Download MBBS Electron Transport Chain Lecture PPT

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DR. S. SHEKHAR

ASSOC. 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 mitochondrial

ETC.

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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to

form

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 regenerate

ATP rapidly, catalyzed by creatine kinase.

? Stored mainly in Muscle, Heart & Brain.

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BIOLOGICAL OXIDATION

The 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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of

oxidation

with

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phosphorylation

is

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called

oxidative

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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brain

B. Malate-aspartate shuttle - In liver and heart
GLYCEROL-PHOSPHATE SHUTTLE

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? Cytosolic glycerol 3-phosphate dehydrogenase

oxidizes 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) escapes

into 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 more

negative 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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enzymes

in

mitochondria , together known as the ETC.

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(the electrons are transferred from higher to
lower potential.)

Significance:
? The free energy released during the transport

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of electrons is utilized for the formation of ATP


MITOCHONDRIAL 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 oxidoreductase
Complex 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 is

utilized 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, the

substrates 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 closely

associated 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, even

if 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 of

electrons.
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 electron

carrier 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 transport
of 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 of

heme 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 mitochondrial

membrane & can be easily extracted.
Complex IV Cytochrome - Oxidase

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? Contains cytochrome a and cytochrome a3 which

is 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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to produce water

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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 phosphorylation

is

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 of

energy 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 are

exergonic,

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 redox

pairesis 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 to
generate 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 the
two processes are coupled by
a proton gradient across the
inner

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mitochondrial

membrane 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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mechanism

of

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 the

electron 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, utilizes

the 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 to

F1
.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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that

accumulate

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 conformational

change 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 subunit

physically 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 adopt

different 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 binds

to 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 chain

fatty acids & unconjugated bilirubin

Significance of uncoupling:

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The maintenance of body temperature is

particularly 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 an

oxidation 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 from

becoming 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 of

ATP, & liberates heat.
IONOPHORES

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? Ionophores: These are lipophilic substances that

are 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 act

as 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 and

prevent 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 transporter
INHERITED DISORDER OF OXIDATIVE

PHOSPHORYLATION

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? 100 polypeptides are required for oxidative

phosphorylation.

? 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 since

mitochondria 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 tissues

with 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 acidosis

stroke like episodes (MELAS)

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STRUCTUTRE OF ATP SYNTHASE.