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Cicia Firakania

Medical Faculty of Unswagati Cirebon


2016

By the end of this lecture,


the student should be able to:
1. Understand the chemiosmotic theory
2. Understand the flow of electron in
respiratory chain
3. Understand the mechanism of ATP
formation in electron transport chain
4. Understand the concept of shuttles
acrross the mitochondrial membrane
5. Understand the example of respiratory
chain inhibitors

Definition of oxidation and


reduction reaction
- Oxidation and reduction in terms of
hydrogen transfer
Definitions
Oxidation is loss of hydrogen.
Reduction is gain of hydrogen.

Oxidation and reduction in


terms of electron transfer
Definitions
Oxidation is loss of electrons.
Reduction is gain of electrons.

Introduction
Aerobic organisms are able to capture a far greater

proportion of the available free energy of


respiratory substrates than anaerobic organisms.

Most of this takes place inside mitochondria,

which have been termed the powerhouses of the


cell.

Respiration is coupled to the generation of the

high-energy intermediate,
phosphorylation.

ATP,

by

oxidative

A number of drugs (eg, amobarbital) and poisons

(eg, cyanide, carbon monoxide) inhibit oxidative


phosphorylation, usually with fatal consequences.

Several

inherited
defects
of
mitochondria involving components
of the respiratory chain and oxidative
phosphorylation have been reported.

Patients

present with myopathy


and encephalopathy and often
have lactic acidosis.

Cellular Respiration

An ATP-generating process in which an


inorganic compound (such as molecular
oxygen) serves as the ultimate electron
acceptor. The electron donor can be either an
organic compound or an inorganic one.

Overview of Cellular
Respiration

Mitochondria
Mitochondria
have an outer
membrane that
is permeable to
most metabolites
and an inner
membrane that
is
selectively
permeable,
enclosing
a
matrix within.

Specific enzymes in the


mitochondrial compartment
The outer membrane:

acyl-CoA
synthetase
and
glycerolphosphate acyltransferase
Intermembrane space:
adenylyl kinase and creatine kinase
Inner membrane:
the phospolipid cardiolipin, enzymes
of the respiratory chain, ATP synthase
and various membrane transporters

Role
of
the
respiratory
chain
of
mitochondria in the conversion of food
energy to ATP

Glycerophospate shuttle for transfer of


reducing equivalents from cytosol into
the mitochondrion

Malate shuttle for transfer of reducing


equivalents from the cytosol into the
mitochondrion

Enzim-enzim dlm siklus Krebs, oksidasi beta


dan rantai respirasi mengumpulkan dan
mentranspor ekivalen pereduksi menuju
reaksi
terakhir
dengan
oksigen

membentuk air
Bersama dengan mesin-mesin fosforilasi
oksidatif,
menjalankan
proses
yg
menghasilkan
energi
bebas
yang
diperangkap dalam bentuk senyawa fosfat
berenergi tinggi (high-energy phosphate).

Chemiosmotic Theory
How is oxidation coupled to produce of
ATP????
Peter Mitchell Propoposed chemiosmotic
hypotheses

Chemiosmostic Model

Chemiosmostic Model
The theory postulates that complexes
I, III, and IV act as proton pumps creating
a proton gradient across the membrane,
which is negative on the matrix side. The
proton motive force generated drives the
synthesis of ATP as the protons flow back
into the matrix through the ATP synthase
enzyme.

Electron Transport System

KOMPONEN DALAM RANTAI


RESPIRASI
Ada 4 kompleks protein yang besar yang
tertanam
dalam
inner
membrane
mitokondria, tetapi Q dan Cyt C bersifat
mobile.
Elektron mengalir melalui rantai respirasi
melalui reaksi-reaksi redoks dg span 1,1 Volt :
mulai dari NAD+/ NADH O2/ 2 H2O
melewati 3 kompleks besar protein: I III
IV

Electron Transport
System
Terdiri dari 5 Kompleks
Kompleks I NADH-CoEnzymeQ

Oxireductase
Kompleks II - Succinate-Q Oxidoreductase
Kompleks III - Q-Cytochrome c
Oxidoreductase
Kompleks IV - Cytochrome C Oxidase
Kompleks V - ATP synthase

Kompleks I IV berfungsi untuk

menciptakan gradien proton yang besar


Kompleks V berfungsi untuk mensintesis
ATP dengan bantuan gradien proton

Complex I NADH-CoEnzymeQ
Oxireductase
elektron
ditransfer/
dipindahkan
dari
NADH ke koenzim
Q (Q= ubiquinone).

Complex II - Succinate-Q
Oxidoreductase
Sebagian substrat dgn
potensial redoks yang
lebih
tinggi
daripada
NAD+/ NADH (contoh:
suksinat)
cenderung
melewatkan elektron ke
koenzim
Q
melalui
kompleks II ini daripada
kompleks I.

Complex III - Q-cytochrome c


Oxidoreductase
kompleks ini
memindahkan
elektron ke
sitokrom c.

