Biological oxidation and Electron transport chain.pptx

Biological Oxidation &
ETC
Dr Sarath Krishnan M P
Junior Resident – 2/Biochemistry
AIIMS Rishikesh

Learning Objectives
 Bioenergetics
 High energy compounds
 Substrate level phosphorylation
 Biological Oxidation
 ETC-Components and working
 Uncouplers
 Inhibitors and disorders of ETC
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Dr Sarath Krishnan M P/ JR-2/ AIIMS Rishikesh
2

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Energy
Heat
energy
Chemical energy
Mechanical
energy
Electrical energy

Bioenergetics
 Biochemical thermodynamics
 Study of energy changes during biochemical reactions.
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Conditions Of Bioenergetics
 Isothermic
 Endothermic/ Endergonic/Anabolic
 Exothermic/Exergonic/Catabolic
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Endergonic ( anabolic) processes proceed by
coupling of exergonic(catabolic) processes
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Energy systems
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High Energy Compounds Of Human Body
 High energy compounds are energy rich compounds.
 Possess high energy bonds in its structures.
 Cleavage of these high energy bonds liberate more energy
than that of ATP hydrolysis.
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S.No Examples Of High Energy
Compounds
Free Energy
Released On
Hydrolysis.
Cal/mol
1 Phospho Enol Pyruvate -14.8
2 Carbamoyl Phosphate - 12.3
3 Cyclic AMP -12.0
4 1,3 Bis Phospho Glycerate -11.8
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S.No Examples Of High Energy
Compounds
Free Energy Released
On Hydrolysis.
Cal/mol
5 Creatine Phosphate -10.3
6 S Adenosine Methionine
( SAM)
-10.0
7 Succinyl CoA -7.7
8 Acetyl CoA -7.7
9 ATP -7.3
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Significance Of High Energy Compounds
 Mode of generation of ATP at substrate level
 Involves cleavage of high energy bond present in high
energy compound
 Bond energy released is used for Phosphorylation reaction
 Generates ATP directly and instantly at reaction level without
involvement of ETC
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Examples Of High Energy Compounds
Undergoing Substrate Level
Phosphorylation
S.No High
Energy
Compound
Enzyme
Catalyzing
Product
Obtained
High
energy
Phosphate
Compound
Generated
Metabolic
Pathway
Involved
1 1,3 Bis
Phospho
Glycerate
Phospho
Glycerate
Kinase
3 Phospho
Glycerate
ATP Glycolysis
2 Phospho
Enol
Pyruvate
Pyruvate
Kinase
Enol
Pyruvate
ATP Glycolysis
3 Succinyl
CoA
Succinate
Thio Kinase
Succinate GTP Krebs/TCA
Cycle
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During Anabolic pathways/reaction
 High energy compounds follow condensation or bond
building reactions.
 High energy compound cleave to generate energy
 Energy used for building C-C bonds.
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High Energy Compounds Generated In
Catabolic Pathways Are Utilized In
Anabolic Reactions
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Important Features Of ATP
 Contains three high energy phosphate bonds
 Drive endergonic reactions
 It is chemical energy currency of body
 Functions in body as a complex with Mg2+
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Important Features Of ATP
 Biosynthesized by ATP synthase
 Couples thermodynamically Unfavorable reactions to
Favorable Ones
 ATP synthesis is inhibited by Uncouplers
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What Is Biological Oxidation?
 Biological Oxidation Reactions/Process
 Involves Oxygen
 Associated with metabolism
 Generates ATP
 Vital for functioning of cells
 Survival and existence of human body.
