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AP0510 Medical Biochemistry > Electron Transport System and Oxidative Phosphorylation > Flashcards

Electron Transport System and Oxidative Phosphorylation Flashcards

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USMLE® Step 1 flashcards
1
Q

Principle of oxidative phosphorylation

A
  • NADH and FADH2 contain energy obtained from catabolism - get reoxidised by transferring electrons to components of Electron Transport System (ETS)
  • Energy is released as electrons are transferred along ETS
  • This energy is used to convert ADP + Pi to ATP i.e. ATP synthesis.
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2
Q

E0

A
  • measure of tendency of a molecule in solution to give or take electrons, to or from an electrode under standard conditions relative to a standard hydrogen electrode
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3
Q

How is free energy released from electron transport?

A
  • ETS is effectively composed of a series of redox pairs - each has its own redox potential E0
  • Tendency to donate electrons to other compounds = reducing agent
  • Tendency to accept electrons from other compounds = oxidising agent
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4
Q

Oxidation and reduction

A
  • oxidation: lose electrons
  • reduction: gain electrons
  • OILRIG; Oxidation Is Loss, Reduction Is Gain
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5
Q

Redox potentials and free energy

A
  • In ETS, electrons are passed from one redox pair to the next – eventually to O2
  • acceptor must have a more positive redox potential than the donor
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6
Q

Nicotinamide Adenine Dinucleotide (NAD+)

A
  • first electron carrier involved in the oxidation of many metabolites
  • NAD+ is oxidised form, NADH is reduced form
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7
Q

Inner mitochondrial membrane

A
  • where enzymes of the ETS and ATP synthase are found
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8
Q

Inner membrane cristae

A
  • increase membrane surface area and its impermeability allows the establishment of chemical gradients
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9
Q

Electron Transport System (ETS)

A
  • function is to regenerate NAD+ and FAD, with free energy released used to generate ATP, and with the reduction of oxygen to water
  • consists of 4 large protein complexes: I to IV, and 2 small, mobile carriers
  • each complex contains various cofactors/coenzymes which are required for the transfer of electrons from one complex to the next
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10
Q

Carriers of ETS

A
  • flavoproteins (with FMN or FAD)
  • non-haem iron (iron sulphur complex)
  • quinone
  • cytochromes (with haem groups)
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11
Q

Flavin adenine dinucleotide (FAD)

A
  • transfers electrons as hydrogen atoms
  • When combined to appropriate proteins, FAD can accept two H atoms and is reduced to FADH2
  • FAD is a prosthetic group = it is covalently attached to the apoenzyme
  • Isoalloxazine ring-ribitol-phosphate-phosphate-ribose-adenine
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12
Q

Flavin Mononucleotide (FMN)

A
  • Prosthetic group – similar to FAD but without AMP
  • No positive charge; isoalloxazine ring structure
  • Accepts two protons and two electrons
  • reduced to FMNH2 in two steps: H+ + FMN –> FMNH and H+ + FMNH –> FMNH2
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13
Q

Non-haem iron

A
  • Non-haem bound iron found in iron-sulphur clusters
  • 4 types – classed on number of atoms of each present: [Fe-S], [2Fe-2S], [3Fe-4S], [4Fe-4S]
  • Bound to protein via 4 cysteines.
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14
Q

Cytochromes

A
  • Electron-transporting proteins with haem as prosthetic group
  • iron in haem is a single-electron carrier
  • ETS contains several different cytochromes
  • cytochromes b, c1, c, a and a3
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15
Q

Cytochrome b

A
  • transmembrane protein composed of two subunits - cytochrome bL and bH
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16
Q

Cytochrome c1

A
  • Found associated with non-haem iron and located in outer layer of phospholipid bilayer
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17
Q

Cytochrome c

A
  • Peripheral protein on cytosolic surface of inner membrane.

- Bound to cytochrome c1 and cytochrome oxidase - acts as ‘electron shuttle’ between them.

