Download MBBS Biochemistry PPT 46 Final Biologcal Oxidation Lecture Notes

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Synopsis
What is Biological Oxidation?
Enzymes and Coenzymes of Biological

Oxidation Reactions.

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Electron Transport Chain(ETC)
Oxidative Phosphorylation Mechanisms
Inhibitors of ETC and Oxidative

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Phosphorylation

Uncouplers
Shuttle Systems
High Energy Compounds

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Substrate Level Phosphorylation.

What Is Biological Oxidation?
Biological oxidation

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are oxidation

reactions taking place

in living systems.

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Importance Of Biological Oxidation
Biological Oxidation

reactions are associated with

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metabolism.

Vital for functioning of

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cells, survival and

existence of human body.

Definition Of Oxidation Reactions

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Oxidation reactions are

biochemical reactions where there is

either:

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Removal / Loss of Hydrogen
(Dehydrogenation)
Removal or Loss of Electrons
Addition of Oxygen

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(Oxygenation)

Most predominant type of

Oxidation reaction in body

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is:

Dehydrogenation Reaction

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Catalyzed by Dehydrogenases
Dehydrogenases

remove Hydrogen from

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substrates.

Which are temporarily

accepted by Coenzymes.

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Coenzymes involved in

Oxidation/Dehydrogenation

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reactions.

NAD+
NADP+
FAD

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FMN
Coenzymes temporarily accept the

hydrogen from substrates and get

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transformed to reduced coenzymes.

NADH+H+

FADH2

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NADPH+H+

FMNH2

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Enzymes

and

Coenzymes

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of

Biological Oxidation

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Reactions
5 Enzymes of Biological Oxidation

1. AEROBIC

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DEHYDROGENASES

2. ANAEROBIC

DEHYDROGENASES

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3. OXYGENASES
4. OXIDASES
5. HYDROPEROXIDASES
All 5 Enzymes of

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Biological Oxidation

reactions are classified

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in

Class I

Oxido Reductases

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Coenzymes

and

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Inorganic Cofactors

Of

Biological Oxidation

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Reactions
FMN
FAD
NAD+

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NADP+
THBP (Tetra Hydro Biopterin)
Cu++
Fe+++

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AEROBIC DEHYDROGENASES
Aerobic Dehydrogenases are Flavoproteins.
Enzymes covalently bound to coenzymes FMN or FAD

MH2 Aerobic DH M

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FMN FMNH2 (Auto

oxidizable)

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Catalase

H2 +O2 H2O2 H2O + O2

FMN/FAD are acceptors

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of removed Hydrogen

Reduced Coenzymes

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(FMNH2/FADH2) formed

are auto oxidizable
Reduced coenzymes get

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reoxidized at reaction

level.

Oxygen gets directly

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involved at reaction level

to reoxidize the reduced

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coenzymes.

H2O2 is a byproduct of

Aerobic Dehyrogenase

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activity.

Catalase then detoxify

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the H2O2 to H2O and O2.
Specific Examples Of

Aerobic Dehydrogenases

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L Amino acid Oxidase
(Oxidative Deamination of A.A)
Xanthine Oxidase
(Purine Catabolism)
Glucose Oxidase

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(Glucose oxidation to Gluconic acid)
Aldehyde Dehydrogenase
( Alcohol Metabolism)

ANAEROBIC DEHYDROGENASES

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Anaerobic Dehydrogenases

catalyzes to remove

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hydrogen from substrates.

With the help of coenzymes

NAD+/NADP+/FAD.

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MXH2 Anaerobic Dehydrogenase MX

NAD+ NADH+ H+ (Non auto oxidizable)

Enter Electron Transport Chain

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For its reoxidation

Coenzymes temporarily accept the

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hydrogen from substrates and get

reduced to

NADH+ H+

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FADH2

NADPH+H+

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FMNH2
Reduced coenzymes formed in

Anaerobic Dehydrogenase

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reactions are :

Non autoxidizable/not reoxidized

at reaction level.

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Reduced coenzymes

NADH+H+ and FADH2

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formed at Anaerobic

Dehydrogenase reaction

enter ETC for its

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reoxidation.
Oxygen is involved

indirectly at the end of

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ETC as electron and

proton acceptor .

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Metabolic water is end

product of ETC.

Reduced coenzyme

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NADPH+H+ do not enter

ETC

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NADPH+H+ is utilized as

reducing equivalent for

reduction reactions

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catalyzed by Reductases.
NAD+ Dependent Anaerobic

Dehydrogenases

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Glyceraldehyde -3-PO4 Dehydrogenase
Pyruvate Dehydrogenase
Isocitrate Dehydrogenase
Ketoglutarate Dehydrogenase

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Malate Dehydrogenase
Lactate Dehydrogenase
Glutamate Dehydrogenase
Hydroxy Acyl Dehydrogenase

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NADP+ Dependent

Dehydrogenases

Glucose -6-Phosphate Dehydrogenase

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( HMP Shunt)

Phospho Gluconate Dehydrogenase

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(HMP Shunt)

Note NADPH+H+does not enter ETC

for its reoxidation instead they are

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involved in reduction reactions.
FAD Dependent Anaerobic

Dehydrogenases

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Succinate Dehydrogenase
(TCA Cycle)
Acyl CoA Dehydrogenase
( Oxidation Of Fatty Acids)

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FMN Dependent Anaerobic

Dehydrogenase

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NADH Dehydrogenase

(Warburg's Yellow

Enzyme)

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First Component of ETC/

Complex I of ETC
OXYGENASES

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Oxygenases add Oxygen

atom from molecular oxygen

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(O2) to the substrate.

Form Oxidized Product.

Mono Oxygenases

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Mono Oxygenases add one oxygen

atom from molecular oxygen to the

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substrate.