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 Oxidation reactions are biochemical reactions where there is
either:
 Removal / Loss of Hydrogen (Dehydrogenation)
 Removal or Loss of Electrons
 Addition of Oxygen (Oxygenation)
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 Oxidation of a molecule (electron donor) is always
accompanied by reduction of a second molecule
(electron acceptor)
 Most predominant type of Oxidation reaction in body is:
 Dehydrogenation Reaction- Catalyzed by
Dehydrogenases
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 Dehydrogenases catalyzes to remove Hydrogen from
substrates.
 Which are temporarily accepted by Coenzymes
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Coenzymes and Inorganic Cofactors Of
Biological Oxidation Reactions
 FMN
 FAD
 NAD+
 NADP+
 THBP (Tetra Hydro Biopterin)
 Cu++
 Fe+++
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 Oxidized Coenzymes involved in
Oxidation/Dehydrogenation reactions.
 NAD+
 NADP+
 FAD
 FMN
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 Oxidized Coenzymes temporarily accept the hydrogen
from substrates and get transformed to reduced
coenzymes.
 NADH+H+
 FADH2
 NADPH+H+
 FMNH2
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5 Enzymes of Biological Oxidation
 Aerobic dehydrogenases
 Anaerobic dehydrogenases
 Oxygenases
 Oxidases
 Hydroperoxidases
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All 5 Enzymes of Biological Oxidation
reactions are classified in
 Class I Oxido Reductases
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AEROBIC DEHYDROGENASES
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 FMN are acceptors of removed Hydrogen
 Reduced Coenzymes (FMNH2) formed are auto oxidizable
 Reduced coenzymes get reoxidized at reaction level.
 Oxygen gets directly involved at reaction level to reoxidize
the reduced coenzymes.
 H2O2 is a byproduct of Aerobic Dehyrogenase activity.
 Catalase then detoxify the H2O2 to H2O and O2
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Specific Examples Of
Aerobic Dehydrogenases
 L Amino acid Oxidase
 Xanthine Oxidase
 Glucose Oxidase
 Aldehyde Dehydrogenase
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ANAEROBIC DEHYDROGENASES
 Anaerobic Dehydrogenases catalyzes to remove hydrogen
from substrates.
 With the help of coenzymes NAD+/NADP+/FAD.
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 Coenzymes temporarily accept the hydrogen from
substrates and get reduced to
 NADH+ H+
 FADH2
 NADPH+H+
 Reduced coenzymes formed in Anaerobic Dehydrogenase
reactions are : Non autoxidizable/not reoxidized at reaction
level.
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 Reduced coenzymes NADH+H+ and FADH2 formed at
Anaerobic Dehydrogenase reaction
 Has to enter ETC for its reoxidation.
 Oxygen is involved indirectly at an end of ETC as electron
and proton acceptor .
 Metabolic water is an end product of ETC
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DEHYDROGENASES CANNOT USE OXYGEN AS A
HYDROGEN ACCEPTOR
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 Reduced coenzyme NADPH+H+ do not enter ETC
 NADPH+H+ is utilized as reducing equivalent for reduction
reactions catalyzed by Reductases.
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NAD+ Dependent Anaerobic
Dehydrogenases
Enzymes Pathway /Reaction
Glyceraldehyde -3-PO4 Dehydrogenase Glycolysis
Pyruvate Dehydrogenase PDH Complex
Isocitrate Dehydrogenase TCA cycle
α Ketoglutarate Dehydrogenase TCA cycle
Malate Dehydrogenase TCA cycle
Lactate Dehydrogenase Pyruvate/Lactate metabolism
Glutamate Dehydrogenase Glutamate metabolism
β Hydroxy Acyl Dehydrogenase Beta Oxidation of Fatty acids