Complex IV - Cytochrome c
Oxidase
melengkapkan
rantai respirasi
dengan
melewatkan
elektron ke O2 ,
dan direduksi
menjadi H2O

Complex V - ATP synthase

Ko-enzim Q terdifusi dalam membran, sedangkan cyt c adalah suatu


protein terlarut.
Aliran elektron melalui kompleks IIIIIV menghasilkan proton yg
terpompa dari matrik menuju celah antar membran mitokondria (lihat
gambar di slide 9).
Kompleks kompleks Komponen Rantai Pernafasan merupakan

suatu Flavoprotein atau Iron-Sulfur Protein

Flavoprotein adl komponen penting dalam kompleks I dan II.


FMN/FAD
Dpt direduksi pd proses pemindahan 2 elektron membentuk FMNH2
atau FADH2
Dpt menerima 1 elektron , membentuk semikuinon.

Iron-sulfur protein :
Disebut juga : Nonheme iron proteins, Fe-S
Dijumpai pada kompleks I, II dan III
Dapat mengandung 1, 2 atau 4 atom Fe yg terikat pada atom sulfur
anorganik dan atau melalui gugus SH sistein terikat pd protein.
Fe-S berperan memindahkan elektron, dimana Fe mengalami oksidasireduksi antara Fe2+ Fe3+

Quinon menerima elektron melalui Kompleks I dan II.


Kompleks I :
Disebut juga NADH-Q oksidoreduktase
Suatu multi subunit besar, berbentuk L
Berfungsi memindahkan elektron dari NADH ke koenzim Q dikopel dgn
transfer 4 ion H+ melintasi membran dalam
NADH + Q + 5H+ matriks NAD + QH + 4H+

Pada komplek I awalnya terjadi transfer elektron dari NADH (hasil


katabolisme nutrien) ke FMN (dlm kompleks).
Kemudian elektron berpindah dari FMN ke pusat Fe-S (serial).
Selanjutnya elektron berpindah dari Fe-S ke koenzim Q.
Kompleks II:
(Suksinat-Q reduktase)
FADH2 hasil siklus Krebs dan elektron ditransfer melalui beberapa
pusat Fe-S ke Quinone
Gliseraldehid 3-P yg berasal dari pemecahan Trigliserida (TG) atau
dari glikolisis dan asetil koA mentransfer elektron ke Quinone melalui
jalur lainnya

Respiratory Control
1. Mainly by availability of ADP
(ATP/ADP transporters may be rate
limiting at certain times)
2. Availability of electrons
NADH/NAD ratio or
FADH2/FAD
3.Availability of O2

The respiratory chain can


be inhibited by:
a. Inhibitors of the respiratory chain,
b. Inhibitors of oxidative
phosphorylation,
c. and uncouplers of oxidative
phosphorylation.

Inhibitor of respiratory chain


Rotenone is a common insecticide that strongly inhibits the
electron transport of complex I. Rotenone is a natural product
obtained from the roots of several species of plants.

Tribes in certain parts of the world beat the roots of trees along
riverbanks to release rotenone into the water which paralyzes
fish and makes them easy prey.

Amytal

is a barbiturate that inhibits the


electron transport of complex I.
Demerol is painkiller that also inhibits
complex I.

All three of the complex I inhibitors block

the oxidation of Fe-S clusters of complex I

2-Thenoylfluoroacetone and

carboxin specifically block electron


transport in Complex II

Malonate is a competitive inhibitor

of Complex II.

Antimycin A and dimercaprol inhibit the

respiratory chain at Complex III.


Antimycin A1 is an antibiotic that inhibits
electron transfer in complex III by blocking
the transfer of electrons between Cyt b H
and coenzyme Q bound at the QN site.

Cyanide,

azide
and
carbon
monoxide
all
inhibit
electron
transport in Complex IV. All of the
inhibitors, inhibit electron transfer by
binding
tightly with the iron
coordinated in Cyt a3.

Carbon monoxide is toxic due to its affinity


for the heme iron of hemoglobin. Animals
carry many molecules of hemoglobin,
therefore it takes a large quantity of
carbon monoxide poisoning. Animals have
relatively few molecules of Cyt a3.
Consequently an exposure to a small
quantity of azide or cyanide can be lethal.
The toxicity of cyanide is solely from its
ability to arrest electron transport.

Inhibitors of oxidative
phosphorylation
Atractyloside

inhibits
oxidative
phosphorylation
by
inhibiting
the
transporter of ADP into and ATP out of
the mitochondrion

The antibiotic oligomycin completely

blocks oxidation and phosphorylation


by blocking the flow of protons through
ATP synthase

Uncouplers of oxidative
phosphorylation
Uncouplers dissociate oxidation in the

respiratory chain from phosphorylation


The uncoupling of oxidative phophorylation

from electron transport generates heat.


Thermogenin (or the uncoupling protein)

is a physiological uncoupler found in brown


adipose tissue that functions to generate body
heat, particularly for the newborn and during
hibernation in animals.

Inhibition sites of the respiratory


chain

Mitochondrial
Abnormalities

The condition known as fatal infantile

mitochondrial myopathy and renal


dysfunction involves severe diminution
or absence of most oxidoreductases of the
respiratory chain.

MELAS (mitochondrial encephalopathy,

lactic acidosis, and stroke) is an inherited


condition due to NADH-Q oxidoreductase
(Complex
I)
or
cytochrome
oxidase
(Complex IV) deficiency

Link Video:

Cellular Respiration:
https://www.youtube.com/watch?v=Fc
u_8URp4Ac
ATP Synthase:
https://www.youtube.com/watch?
v=PjdPTY1wHdQ