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18
Q

Cytochrome a and a3

A
  • Transmembrane protein composed of two distinct haem groups.
  • Also has copper associated – CuA and CuB
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19
Q

Ubiquinone (Coenzyme Q - Q10)

A
  • called because of ubiquitous “expression” and its 10 isoprenoid residue hydrophobic tail
  • non-protein lipid soluble molecule – freely mobile in the phospholipid bilayer
  • receive 2 protons and two electrons - quinone is reduced to hydroquinone
  • link between Complex I or II and Complex III
  • move protons from the matrix to inter-membrane space
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20
Q

Complex I

A
  • oxidize NADH and reduce CoQ
  • Large membrane spanning complex, contains binding sites for NADH and CoQ
  • Contains 6-7 Fe-S clusters through which e- are carried in a zig-zag pattern and transferred to CoQ
  • Net movement of protons occurs – provide energy for ATP synthesis
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21
Q

Complex II

A
  • oxidize succinate via the generation of FADH2
  • not enough energy to pump H+ across the membrane
  • also not a membrane spanning complex, like complex I, so cannot act as a proton pump
  • Contains binding sites for succinate and Coenzyme A
  • FADH2 then reduces Coenzyme Q
22
Q

Complex III

A
  • oxidize CoQ and reduce Cytochrome c

- similar to Complex I - large membrane spanning complex that contains binding sites for CoQ and Cytochrome c

23
Q

Q cycle

A
  • Transfer of 2e- from CoQ to cytochrome c1
  • Composed of 2 loops
  • Results in pumping of 4H+ across the membrane
24
Q

Complex IV

A
  • oxidize cytochrome c and reduce oxygen to water
  • large membrane spanning complex, contains binding sites for cytochrome c and molecular oxygen
  • bound copper facilitates the collection of the 4 electrons needed to reduce O2
25
Q

Mitochondrial shuttles

A
  • During Glycolysis and the TCA Cycle reducing equivalents in the form of NADH are produced
  • essential that NADH is reconverted to NAD+ to allow continuation of metabolism
26
Q

NADH to NAD+ conversion in anaerobic conditions

A
  • converting pyruvate to lactate
27
Q

NADH to NAD+ conversion in aerobic conditions

A
  • NADH generated in the mitochondria is converted back to NAD+ via the ETS
  • NADH generated in the cytosol cannot pass directly into the mitochondria to be reconverted to NAD+ by the ETS and is regenerated through the mitochondrial shuttles
28
Q

Glycerol-3-phosphate shuttle

A
  • major shuttle in most tissues
  • enzyme in cytosol transfers e- from NADH to dihydroxyacetone phosphate
  • enzyme is glycerol-3-phosphate dehydrogenase
  • flavoprotein dehydrogenase transfers e- to ET chain
29
Q

Aspartate-malate shuttle

A
  • NADH produced in glycolysis is used to reduce oxaloacetate into malate
  • malate moves into the intermembrane space, then enters the matrix via an antiporter transport system in exchange for an alpha-ketoglutarate
  • malate is then oxidized back into oxaloacetate and the pair of electrons are collected by NAD+ to form NADH
  • oxaloacetate cannot move across inner mitochondrial membrane and converted into aspartate
  • aspartate can now flow out of inner membrane via an antiporter system in exchange for glutamate
  • glutamate that moves into the matrix transfers an amino group onto oxaloacetate to form aspartate and a-ketoglutarate
  • aspartate transported into the cytoplasm is deaminated to form oxaloacetate
30
Q

Link between ETS and ATP synthesis

A
  • ETS facilitates regeneration of NAD+ and FAD via transfer of electrons to O2
  • Mitchell’s Chemiosmotic Theory explains the link between the ETS and oxidative phosphorylation (OxP)
  • Two steps: generation of an electrochemical gradient, synthesis of ATP by ATP synthase
31
Q

Assumptions of Chemiosmotic Mechanism

A
  • inner mitochondrial membrane is impermeable to protons
  • Protons can only cross inner membrane via carriers of the ET chain or ATP synthase
  • Carriers of ET chain are vectorially arranged so protons move matrix to inter-membrane space
  • ATP synthase is also vectorially arranged
32
Q

Electrochemical Potential Gradient

A
  • electrons are transferred from one redox pair to the next – release of energy
  • 3 membrane spanning complexes – I, III and IV, use the energy released to pump H+ across the inner membrane
  • H+ can’t re-enter the matrix as the inner membrane is impermeable – H+ gradient
  • have movement of charge - electrochemical potential (ECP)
  • ECP and H+ gradient generate a force that wishes to re-establish an equilibrium – Proton Motive Force
33
Q

ATP Synthase

A
  • According to Mitchell’s Chemiosmotic Theory, the energy of the Proton Motive Force is used by ATP synthase to generate ATP.
  • re-entry of H+ into the matrix is facilitated by the F0 subunit of ATP synthase which forms a pore through the inner membrane
  • “discharges” the pH and electrical gradients across the membrane, with the energy released being used by the F1 subunit of ATP synthase to drive ATP synthesis from ADP + Pi
34
Q

