavoprotein with FAD as coenzyme.
? The 3 major enzyme systems that transfer their
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electrons directly to ubiquinone are:a. Succinate dehydrogenase
b. Fatty acyl CoA dehydrogenase
c. Mitochondrial glycerol phosphate
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dehydrogenase.
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Iron-sulfur centers? Iron-sulfur centers (Fe-S) are prosthetic groups
containing 1-4 iron atoms
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? Iron-sulfur (Fe-S) proteins exist in the oxidized
(Fe3+) or reduced (Fe2+) state.
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? Iron-sulfur centers transfer only one electron, evenif they contain two or more iron atoms
? Fe-S participates in the transfer of electrons from
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FMN to coenzyme Q.
? Other Fe-S proteins associated with cytochrome b
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& cytochrome c1 participate in the transport ofelectrons.
Coenzyme Q
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? It is also known as ubiquinone.? It is a quinone derivative with isoprenoid side chain
? The ubiquinone is reduced successively to
semiquinone (QH) & finally to ubiquinol (QH2)
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? It accepts a pair of electrons from NADH or
FADH2 through complex I or complex II
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respectively.? 2 molecules of cytochrome c are reduced.
? The Q cycle facilitates the switching from the 2
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electron carrier ubiquinol to the single electroncarrier cytochrome c.
? This is a mobile carrier.
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Complex III Cytochrome - Reductase
? This is a cluster of iron-sulphur proteins, cytochrome b
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& cytochrome c1, both contain heme prosthetic group.? Consists of a porphyrin ring with iron atom.
? The iron of heme in cytochromes is alternately oxidized
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(Fe3+) & reduced (Fe2+ ) which is essential for transportof electrons in the ETC.
? In this, 4 protons are pumped out.
? This complex transfers 2 electrons to cytochrome c from
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2 molecules of CoQH2 along with the vectorial
movement of 4H+ from mitochondrial matrix to
intermembranous space.
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? The property of
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reversible oxidation reduction ofheme iron present in cytochromes allows them to
function as effective carriers of electrons in ETC.
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? Cytochrome C:It is a small protein containing 104 amino acids & a
heme group.
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It is a loosely bound to inner mitochondrialmembrane & can be easily extracted.
Complex IV Cytochrome - Oxidase
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? Contains cytochrome a and cytochrome a3 whichis the terminal component of ETC
? Tightly bound to inner mitochondrial membrane.
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? Cytochrome oxidase is the only electron carrier,heme iron of which can directly react with
molecular oxygen.
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? It also contains copper that undergoes oxidation
reduction during transport of electrons.
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? 2 protons are pumped out.? In the final stage of ETC, the transported electrons,
the free protons & the molecular oxygen combine
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INHIBITORS OF ETC
? The inhibitors bind to one of the components of ETC
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& block the transport of electrons
? This causes the accumulation of reduced
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components before the inhibitor blockade step &oxidized components after that step.
? The synthesis of ATP is dependent on ETC.
? All the site-specific inhibitors of ETC also inhibit
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ATP formation.
Complex I: NADH & coenzyme Q
? Fish poison rotenone, barbiturate drug amytol &
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antibiotic piercidin A inhibit this.
Complex II:
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Carboxin inhibit this site.Complex III Between cytochrome b & c1
? Antimycin A ?an antibiotic,
? British antilewisite (BAL) ?an antidote used
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against war-gas? Naphthoquinone are important inhibitors of the
site between cytochrome b & c1.
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Cytochrome oxidase (Complex IV):
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Carbon monoxide, cyanide, hydrogen sulphide& azide
? Effectively inhibit cytochrome while cyanide &
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azide react with oxidized form of cytochrome.
? Cyanide is most potent inhibitor of ETC
? It binds to Fe3+ of cytochrome oxidase blocking
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mitochondrial respiration leading to cell death.
? Cyanide poisoning causes death due to tissue
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asphyxia (mostly of CNS)Site specific inhibitors of ETC.
Biological Oxidation:
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? The transfer of electrons from the reduced co
enzymes though the respiratory chain to oxygen is
known as biological oxidation.
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? Energy released during this process is trapped as
ATP.
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? This coupling of oxidation with phosphorylationis
called
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as
OXIDATIVE
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PHOSPHORYLATION.? Complex V of the inner mitochondrial membrane
is the site of oxidative phosphorylation.
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PHOSPHAGENS? Phosphagens act as storage forms of high energy
phosphate and include creatine phosphate, which
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occurs in vertebrate skeletal muscle, heart,spermatozoa & brain.
? Arginine phosphate, in invertebrate muscle.