Forms Hydroxyl group (-OH )
Monoxygenases are also termed as

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Hydroxylases or Mixed Function

Oxidase.
AH + O2+BH2 Mono Oxygenase AOH+ B+H2O

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Tyrosine+O2+THBP Tyrosine

DOPA+DHBP+H2O

Hydroxylase

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Examples Of Mono Oxygenases

Phenylalanine Hydroxylase
(Phenylalanine to Tyrosine)

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Tryptophan Hydroxylase
(Tryptophan to 5HydroxyTryptophan)
25 Hydroxylase
(Vitamin D - Cholecalciferol activation)
1 Hydroxylase

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(Vitamin D - Cholecalciferol activation)
Di Oxygenases

Dioxygenases are true Oxygenases
Incorporates two Oxygen atoms

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from O2.

A+ O2 Dioxygenase AO2

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Examples Of Dioxygenases

Tryptophan Di Oxygenase/

Tryptophan Pyrrolase

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(Tryptophan NFormyl Kynurenine )
PHPP Dioxygenase
Cysteine Dioxygenase
Homogentisate Oxidase

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(Homogentisate to 4 Maleyl Acetoacetate)


Oxidases

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Oxidases involve molecular

Oxygen as Hydrogen (electron

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and proton ) acceptor.

Oxidases reduces

molecular Oxygen to Water

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(H2O)

AH2 + ? O2 Oxidase A+ H2O

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Tyrosine+ O2 Tyrosinase -Cu++ DOPA +

H2O
Examples Of Oxidases

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Cytochrome Oxidase
(ETC enzyme) Classic Example
Ascorbate Oxidase
Mono Amine Oxidase
Catechol Oxidase

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Hydroperoxidases

Hydroperoxidases detoxify

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Hydrogen Peroxide in body.

H2O2 is a substrate/reactant

for Hydroperoxidases.

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Hydroperoxidases are

Hemoproteins.

Contains loosely

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bound Heme as

prosthetic group.

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Hydroperoxidases prevent

accumulation of H2O2 in cells.

H2O2 if accumulated in cells is

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toxic

Leads to disruption of

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membranes(Hemolysis).

Increases risk of cancer and

atherosclerosis.

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Specific Examples Of

Hydroperoxidases

Peroxidases

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Catalase

Peroxidases

Indirectly react with H2O2.

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Glutathione Peroxidase
(In R.B.C's)
Leukocyte Peroxidase
(In W.B.C's)

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H2O2 + 2 GSH Glutathione Peroxidase 2H2O + GSSG
(Reduced (Oxidized

active Form)

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inactive Form)



Catalase

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Directly reacts with H2O2.
Associated with Aerobic

Dehydrogenase catalyzed

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reaction.

2H2O2 Catalase 2H2O +O2
Biological Oxidation Process

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Electron Transport Chain

(ETC)

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Synonyms
Electron Transport Chain (ETC)
Electron Transport System (ETS)
Respiratory Chain
Internal/Cellular Respiration

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Tertiary metabolism
Fate of reduced Coenzymes

NADH+H+/FADH2

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Final Oxidative Pathway
Oxidative Phosphorylation

What is Electron Transport Chain?
Electron Transport chain

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Vital biological oxidation

process.

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Carried out in aerobic

condition.

Located at inner membrane

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of Mitochondria.

Fate of ETC is to

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reoxidize the reduced

coenzymes

NADH+H+/FADH2.

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Formed during Anaerobic

Dehydrogenase reactions.
Electron Transport Chain

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Transports Electrons and

Protons

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Through a series of ETC

components and

Finally to activated molecular

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oxygen.

Generates ATP and metabolic

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water.

What is Oxidative Phosphorylation?
Oxidative process (ETC)

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is tightly coupled with

Phosphorylation of ADP

with pi to generate ATP.

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Oxidative

Phosphorylation is a

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major mode of ATP

generation.
Location Of ETC

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ETC is carried out in all cells

which contain mitochondria

(Power house of Cell).

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(Except mature Erythrocytes which

are devoid of mitochondria)

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Components and Enzymes of

ETC are arranged towards inner

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surface of inner membrane of

mitochondria.

In vectorial conformation

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In increased order of positive

redox potential

Location of Mitochondrial ETC Complexes

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? Inner membrane of mitochondria
Condition Of ETC Operation

ETC operates in truly aerobic

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condition.

Oxygen unloaded at cellular level

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by HbO2 gets utilized at the

end of ETC process.

(Respiratory Chain)

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ETC depends on

Respiration Process
Oxygen Concentration

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Hemoglobin Structure and

Function

Metabolic Status

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Components Of ETC

Flavo Protein- (First Component)
NADH Dehydrogenase-FMN and FeS

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centers(Warburg's Yellow Enzyme)

Coenzyme Q/ Ubiquinone
Series of Cytochromes-
Cytochrome b-Cytochrome c1-

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Cytochrome c- Cytochrome aa3
Iron-sulfur centers (Fe-S) are prosthetic groups

containing 2, 3 , 4 or 8 iron atoms complexed to elemental

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& cysteine S.
4-Fe centers have a tetrahedral structure, with Fe & S

atoms alternating as vertices of a cube.

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Cysteine residues provide S ligands to the iron, while also

holding these prosthetic groups in place within the protein.

Electron transfer proteins

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may contain multiple Fe-S

centers.
Iron-sulfur centers

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transfer only one electron,

even if they contain two or

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more iron atoms, because

of the close proximity of

the iron atoms.

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Fe+++ (oxidized) + 1 e- Fe++ (reduced)


Coenzyme Q / Ubiquinone

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Coenzyme Q (CoQ)/ Ubiquinone)

is located in the lipid core of the

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mitochondrial membrane.

It is a Quinone derivative
Lipophilic dissolves in the

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hydrocarbon core of a membrane.

Cytochrome has a long Poly

isoprenoid tail, with multiple

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units of isoprene.

In human cells, most often n = 10.
Q10 isoprenoid tail is longer than

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the width of a bilayer.
Coenzyme Q is very

hydrophobic.

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Coenzyme Q functions as a

mobile e- carrier within the

mitochondrial inner

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membrane.

Its role in trans-membrane

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H+ transport coupled to e-

transfer (Q Cycle).