ETC and ATP synthase

A
  • ETC complexes are associated into supercomplexes

- ATP synthase forms dimers or oligomers (associations of dimers) – in yeast, mammals, plants and fungi

35
Q

Uncoupling of oxidative phosphorylation

A
  • Uncoupling occurs when H+ re-enter mitochondrial matrix without going through ATP synthase i.e. the electrochemical gradient is dissipated without the generation of ATP
  • Can be brought about by: chemicals and physiologically by uncoupling proteins
  • Results in increased oxygen consumption and the release of energy as heat
36
Q

Chemical uncouplers

A
  • aka proton ionophores – lipid soluble and dissociable H+

- Examples: 2,4-Dinitrophenol, Valinomycin, Gramicidin A

37
Q

2,4-Dinitrophenol

A
  • crosses inner mitochondrial membrane (IMM) and releases protons in matrix – reduces the proton gradient
38
Q

Valinomycin

A
  • antibiotic that makes the IMM permeable to K+ and dissipates the membrane potential (no effect on proton gradient)
39
Q

Gramicidin A

A
  • a channel forming drug – makes the IMM permeable to protons and reduces the proton gradient
40
Q

Physiological uncouplers

A
  • involves uncoupling proteins (UCPs)
  • UCPs, 5 isoforms – form channels through the inner membrane which conduct H+ back into the matrix
  • UCPs increase the amount of energy from oxidation released as heat, when activated
41
Q

Types of uncoupling proteins

A
  • UCP1: (thermogenin) expressed in brown adipose tissue.
  • UCP2: expressed in most cells.
  • UCP3: expressed principally in skeletal muscle.
  • UCP4 & 5: expressed in the brain
42
Q

Inhibition of ETS

A
  • common end result is reduction or inhibition of electron flow, proton pumping and reduction or cessation of ATP synthesis
  • Absence of oxygen, anoxia will also result in inhibition of the ETS – no terminal acceptor
  • Iron deficiency, anaemia, result in inhibition of the ETS – no iron for cytochromes or Fe-S
43
Q

Examples of ETS inhibitors

A
  • Rotenone, Amytal, Piericidin A (Complex I)
  • Thenoyltrifluoroacetone (Complex II)
  • Antimycin (Complex III)
  • Cyanide, Azide, Hydrogen sulphide, Carbon monoxide (Complex IV)
44
Q

Oligomycin (ATP synthesis inhibitor)

A
  • site of action: F0 ATPase

- effect: Inhibition of H+ channelling, no ATP generation, failure to dissipate H+ gradient, shut down of ETC

45
Q

Inhibitors of ATP/ADP transport

A
  • Atractyloside, Bongkrekic acid
  • site of action: ANT
  • effect: Deletion of intramitochondria ADP, inhibition of ATPase, failure to dissipate H+ gradient shut down of ETC
46
Q

Uncouplers

A
  • 2,4-DNP, Valinomycin, Gramicidin A
  • site of action: IM
  • effect: Dissipate H+ gradient, no ATP generation
47
Q

Aerobic breakdown of glucose (equation)

A
  • Glucose + 6O2 + 30ADP + 30Pi –> 6CO2 + 6H2O + 30ATP
48
Q

Anaerobic breakdown of glucose (equation)

A
  • Glucose + 2ADP + 2Pi –> 2 lactate + 2ATP
49
Q

Diseases associated with mitochondrial DNA (mt DNA)

A
  • Mutation rate of mt genome is 10x that of nuclear genome
  • Defects of OxP likely to arise from mutations in mt genome
  • Mitochondria are maternally inherited and thus are associated disorders– effect both sexes
  • Mitochondria replicate by fission during cell division – variation in amounts of normal and mutant mt DNA within cell – Heterplasmy
  • Disease severity/pathology worsens with age due accumulation of mutations – inability of mt DNA to be repaired
50
Q

Leber Hereditary Optic Neuropathy (LHON)

A
  • Cause: mutation in NADH dehydrogenase (Complex I)
  • Late onset loss of bilateral vision due to neuroretinal degeneration – optic nerve
  • High energy demand, depends almost entirely on oxidative phosphorylation
  • Affected mother will pass LHON to all offspring

AP0510 Medical Biochemistry (21 decks)

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