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? When ATP is rapidly being utilized as a source ofenergy for muscular contraction, phosphagens permit
its concentrations to be maintained, but when the
ATP/ADP ratio is high, their concentration can
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increase to act as a store of high-energy phosphate.SITES OF OXIDATIVE PHOSPHORYLATION
IN ETC
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? There are 3 reactions in the ETC that areexergonic,
Where the energy change is sufficient to
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drive the synthesis of ATP from ADP and Pi.
? Site1:
Oxidation of FMNH2 by coenzyme Q.
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? Site2:Oxidation of cytochrome b by cytochrome c1
? Site3:
Cytochrome oxidase.
ENERGETICS OF OXIDATIVE
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PHOSPHORYLATION
? ? O2 + NADH + H+ H2O + NAD+
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The redox potential difference between these two redoxpairesis 1.14V, which is equivalent to an energy 52
Cal/mol
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3 ATP are synthesized in ETC when NADH is
oxidized which equals to 21.9 Cal.
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(each ATP=7.3 Cal)The efficiency of energy conservation is calculated as
21.9 ? 100
52 = 42%
.
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When NADH is oxidized, about 42% of energy
is trapped in the form of 3ATP & remaining is
lost as heat.
The heat liberation is not a wasteful process,
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since it allows ETC to go on continuously togenerate ATP.
This heat is necessary to maintain body
temperature.
MECHANISM OF OXIDATIVE
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PHOSPHORYLATION
? Two important hypothesis to explain the
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process of oxidative phosporylation.? Namely
Chemical coupling &
Chemiosmotic
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Chemical coupling hypothesis:
? This hypothesis was put forth by Edward
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Slater (1953)? According to this, during the course of electron
transfer in respiratory chain, a series of
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phosphorylated high-energy intermediates are
first produced which are utilized for the
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synthesis of ATP.? These reactions are believed to be analogous to
the substrate level phosphorylation that occurs
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in glycolysis or citric acid cycle.
? This hypothesis lacks experimental evidence.
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CHEMIOSMOTIC THEORY
Chemiosmotic theory,
proposed by Peter Mitchell
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in 1961, postulates that thetwo processes are coupled by
a proton gradient across the
inner
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mitochondrialmembrane so that the proton
motive force caused by the
electrochemical
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potential
difference (negative on the
matrix side) drives the
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mechanismof
ATP
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synthesis.
.
? The transport of electrons through the
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respiratory chain is effectively utilized to
produce ATP from ADP + Pi.
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? PROTON GRADIENT:The inner mitochondrial membrane, is
impermeable to protons (H+) & hydroxyl ions
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(OH-).The transport of electrons through ETC is
coupled with the translocation of protons
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(H+)across the inner mitochondrial membrane
from the matrix to the inter membrane space.
.
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? The pumping of protons results in an
electrochemical or proton gradient
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? This is due to the accumulation of more H+ions(low pH) on the outer side of the inner
mitochondrial membrane than the inner side.
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? The proton gradient developed due to theelectron flow in the respiratory chain is
sufficient to result in the synthesis of ATP
from ADP +Pi.
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Enzyme systems for ATP synthesis
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? ATP synthase, present in the complex V, utilizesthe proton gradient for the synthesis of ATP.
? This enzyme is also known as ATPase, since it
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can hydrolyze ATP to ADP + Pi.
? ATP synthase is a complex enzyme & consists of
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two functional subunits, namely F1 & Fo.? Fo unit: O stands for oligomycin,
? Fo inhibited by oligomycin.
? Fo spans inner mitochondrial membrane acting as
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a proton channel through which protons enter the
mitochondria
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? Fo unit has 4 polypeptide chains & is connected toF1
.F1 UNIT
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? F1 unit: It projects into the matrix.? F1 has 9 polypeptide chains, (3 alpha, 3 beta, 1
gamma, 1 delta, 1 epsilon)
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? The chains have binding sites for ATP & ADP& beta chains have catalytic activity.
? ATP synthesis requires Mg +2 Ions.
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? Its structure is comparable with lollipops.? The
protons
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thataccumulate
on
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the
intermembrane space re-enter the mitochondrial
matrix leading to the synthesis of ATP
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ROTOR MOTOR MODEL FOR ATP
GENERATION
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? Paul Boyer in 1964 proposed that a conformationalchange in the mitochondrial membrane proteins
leads to the synthesis of ATP
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? This is now considered as rotary motor/engine
driving model or binding change model.
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? widely accepted for the generation of ATP.? The enzyme ATP synthase is Fo & F1 complex
? The Fo sub complex is composed of channel
protein `C' subunits to which F1-ATP synthase is
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attached.
.
? F1-ATP synthase consists of a central gamma
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subunit surrounded by alternating alpha & beta
subunits ( 3 & 3).