The Quinone

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ring of coenzyme

Q can be reduced

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to the Quinol in

a 2e- reaction:

Q + 2 e- + 2 H+ QH .

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2
When bound to special sites in respiratory complexes,

CoQ can accept 1 e- to form a semiquinone radical (Q?

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-).

Thus CoQ, like FMN, can mediate between 1 e- & 2 e-

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donors/acceptors.

Cytochromes

Cytochromes are Hemoproteins

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conjugated proteins in ETC

Carrier of electrons
Contain heme as prosthetic

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group.

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Cytochromes absorb light at

characteristic wavelengths.

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Absorbance changes upon

oxidation/reduction of the

Heme Iron

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Cytochrome Heme

Cytochrome heme Iron is in

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transitional state

Carries electrons only:
Fe (III) + e- Fe (II)
Only one electron is transferred

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at a time.
Cytochrome heme iron

can undergo a 1 e-

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transition between ferric

and ferrous states:

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Fe+++ + e- Fe++
(oxidized) (reduced)
Series of Cytochromes b, c , c, aa

1

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3

relay electrons (one at a time, in this

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order

Cytochrome c is a small,

water soluble protein with a

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single heme group.
Cytochromes a & a3 are

often referred to as

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Cytochrome Oxidase

/complex IV.

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Cytochrome aa3 has Fe and

Cu.

All Cytochromes

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except Cytochrome

Oxidase are Anaerobic

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Dehydrogenases.
ETC Complexes

ETC complexes are

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combination of one or two

components of ETC.

There are 5 ETC complexes.

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Complex I- NADH CoQ Reductase
NADH Dehydrogenase FMN and FeS centre
Complex II ? Succinate CoQ Reductase
Succinate Dehydrogenase FAD and FeS centre.

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Complex III?CoQ Cytochrome C Reductase
Cytochrome b ? Cytochrome c1
Complex IV- Cytochrome Oxidase
Cytochrome aa3
Complex V ? ATP Synthetase

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F0 and F1 of ATP Synthase
Composition of Respiratory Chain Complexes

No. of

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Prosthetic Groups

Complex

Name

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Proteins

Complex I

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NADH

46

FMN,

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Dehydrogenase

9 Fe-S centers

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Complex II

Succinate-CoQ

5

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FAD, cyt b ,

560

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Reductase

3 Fe-S centrs.

Complex III

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CoQ-cyt c Reductase

11

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cyt b , cyt b , cyt c ,

H

L

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1

Fe-SRieske

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Complex IV

Cytochrome Oxidase

13

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cyt a, cyt a , Cu , Cu

3

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A

B
Electrons are transferred from

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NADH O via multisubunit

2

inner membrane complexes I, III

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& IV, plus CoQ & Cytochrome c.

Within each complex, electrons

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pass sequentially through a series

of electron carriers.
Complex I catalyzes

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oxidation of NADH+H+ with

reduction of coenzyme Q:

NADH + H+ + FP NAD+ + FPH2

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Coenzyme Q accepts 2 e- and picks

up 2 H+ from FPH2 to yield the fully

reduced QH2.

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Succinate Dehydrogenase of the Krebs Cycle is

also called complex II or Succinate-CoQ

Reductase.

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FAD is the initial e- acceptor.

FAD is reduced to FADH2 during oxidation of

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Succinate to Fumarate.

FADH2 is then reoxidized by

transfer of electrons through a

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series of 3 iron-sulfur centers to

CoQ, yielding QH2.

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The QH2 product may be

reoxidized via complex III.

Providing a pathway for transfer of

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electrons from Succinate into the

respiratory chain.
CoQ accepts electrons via

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ETC complexes I and II.

Complex III/ Cytochrome b-c1

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complex accepts electrons from

coenzyme QH2 that is generated

by electron transfer in complexes

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I & II.


Cytochrome c resides in the

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intermembrane space.

It alternately binds to

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complex III or IV during e-

transfer.

COMPLEX IV

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Cytochrome a-a3/ Cytochrome Oxidase
large protein
Both a and a3 contain heme and Cu
a3 Cu binds to oxygen and donates

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electrons to oxygen

Cytochrome a3 - only component of
ETC that can interact with O2

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Cytochrome oxidase (complex IV) carries out

the following irreversible reaction:
O + 4

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O

2

H+ + 4 e- 2 H2

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The four electrons are transferred into the

complex one at a time from Cytochrome c.

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Complex IV/Cytochrome

Oxidase reduces

molecular Oxygen to

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water.


Cytochrome Oxidase

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Cu(II) Cu(I)

e- from cyt c to a

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Heme A and Cu act together to
transfer electrons to oxygen

Metal centers of cytochrome oxidase (complex IV):

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heme a & heme a3,

CuA (2 adjacent Cu atoms) & CuB.
O2 reacts at a binuclear center consisting of heme

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a and Cu .

3

B

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An Iron-Copper Center in

Cytochrome Oxidase

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Catalyzes Efficient O2

Reduction

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Complex V

ATP Synthase

Two units, Fo and F1

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("knob-and-stalk"; "bal on a stick")

F1 contains the catalytic subunits

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where ADP and Pi are brought

together for combination.

F0 spans the membrane and serves as

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a proton channel.


? F1 contains 5 types of

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polypeptide chains - a3b3gde

? Fo - a1b2c10-14

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(c subunits form cylindrical,

membrane-bound base)

? Fo and F1 are connected by a ge

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stalk and by exterior column

(a1b2 and d)

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? The proton channel ? between c

ring and a subunit.

Complex V ATP Synthase

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ATPase is a Rotating Motor

Complex I ,III and IV act as a

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Proton Pump.

Pump out the protons from

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matrix side to inter membrane

space of mitochondria.

Develop a proton gradient in

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inter membrane space.

This supports the mechanism of

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Oxidative Phosphorylation.



F F couples ATP synthesis to H+

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1 o

transport into the mitochondrial matrix.
Transport of at least 3 H+ per ATP is

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required.