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NADP+ Dependent Dehydrogenases
 Glucose -6-Phosphate Dehydrogenase
 Phospho Gluconate Dehydrogenase
 Note NADPH + H+ does not enter ETC for its reoxidation
instead they are involved in reduction reactions.
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FAD Dependent Anaerobic
Dehydrogenases
 Succinate Dehydrogenase
 Acyl CoA Dehydrogenase
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FMN Dependent Anaerobic
Dehydrogenase
 NADH Dehydrogenase (Warburg's Yellow Enzyme)
 First Component of ETC/ Complex I of ETC
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OXYGENASES
 Oxygenases add Oxygen atom from molecular oxygen (O2)
into substrate.
 Form Oxidized Products
 Oxygenases catalyze direct transfer and incorporation of
oxygen into a substrate molecule
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Mono Oxygenases
 Mono Oxygenases add one oxygen atom from molecular
oxygen to the substrate.
 Forms Hydroxyl group (-OH )
 Monoxygenases are also termed as Hydroxylases or Mixed
Function Oxidase.
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Examples Of Mono Oxygenases
 Phenylalanine Hydroxylase
 Tryptophan Hydroxylase
 25 Hydroxylase
 1 α Hydroxylase
 Cytochromes P450 Are Monooxygenases Important in
Steroid Metabolism & for Detoxification of Many Drugs
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Di Oxygenases
 Dioxygenases are true Oxygenases
 Incorporates two Oxygen atoms from O2
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Examples Of Dioxygenases
 Tryptophan Di Oxygenase/ Tryptophan Pyrrolase
 Homogentisate Oxidase
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Oxidases
 Oxidases involve activated molecular Oxygen as Hydrogen
(electron and proton ) acceptor.
 Oxidases Reduce Oxygen to form Water (H2O)
 OXIDASES USE OXYGEN AS A HYDROGEN ACCEPTOR
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Examples Of Oxidases
 Cytochrome Oxidase-Classic Example (Hemoprotein ETC
enzyme)
 Ascorbate Oxidase
 Mono Amine Oxidase
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Hydroperoxidases use hydrogen peroxide
or an organic peroxide as substrate
 Hydroperoxidases detoxify Hydrogen Peroxide in body.
 H2O2 is a substrate/reactant for Hydroperoxidases.
 Hydroperoxidases are Hemoproteins.
 Contains loosely bound Heme as prosthetic group.
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 Hydroperoxidases prevent accumulation of H2O2 in cells.
 H2O2 if accumulated in cells is toxic
 Leads to disruption of membranes(Hemolysis).
 Increases risk of cancer and atherosclerosis.
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Specific Examples Of Hydroperoxidases
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Peroxidases Reduce Peroxides Using
Various Electron Acceptors
 Indirectly react with H2O2
 Glutathione Peroxidase (In R.B.C’s)
 Leukocyte Peroxidase (In W.B.C’s)
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Catalase
 Directly reacts with H2O2.
 Associated with Aerobic Dehydrogenase catalyzed reaction.
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What is ETC????
 Truly Aerobic in nature (indispensable on O2)
 Located and operated at - Inner membrane of Mitochondria
 Accepts reducing equivalents from reduced coenzymes to
reoxidize
 Transfer protons and electrons serially which are finally
accepted by activated molecular oxygen
 Alternate Oxidation and Reduction Reactions carried out in
its process
Dr Sarath Krishnan M P/ JR-2/ AIIMS Rishikesh 07-11-2022
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 Oxidation process (ETC) is tightly coupled with
Phosphorylation of ADP with pi to generate ATP
 Fate of ETC
 Location of ETC components
 Mature erythrocytes ????
54