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? In response to the proton flux, the gamma subunitphysically rotates.
? This induces conformational changes in the 3
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subunits that finally lead to the release of ATP.
? According to the binding change mechanism, the
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three subunits of F1 - ATP synthase adoptdifferent conformations.
? One subunit has Open (O) conformation, the
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second has loose (L) conformation while the third
one has tight (T) conformation.
.
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? By an known mechanism, protons induce the
rotation of gamma subunit, which in turn induces
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conformation changes in subunits,.? The substrates ADP & Pi bind to subunit in L
conformation.
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? The L site changes to T conformation, & this
leads to the synthesis of ATP.
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? The O site changes to L conformation which bindsto ADP + Pi.
? The T site changes to O conformation & releases
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ATP.
? This cycle of conformation changes of subunits
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is repeated.? Three ATP are generated for each revolution.
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.BOYER'S BINDING CHANGE MODEL FOR ATP SYNTHESIS BY ATP SYNTHASE.
INHIBITORS OF OXIDATIVE PHOSPHORYLATION
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? The mitochondrial transport of electrons is
tightly coupled with oxidative phosphorylation.
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? Oxidation&
phosphorylation
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proceed
simultaneously.
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? There are certain compounds that can uncouple(or delink) the electron transport from oxidative
phosphorylation.
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? Such compounds are known as uncouplers,
? Causes increase in the permeability of inner
mitochondrial membrane to protons (H+).
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? The result is that ATP synthesis does not occur
.
? The energy linked with the transport of electrons
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is dissipated as HEAT.
? The uncouplers allow (often at accelerated rate)
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oxidation of substrates (via NADH or FADH2)without ATP formation
? Examples:
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? 2,4-dinitrophenol (DNP):It is small lipophilic molecule.
DNP is a proton ? carrier & easily diffuse through
the inner mitochondrial membrane.
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Others ?dinitrocressol, pentachlorophenol,
trifluorocarbonylcyanide, phenylhydrazone.
PHYSIOLOGICAL UNCOUPLERS
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? Certain physiological substances which act as
uncouplers at higher concentration.
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? These are thermogenin, thyroxine and long chainfatty acids & unconjugated bilirubin
Significance of uncoupling:
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The maintenance of body temperature isparticularly important in hairless animals,
hibernating animals & the animals adopted to cold
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? These animals possess a specialized tissue called
brown adipose tissue in the upper back & neck
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portions..
? The mitochondria of brown adipose tissue are rich in
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electron carriers & are specialized to carry out anoxidation uncoupled from phosphorylation.
? This causes liberation of heat when fat is oxidized in
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the brown adipose tissue.
? The presence of brown adipose tissue in certain
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individuals is believed to protect them frombecoming obese.
? Thermogenin is a natural uncoupler located in the
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inner mitochondrial membrane of brown adipose
tissue
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? It acts like an uncoupler, blocks the formation ofATP, & liberates heat.
IONOPHORES
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? Ionophores: These are lipophilic substances thatare lipid soluble and increases the permeability of
inner motochondrial membrane to ions and
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thereby destroy the proton gradient leading to
inhibition of ATP synthesis.
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? By either forming channel or? By binding an ion and then diffusing into
membrane.
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? Valinomycin ( binds with K+) & Nigercin also actas uncouplers
INHIBITORS OF OXIDATIVE
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PHOSPHORYLATION? Oligomycin: This antibiotic binds with enzyme
ATP synthase & blocks the proton(H+)
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channels.
? Thus it prevents the translocation (re-entry) of
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protons into the mitochondrial matrix andprevent ATP synthesis
? Atractyloside: It is a plant toxin & inhibits
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oxidative phosphorylation.
? It blocks the adequate supply of ADP by
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inhibiting ADP/ATP transporterINHERITED DISORDER OF OXIDATIVE
PHOSPHORYLATION
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? 100 polypeptides are required for oxidativephosphorylation.
? Of these, 13 are coded by mitochondrial DNA
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& synthesized in the mitochondria, while the
rest are produced in the cytosol (coded by
nuclear DNA) & transported.
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? mtDNA is maternally inherited sincemitochondria from the sperm do not enter the
fertilized ovum.
.
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? Mitochondrial DNA is 10 times more susceptible
to mutations than nuclear DNA.
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? mtDNA mutations are commonly seen in tissueswith high rate of oxidative phosphorylation (e.g.
CNS, skeletal & heart muscle, liver).
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? Diseases:
Lethal infantile mitochondrial opthalmoplegia
Leber's hereditary optic neuropathy (LHON)
Myoclonic epilepsy
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Mitochondrial encephalopathy lactic acidosisstroke like episodes (MELAS)
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STRUCTUTRE OF ATP SYNTHASE.