Electron Transport is coupled to

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Oxidative Phosphorylation
Salient Features Of

ETC/ETS/Oxidative Phosphorylation

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Reduced coenzymes NADH and

FADH2 are formed in matrix from:

Oxidative Decarboxylation of Pyruvate to

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Acetyl CoA by PDH complex.

Oxidation of acetyl CoA by the citric acid

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cycle

Beta Oxidation of fatty acids
Amino acids metabolism
Reduced coenzymes

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NADH+H+/FADH2

Generated during Anaerobic

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Dehydrogenase reactions of

Carbohydrates, Lipids metabolic

pathways.

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Get reoxidized on entering

E.T.C

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The NADH+H+ and

FADH2 are energy rich

molecules

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Each contains a pair of

electrons having a high

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transfer potential.


Glycolysis, Fatty

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acid oxidation

TCA cycle

supplies NADH

--- Content provided by‌ FirstRanker.com ---

and FADH2 to

the Electron

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Fatty Acids

Acetyl Co A

Transport Chain

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Pyruvate

Amino Acids

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Glucose


The reduced and oxidized forms of NAD

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The reduced and oxidized forms of FAD

Redox Couples and Redox

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Potentials
The components of ETC has

capacity to exist in oxidant and

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reductant forms.

This pair is known as redox

couple.

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CoQ/CoQH2
Cyt b Fe+++/Cyt b Fe++

Redox Potential is a

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measure of the tendency of

a redox couple to accept

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or donate electrons under

standard condition.
Components that have

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the most negative redox

potentials have the

weakest affinity for

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electrons.

Redox couple with most

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positive redox potentials

have

The strongest affinity for

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electrons therefore

Possess strongest tendency to

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accept electrons.
In ETC electrons flow from most

electro negative potential

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NADH+H+ (-0.32) to most

electro positive potential

(+0.82) ? O2 .

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In E.T.C both Protons and Electrons

are transferred up to Coenzyme Q

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level.

At coenzyme Q level protons (2H+)are

released in the medium.

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From Coenzyme Q onwards only

electrons are transferred through a

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series of Cytochromes in E.T.C.
Electrons get transfer through

series of Cytochromes

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Cytochrome Fe is in transitional

state (Ferric/Ferrous ).

In E.T.C there are

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alternate reduction

and oxidation

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reactions.
During E.T.C there is transfer

of reducing equivalents from

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low redox potential to high

redox potential.

This exhibit free energy

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change there by liberating

heat energy.

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Electrons move spontaneously

from one component of ETC to

another with a

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low redox potential (a low

affinity for electrons) to a

--- Content provided by‌ FirstRanker.com ---

component with a

high redox potential (a high

affinity for electrons)

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In ETC electrons move from a

carrier with

low redox potential

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(high tendency to donate

electrons) toward carriers with

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higher redox potential

(high tendency to accept

electrons).

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The proton gradient

runs downhill to drive

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the synthesis of ATP
Oxygen is the terminal

acceptor of electrons in

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the electron transport

chain.

At the end of E.T.C by the catalytic

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activity of Cytochrome Oxidase

Protons released at Coenzyme Q

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and electrons transported by

Cytochromes are

Accepted by activated molecular

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oxygen (1/2 O2) to form metabolic

water.
Oxygen has the highest (most

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positive) standard redox

potential .

--- Content provided by‍ FirstRanker.com ---

Most likely to accept electrons

from other carriers.

Electrons ultimately reduce Oxygen

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to water (metabolic water)

2 H+ + 2 e- + ? O2 -- H2O

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Cytochrome oxidase

controls the rate of O2

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uptake which

Means this enzyme

determines how rapidly

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we breathe.

F F couples ATP synthesis to H+

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1 o

transport into the mitochondrial matrix.
Transport of at least 3 H+ per ATP is

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required.
The respired Oxygen

transported by Hb

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unloaded at tissue/

cellular level is

utilized during E.T.C.

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WHY ETC OPERATES ?
During E.T.C operation the

total energy change is

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released in small increments

So that energy can be trapped

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as chemical bond energy to

form ATP.

When two redox couples of ETC

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differ from each other by 0.22 volts

in standard redox potential.

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The free energy in the form of heat

released is more than 7.3 Kcal.

This free heat energy is conserved

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to chemical form of energy-ATP.
The sites in E.T.C at

which energy liberated

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is less than 7.3 Kcal is

simply dissipiated in

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the form of heat.

Certain sites in E.T.C

where the heat energy

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liberated more than 7.3

Kcal is utilized for

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phosphorylation

reaction of ADP with pi

to form ATP.

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Thus heat energy is

transformed to

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chemical form of

energy (ATP) in E.T.C.

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THE ELECTRON TRANSPORT CHAIN

Series of enzyme complexes (electron carriers)

embedded in the inner mitochondrial membrane,

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which oxidize NADH+H+ and FADH2 and

transport electrons to oxygen is cal ed

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Respiratory Electron-Transport Chain (ETC).

The sequence of electron carriers in ETC

NADH FMN-Fe-S Co-Q Fe- cyt b

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S cyt c1 cyt c cyt a cyt a3 O2

Succinate FAD Fe-

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S


Electrons of NADH or FADH2 are used to

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reduce molecular oxygen to water.

A large amount of free energy is liberated.

The electrons from NADH+H+ and FADH2 are not

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transported directly to O2 but are transferred

through series of electron carriers that undergo

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reversible reduction and oxidation.

A PROTON GRADIENT POWERS

THE SYNTHESIS OF ATP

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The transport of electrons from NADH or FADH2 to

O2 via the electron-transport chain is exergonic

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process:
NADH + ?O2 + H+ H2O + NAD+
FADH2 + ?O2 H2O + FAD+
Go' = -52.6 kcal/mol for NADH
-36.3 kcal/mol for FADH2

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This process is coupled to the synthesis of ATP

(endergonic process)

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ADP + Pi ATP + H2O Go'=+7.3 kcal/mol


The flow of electrons through ETC

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complexes leads to the pumping of

protons out of the mitochondrial

matrix in intermembrane space.