 Components and Enzymes of
ETC are arranged towards inner
surface of inner membrane of
mitochondria as
 Vectorial conformation
 Increased order of positive
redox potential
55

 Role of mitochondrial DNA in ETC
 Condition in which ETC/oxidative phosphorylation operates
56

ETC Components
1.Flavo Protein- (First Component
of ETC)
NADH Dehydrogenase-FMN and
FeS centres (Warburg's Yellow
Enzyme)
2. Coenzyme Q / Ubiquinone
(Hydrophobic)
57

3. Series of Cytochromes-
(Haemoproteins)
Cytochrome b-Cytochrome c1-
Cytochrome c- Cytochrome aa3
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4. Iron Sulphur Proteins
59

Complexes OF ETC and oxidative
phosphorylation
 Complex I- NADH CoQ Reductase NADH Dehydrogenase FMN and FeS
centre
 Complex II – Succinate CoQ Reductase Succinate Dehydrogenase FAD and
FeS centre
 Complex III–CoQ Cytochrome C Reductase Cytochrome b – Cytochrome c1
 Complex IV- Cytochrome Oxidase Cytochrome aa3
 Complex V – ATP Synthetase F0 and F1 of ATP Synthase
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NADH CoQ Reductase ETC Complex I
61

Complex II – Succinate CoQ Reductase –
Succinate Dehydrogenase FAD and FeS centre
62

Complex III–CoQ Cytochrome C Reductase
Cytochrome b – Cytochrome c1
63

Q -cycle
64

Complex IV- Cytochrome Oxidase
Cytochrome Aa3
65

Complex I,III and IV Serves As Proton
Pumps To Generate Proton Gradient in
Intermembrane space
 Complex I,III and IV serves as Proton Pumps
 A proton gradient is created in intermembrane space
 Complex I,III and IV serves as ATP generating sites
 Complex I and III sites where 4 protons are pumped 1 ATP is
generated at each site
 At Complex IV Site where 2 Protons are pumped 0.5 ATPs
are generated
66

COMPLEX V- ATP SYNTHASE
67

 F1 contains 5 types of polypeptide
chains - α3β3γδε
 Fo - a1b2c10-14
(c subunits form cylindrical,
membrane-bound base)
 Fo and F1 are connected by a
γεstalk and by exterior column
(a1b2 and δ)
 Proton channel is – between c ring
and a subunit.
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 F0 is hydrophobic interspersed in inner membrane of
mitochondria composed of 10 C protein subunits
 F0 serves as Proton channel, 4 protons from intermembrane
space move back to matrix through it
 F1 is hydrophilic and projects into mitochondrial matrix
 Gamma (bent axle) and F0- C subunit are rotatory , other all
are static subunits
 Beta subunit is catalytic unit where ADP is phosphorylated
with pi to generate ATP
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 ATP Translocation From
Mitochondria
 Through ATP/ADP
Translocases
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Chemiosmotic Theory
 Peter Mitchell
 Oxidative process E.T.C and ATP synthesis are tightly
coupled by a proton gradient developed in an intermembrane
space of mitochondria.
74

Regulation of ATP Synthesis
 Intramitochondrial ratio ATP/ADP is a control mechanism
 At high ATP/ADP ratio
 ATP acts as an allosteric inhibitor for Complex IV
(Cytochrome Oxidase)
 Inhibition is reversed by increasing ADP levels
 Respiratory control or Acceptor control.
75

Significance of ETC/oxidative
phosphorylation
 Reduced coenzymes gets reoxidized to NAD+ /FAD in ETC
for its reutilization in metabolic oxidation reactions.
 Oxidative phosphorylation generates chemical form of energy
ATP as a valuable by product
76

Shuttle Systems
 Malate-Aspartate Shuttle
 Glycerol 3-phosphate Shuttle
 Significance???
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Malate-Aspartate Shuttle
78

Glycerol-3-Phosphate Shuttle
79

80

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Inhibitors Of ETC Complexes
Complex I
 Amobarbital /Amytal-
Barbiturates
 Rotenone (Fish/Rat Poison)
 Piericidin A
 Halothane
Complex II
 Carboxin
 TTFA (Thenoyl Trifluoro
Acetone)
82

Complex III
 Antimycin A
 Naphthoquinone
 Dimercaprol / British Anti
Lewisite ( BAL)
Complex IV
 Carbon Monoxide
 CN
 Azide
83

Inhibitors of Complex V
 Oligomycin: Bind to Fo domain of ATP synthase
 Atractyloside
Inhibit ATP-ADP translocase
 Bongregate
84

Uncouplers Of
Oxidative phosphorylation
85

Mode of Action
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Physiological Uncouplers
 Thermogenin /UCP-1
 Excess of Thyroxine
 Long Chain Fatty acids
 Unconjugated
Hyperbilirubinemia
Synthetic Uncouplers
 2,4 Di Nitro Phenol (2,4 DNP)
 Di Nitro Cresol
 Valinomycin
87

Disorders associated to ETC and oxidative
phosphorylation
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91

Thank You
92

Biological oxidation and Electron transport chain.pptx

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