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The resulting distribution of protons

generates a pH/Proton gradient and

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a transmembrane electrical potential

that creates a proton motive force.
A Large Drop in Redox

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Potential across each of the

three Respiratory Enzyme

Complexes (I,III,IV).

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Provides the Energy for H+

Pumping

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ATP is synthesized when

protons flow back from

intermembrane space of

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mitochondria to the

mitochondrial matrix

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through an enzyme complex

ATP synthase.
The oxidation of fuels

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and the phosphorylation

of ADP are coupled by a

proton gradient across

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the inner mitochondrial

membrane.

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Oxidative phosphorylation is

the process in which ATP is

formed

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As a result of the transfer of

electrons from NADH or

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FADH2 to O2 by a series of

electron carriers.

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E.T.C is a Mode For Free Radical

Generation
During E.T.C operation there

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occurs leakage of small amounts

of electrons

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Which are transferred directly

to oxygen to form super oxide

ion (Free radicals).

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What is a Free Radical ?

Any chemical species with one of

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more unpaired electrons.

Unstable/Highly Reactive
Powerful Oxidant
Short half life (nanoseconds)

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Can exist freely in the environment
Significance Of ETC

Reduced coenzymes gets reoxidized

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to NAD+ /FAD in ETC for its

reutilization in metabolic oxidation

reactions.

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Reduced coenzymes NADH+

H+/FADH2 give its reducing

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equivalents to E.T.C components and

get reoxidized.

E.T.C generates chemical form of

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energy ATP as a valuable by product.
P/O Ratio

The ratio of ATPs formed

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per oxygen reduced

OR

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Number of ATPs generated

per Oxygen atom used in

ETC process.

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To make 1 ATP need 30

kJ/mole.

There needs more than one

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proton to translocate during

ETC process to generate 1 ATP.

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Ten protons are pumped out of

the matrix during the two electrons

flowing from NADH+H+ to O2

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(Complex I, III and IV).

Six protons are pumped out of the

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matrix during the two electrons

flowing from FADH2 to O2

(Complex III and IV).

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Spontaneous

electron flow

through each

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of complexes I,

III, & IV
is coupled to

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H+ ejection

from the

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matrix.

A total of 10 H+ are ejected from the mitochondrial matrix per

2 e- transferred from NADH to oxygen via the respiratory

--- Content provided by⁠ FirstRanker.com ---

chain.
A total of 6 H+ are ejected from the mitochondrial matrix per

2 e- transferred from FADH2 to oxygen via the respiratory

--- Content provided by​ FirstRanker.com ---

chain.

Complex I and Complex III transports 4H+

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out of the mitochondrial matrix per 2e-

transferred from NADH.

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Thus there are 2H+ per 2e- that are

effectively transported by complex

IV.

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ATP Yield

3

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4

4

2

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ETC translocates 10

protons per NADH+H+

ETC translocates 6

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protons per FADH2

Proton gradient created

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as electrons transferred to

oxygen forming water

10 H+ / NADH+H+

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6 H+ / FADH2
Translocation of 3H+ required

by ATP Synthase for each ATP

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produced

1 H+ needed for transport of Pi.

Net: 4 H+ transported for

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each ATP synthesized

through ATP Synthase.

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F F couples ATP synthesis to H+

1 o

transport into the mitochondrial matrix.

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Transport of least 3 H+ per ATP is

required.
P:O Ratio for NADH+H+

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10 H+ X 1 ATP = 2.5 ATP

4 H+

P.O Ratio for FADH2

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6 H+ X 1 ATP = 1.5 ATP

4 H+

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P:O ratio for NADH: 10 H+/4H+ =

2.5 ATP

P:O ratio for FADH2: 6 H+/ 4H+ =

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1.5 ATP
ATP Is A Valuable Byproduct Of

E.T.C/ Oxidative Phosphorylation.

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ATP is a high energy phosphate

compound

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Biologically important free

nucleotide

ATP has 2 high energy Phospho

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anhydride bonds.
ATP is energy currency of

cell.

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Predominantly generated

through Oxidative

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Phosphorylation.

Sites Of ATP Production In ETC
3 sites Of ATP Generation in ETC

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Site I/Complex I-

Electrons transferred from Complex I to

CoQ

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Site II/Complex III-

Electrons transferred from Cyt b to Cyt c1.

--- Content provided by‌ FirstRanker.com ---

Site III/Complex IV-

Electrons transferred from Cytochrome

aa3/Complex IV/Cytochrome Oxidase to ?

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O2

Uses of ATP generated in

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Oxidative Phosphorylation

?Synthetic/Anabolic reactions
?Active transport mechanism.
?Muscular contraction

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?Nerve impulse conduction.
ATP allows the coupling

of thermodynamically

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unfavorable reactions to

favorable reactions.

ATP is continually being

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hydrolyzed and

regenerated

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A person at rest

consumes and regenerate

3 ATP/ sec

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Staying Alive Energy Wise

We need 2000 Cal/day or 8,360 kJ of energy per day
Each ATP gives 30.5 kJ/mole of energy on hydrolysis
We need 246 moles of ATP

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Body has less than 0.1 moles of ATP at any one time
We need to make 245.9 moles of ATP
Each mole of Glucose yields 38 ATPs or 1160 kJ
We need 7.2 moles of Glucose (1.3 kg or 2.86 pounds)
Each mole of Stearic acid yields 147 ATPs or 4,484 kJ

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We need 1.86 moles of stearic acid (0.48 kg or 1.0

pound of fat)

Shuttling Electron Carriers from

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Cytosol into the Mitochondrion


NADH+H+ carrier of reducing

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equivalents generated in the cytosol via

Glycolysis should make its entry into

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mitochondrial ETC.

Since the inner mitochondrial membrane

is impermeable to NAD+ and NADH.

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This reducing equivalents must be

shuttled into the mitochondrial matrix

--- Content provided by​ FirstRanker.com ---

before they can enter the ETC.

NADH+H+ is

generated in

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the cytosol in

Glycolysis
Reducing Equivalents

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from

Cytosolic NADH+H+

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Enter Mitochondria

via

Shuttle Systems

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NADH itself is not carried

across the mitochondrial

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membrane.

Protons and Electrons of

Cytosolic NADH+H+ are carried

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through shuttle systems.


Two shuttles Involved:

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Glycerol 3-phosphate Shuttle
Malate-Aspartate Shuttle

Glycerol-3-Phosphate Shuttle

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Glycerol Phosphate Shuttle

Glycerol Phosphate Shuttle is

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active in Skeletal muscles and

Brain.

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FADH2 formed enter the

electron-transport chain

through CoQ.

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Therefore only 1.5 molecules of

ATP are produced.

--- Content provided by FirstRanker.com ---

Malate-Aspartate Shuttle

Malate/Aspartate Shuttle System
Malate Aspartate Shuttle

--- Content provided by‌ FirstRanker.com ---

Active in Heart and Liver.
2.5 molecules of ATP are

produced.

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Summary

Total ATP Generated / 1 Glucose Oxidation

--- Content provided by‌ FirstRanker.com ---

Muscle and Brain

30.0 ATP

Uses Glycerol phosphate Shuttle

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Heart and Liver

32.0 ATP

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Uses Malate Aspartate Shuttle
E.T.C Inhibitors

Chemical substances having

--- Content provided by⁠ FirstRanker.com ---

affinity for ETC components.

Chemically interact with ETC

complexes and functionally

--- Content provided by‌ FirstRanker.com ---

inactivate them.
ETC Inhibitors

Enemies of ETC components who

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stop its normal operation.

No ETC and No ATP generation.

--- Content provided by‍ FirstRanker.com ---

Site I/Complex I- E.T.C Inhibitors.

vAmobarbital /Amytal
vRotenone (Fish/Rat Poison)
vMercurials

--- Content provided by‌ FirstRanker.com ---

vPiercidin -A
Site II/Complex III- E.T.C Inhibitors.

vBritish Anti Lewisite ( BAL)
vAntimycin ?A

--- Content provided by⁠ FirstRanker.com ---

vDimercaprol

Site III/Complex IV- E.T.C

Inhibitors/Cytochrome Oxidase

--- Content provided by‌ FirstRanker.com ---

Inhibitors.

vCyanide
vCarbon Monoxide

--- Content provided by⁠ FirstRanker.com ---

vH2S
vAzide


These chemicals

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arrest respiration

by inhibition of the

--- Content provided by FirstRanker.com ---

ETC.

Sequence of

Respiratory

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Electron

Carriers

--- Content provided by FirstRanker.com ---

Inhibitors

in green

--- Content provided by FirstRanker.com ---

Specific inhibitors of

Electron Transport

Chain

--- Content provided by​ FirstRanker.com ---

and

ATP-Synthase
Mechanism Of

--- Content provided by‌ FirstRanker.com ---

Oxidative Phosphorylation

Oxidation tightly coupled

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with Phosphorylation

E.T.C Process coupled with

phosphorylation of ADP+pi

--- Content provided by‍ FirstRanker.com ---

to generate ATP.
Chemical Coupling Hypothesis

Conformational Coupling Hypothesis

--- Content provided by​ FirstRanker.com ---

Chemiosmotic Theory

Chemical Coupling Hypothesis:

--- Content provided by FirstRanker.com ---

Put forward by Edward Slater

(1953)

Proposed series of high energy

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phosphorylated intermediates

are produced during E.T.C

--- Content provided by‌ FirstRanker.com ---

operation.

Which are used to produce ATP.

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Conformational Coupling

Hypothesis

Paul Boyer 1964

--- Content provided by‍ FirstRanker.com ---

Mitochondrial Cristae undergo

conformational change in the

components of E.T.C.

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E.T.C components attain high

energy state which are

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responsible for the ATP production.

Chemiosmotic Theory

Put forward by Peter Mitchell (1961)

--- Content provided by​ FirstRanker.com ---

(Nobel Prize, 1978)

E.T.C process and ATP synthesis are

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coupled by a proton gradient

developed in intermembrane space of

mitochondria.

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Mitchell's Postulates for

Chemiosmotic Theory

Intact inner mitochondrial

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membrane is required

Electrons are pumped through ETC

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complex I,III and IV.

Generates a proton gradient in

intermembrane space of

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mitochondria.

Proton gradient in inter

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membrane space creates

Proton Motive Force.

Due to electrochemical

--- Content provided by‌ FirstRanker.com ---

potential difference.
The proton gradient

have a thermodynamic

--- Content provided by‍ FirstRanker.com ---

tendency.

Proton Motive Force drives the

--- Content provided by​ FirstRanker.com ---

Protons from mitochondrial

intermembrane space back to

matrix side

--- Content provided by‌ FirstRanker.com ---

Through a specific site of F0

and F1 particle of ATP

--- Content provided by​ FirstRanker.com ---

Synthase.
ATP Synthase catalyzes the

phosphorylation of ADP with pi

--- Content provided by‌ FirstRanker.com ---

In a reaction driven by

movement of H+ across the

inner membrane back into the

--- Content provided by​ FirstRanker.com ---

matrix.

Translocation of protons

--- Content provided by‌ FirstRanker.com ---

through ATP Synthase

Stimulates and activates ATP

Synthase

--- Content provided by⁠ FirstRanker.com ---

For the catalytic action of

phosphorylation- ADP with pi to

--- Content provided by‌ FirstRanker.com ---

form ATP.

Supports the mechanism of

Oxidative Phosphorylation.

--- Content provided by⁠ FirstRanker.com ---

The flow of three H+ through

an ATP Synthase complex

Causes a conformational

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change, which causes the

ATP synthase to synthesize

--- Content provided by‌ FirstRanker.com ---

ATP from ADP + Pi.

This process of producing ATP

is known as oxidative

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phosphorylation.

The entire process of using the

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proton motive force to make

ATP is called Chemiosmosis.
During oxidative

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phosphorylation the total

energy change is released

in small increments.

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So that energy can be

trapped as chemical bond

--- Content provided by‌ FirstRanker.com ---

energy and form ATP.

Coupling of ATP synthesis to

respiration is indirect, via a H+

--- Content provided by‍ FirstRanker.com ---

electrochemical gradient.

--- Content provided by FirstRanker.com ---

The proton pumps are Complexes I,
III and IV.

Protons return through ATP synthase

--- Content provided by‌ FirstRanker.com ---

ATP synthesis at F1 results from

--- Content provided by FirstRanker.com ---

repetitive comformational changes
as rotates

rotates 1/3 turn-
energy for ATP release

--- Content provided by‌ FirstRanker.com ---

ATP Synthase, a molecular mill.


Overview of Oxidative Phosphorylation

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+

+

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+

+ +

+

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-

-

--- Content provided by‍ FirstRanker.com ---

-

-

As electrons flow through complexes of ETC, protons are translocated

--- Content provided by⁠ FirstRanker.com ---

from matrix into the intermembrane space.
The free energy stored in the proton concentration gradient is tapped

as protons reenter the matrix via ATP synthase.

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As result ATP is formed from ADP and Pi.
ATP molecules are

transported out of the

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mitochondrial matrix

through specific

transporters.

--- Content provided by FirstRanker.com ---

REGULATION OF OXIDATIVE

PHOSPHORYLATION

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Important substrates:

NADH/FADH2

O2

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ADP
Electron transport is tightly coupled

to phosphorylation.

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ATP cannot be synthesized by

oxidative phosphorylation unless

--- Content provided by‍ FirstRanker.com ---

there is energy from electron

transport.

Electrons do not flow through the

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electron-transport chain to O2 unless

ADP is phosphorylated to ATP.

--- Content provided by⁠ FirstRanker.com ---

ADP and pi is required for ETC

process.

Intramitochondrial ratio

--- Content provided by⁠ FirstRanker.com ---

ATP/ADP is a control

mechanism
At low ADP levels oxidative

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phosphorylation low.

ADP levels reflect rate of ATP

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consumption and energy state

of the cell.

At high ATP/ADP

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ATP acts as an allosteric

inhibitor for Complex

IV (Cytochrome Oxidase)

--- Content provided by‌ FirstRanker.com ---

Inhibition is reversed by

increasing ADP levels.

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Respiratory Control

The most important factor in determining the

--- Content provided by‍ FirstRanker.com ---

rate of oxidative phosphorylation is the level of

ADP.
The regulation of the rate of oxidative

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phosphorylation by the ADP level is cal ed

respiratory control

Inhibitors Of

--- Content provided by⁠ FirstRanker.com ---

Oxidative

Phosphorylation
Oligomycin

--- Content provided by⁠ FirstRanker.com ---

An antibiotic binds with Fo particle

of ATP Synthase

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Fo particle serve as proton channel.
Inhibits phosphorylation of ADP to

ATP.

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Atractyloside

A Glycoside prevents the

translocation of ADP across

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mitochondrial membrane.

Make it unavailable for

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phosphorylation reaction.
Bongregate

Pseudomonas toxin has

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inhibitory action similar

like Atractyloside.
Uncouplers Of

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Oxidative

Phosphorylation

What are Uncouplers?

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Uncouplers are chemical agents

That uncouple the two tightly

coupled processes E.T.C

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(Oxidation) from Phosphorylation.

Uncouplers break the

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connection between

Electron Transport Chain and

Phosphorylation

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Electron transport is a motor

Phosphorylation is the transmission

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Uncouplers put the car in NEUTRAL
?Uncouplers are mostly

lipid soluble aromatic

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weak acids.

Uncouplers deplete proton

gradient of intermembrane

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space during ETC operation.
Uncouplers just bring oxidation

(E.T.C) without phosphorylation.

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Uncouplers inhibit generation

of ATP.

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Physiological Uncouplers

Thermogenin /UCP-1
Excess of Thyroxine
Long Chain Fatty acids

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Unconjugated Hyperbilirubinemia
Chemical Uncouplers

2,4 Di Nitro Phenol
Di Nitro Cresol

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Dicumarol
Aspirin
FCCP
Valinomycin

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Mode Of Action Of Uncouplers

Certain Uncouplers are ionophores,

lipophilic substances.

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They carry protons from

intermembrane space across

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mitochondrial membrane to matrix

From the site other than specific

site. (i.e through F0 and F1 particles of

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ATP Synthase).
Certain Uncouplers changes

the permeability of the

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mitochondrial membrane to

protons.

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Translocate protons easily

through mitochondrial

membrane.

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2,4 DNP dissolve in the membrane and function as

carriers for H+.

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Do not allow to develop proton

gradient and proton motive force

in the intermembrane space of

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mitochondria.

Causes no stimulation or

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activation of ATP Synthase

No catalysis of Phosphorylation of

ADP with pi to generate ATP.

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During uncoupling phenomena

Heat energy dissipiated as it is and

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causes swelling of mitochondria.
Uncouplers block oxidative phosphorylation by

dissipating the H+ electrochemical gradient.
Protons pumped out leak back into the mitochondrial

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matrix,
preventing development of proton gradient and

proton motive force.

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Respiration proceeds in the

presence of an uncoupler,

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whether or not ADP is present.
The ATP Synthase reaction runs

backward in presence of an uncoupler.
w Hydrolysis of ATP is spontaneous.

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Physiological Uncoupling

By

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Uncoupling Protein (UCP-1)


An Uncoupling Protein (UCP-1)/

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Thermogenin is produced in brown

adipose tissue of newborn mammals and

hibernating mammals.

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This protein of the inner mitochondrial

membrane functions as a H+carrier.
The uncoupling protein blocks

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development of a H+ electrochemical

gradient, thereby stimulating

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respiration.

Free energy of ETC is dissipated as

heat.

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Uncoupling of ETC and

phosphorylation occurs in animals

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as a means to produce heat

Non shivering thermogenesis.
Occurs in brown adipose tissues

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(rich in mitochondria)
This "non-shivering

thermogenesis" is costly in

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terms of respiratory energy,

Heat energy unavailable for ATP

synthesis, but provides valuable

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warming of the organism.

Significance Of Physiological

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Uncouplers

In extreme cold conditions and in

hibernating animals

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Physiological Uncouplers bring

uncoupling phenomena

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The heat liberated inside the body

helps to restore and maintain the

body temperature.

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Brown adipose
(fat) cells
contain natural

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Uncouplers to
warm animals
cold adaptation
and hibernation.

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ETC Inhibitors and Uncouplers

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Any compound that stops

electron transport will stop

respiration...this means you

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stop breathing

Electron transport can be

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stopped by inhibiting ATP

synthesis

An uncoupler breaks the

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connection between ATP

synthesis and electron

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transport
Inherited Disorders

Related To E.T.C

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Infantile Mitochondrial Myopathy

Defect in E.T.C components

located in mitochondria.

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Associated with renal

dysfunction.

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Mostly fatal in early age.
MELAS

An inherited disorder caused due to

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deficiency of complex I or IV of

E.T.C

Associated with

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Mitochondrial Myopathy
Encephalopathy
Lactic Acidosis
Stroke

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Inherited Disorders of

Oxidative Phosphorylation

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Leber's Hereditary

Optic Neuropathy (LHON)

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Caused due to mutations in

mitochondrial DNA

Affects oxidative

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phosphorylation.

Loss of bilateral vision due to

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neuroretinal degeneration.
Factors Affecting ETC Process

Oxygen supply to cells.
Hemoglobin structure and

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function

Respiratory system and its function
Mitochondrial structure and ETC

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components.

Availability of reduced

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coenzymes.

Adequate amount of ADP

and pi.

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Presence of ETC inhibitors.
Conditions Affecting ETC and ATP

Low/slow operation

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of ETC and less

production of ATPs

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is noted in

conditions of:

Hypoxia

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Anemia
Ischemia

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Hemoglobinopathies
Emphysema
Respiratory Distress Syndrome
Asthma
Inherited Disorders of Mitochondria

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ETC inhibition by chemicals/drugs.
High Energy Compounds Of

Human Body.

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High energy compounds are

energy rich compounds.

Possess high energy bonds in its

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structures.

Cleavage of these high energy

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bonds liberate more energy than

that of ATP hydrolysis.
S.No

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Examples Of High

Free Energy

Energy Compounds

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Released On

Hydrolysis.

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Cal/mol

1

Phospho Enol Pyruvate

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-14.8

2

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Carbamoyl Phosphate

- 12.3

3

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Cyclic AMP

-12.0

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4

1,3 Bis Phospho Glycerate

-11.8

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S.No

Examples Of High Energy

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Free Energy

Compounds

Released On

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Hydrolysis.

Cal/mol

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5

Creatine Phosphate

-10.3

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6

S Adenosine Methionine

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-10.0

( SAM)

7

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Succinyl CoA

-7.7

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8

Acetyl CoA

-7.7

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9

ATP

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-7.3
Significance Of High Energy

Compounds.

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In catabolic pathways/reaction

High energy compounds follow

substrate level phosphorylation

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reaction.

High energy compounds cleave to

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generate energy used for

phosphorylation of ADP with pi at

reaction level.

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Generate ATP at substrate level.
Substrate Level Phosphorylation

Mode of generation of ATP at

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substrate level.

Involves cleavage of high energy bond

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present in high energy compound.

Bond energy released is used for

Phosphorylation reaction.

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Generates ATP directly and instantly

without involvement of ETC process.

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Examples Of High Energy

Compounds Undergoing Substrate

Level Phosphorylation.

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S.No

High Energy

Enzyme

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Product

High

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Metabolic

Compound

Catalyzing

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Obtained

energy

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Pathway

Phosphate

Involved

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Compound

Generated

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1

1,3 Bis

Phospho

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3

ATP

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Glycolysis

Phospho

Glycerate Phospho

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Glycerate

Kinase

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Glycerate

2

Phospho

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Pyruvate

Enol

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ATP

Glycolysis

Enol

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Kinase

Pyruvate

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Pyruvate

3

Succinyl

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Succinate Succinate

GTP

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Krebs/TCA

CoA

Thio

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Cycle

Kinase

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In anabolic pathways/reaction

High energy compounds follow

condensation or bond building

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reactions.

High energy compound cleave to

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generate energy

Energy used for building C-C

bonds.

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Questions

Long Essays.

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Q.1 Define Biological oxidation.

Enumerate and Describe various

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enzymes carrying out biological

oxidation reactions with suitable

examples.

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Q.2 Describe Respiratory chain and

Give its significance.

OR

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Explain the Electron. Transport chain

(E.T.C.) and its significance.

OR

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How the reduced equivalents generated

in anaerobic dehydrogenase reactions

are reoxidized.

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Q.3 What is oxidative

phosphorylation? Explain

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the mechanism with

respect to various theories

and hypothesis.

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Short Notes

Cytochromes
Inhibitors of E.T.C
Shuttle systems and its

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significance

Inhibitors and Uncouplers of

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oxidative phosphorylation

Complexes of E.T.C.
Redox potential and free energy

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changes.

Inherited Disorders related to E.T.C.

abnormality.

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ATP ? Mode of its formation and

it's role in the Body.
Short Answer Questions

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Give the sites for ATP generation of

in E.T.C.

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Enumerate the High energy

compounds of our body

Substrate level phosphorylation and

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it's importance.

Enumerate the Enzymes

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catalyzing Biological oxidation

reactions. Write the class to

which these enzymes classified.

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Define P.O ratio. What is the P:O

ratio for reduced NADH+H+ &

FADH2 respectively.

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List the components of E.T.C. and

their location.

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Redox couple & Redox potential.

FlavoProteins
Product of Aerobic and

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Anaerobic dehydrogenation

reactions.

Write enzymes catalyzing

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Aerobic and Anaerobic

dehydrogenation reaction's

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during metabolism.
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