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BIOL304 > Test #4 > Flashcards

Test #4 Flashcards

1
Q

ATP requirement for men

A

8400 kJ (2000 kCal) – 83 kg of ATP

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2
Q

How much ATP do human posses

A

250 g at any given moment

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3
Q

Compensating the disparity between amount of ATP available and amount of ATP needed

A

Compensate by constantly recycling ADP and ATP

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4
Q

How many times is a molecule of ATP recyled each day

A

300 times

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5
Q

How are ATP molecules recycled

A

Recycled through Oxidative Phosphorylation

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6
Q

Overall Delta G of Reaction of ETC

A

Exothermic

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7
Q

What does ETC make

A

Makes Proton gradient –> Resulting proton gradient and transmemebrane electrical potential creates proton motive force

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8
Q

How is ATP synthesized (overall)

A

ATP is synthesized when electrons flow back to Mitocondrial matrix through enzyme complex
***ATP is synthesized by oxidation of a fuel + phosphorylation of ADP that are coupled by a proton gradient across the mitocondrial membrane

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9
Q

What couples Oxidation of fuel and Phosphorylation of ADP

A

Coupled by a proton gradient across mictocondrial membrane

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10
Q

Cell respiration

A

Generation if Hight Transfer Potential Electrons by TCA cycle and flow through respiratory chain

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11
Q

Membrane system of MItocondria

A

Mitocondria are bound by a double membrane
1. Outter memebrane
2. Highly folded inner memebrane

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12
Q

Inner memebrane of Mitocondria

A

Folded into a series of interanl ridges called “cristea”

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13
Q

Compartments of Mitocondria

A
  1. Intermemebrane space
  2. Matrix
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14
Q

Mitocondrial Matrix

A

Bound by inner memebarne – Matrix is the site of most of the reactions of the TCA cycle and Fatty acid oxidation

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15
Q

Where does ETC take plase

A

ETC takes place in the inner memebrane

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16
Q

Surface area of inner memebrane

A

Has increased SA because of cristae –> Increases SA of Inner memebrane creates more sites for Oxidative Phosphorylation

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17
Q

Permability of outter memebrane

A

The outter memebreane is permeable to most small molecules + ions – BECAUSE it has proins –> has pore forming proeteins

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18
Q

Pore forming proteins in outter memebrane

A

VDAC – Volt dependet anion Chanel –> most prevelant protein in mitocondrial memebarne
***Plays a role is regulated flux of metabolites across the memrbane (Phophates + Cl- + Organic anions + Adenine)

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19
Q

Permability of inner membrane

A

Inner memebrane = impermaeble
***There is a large family of transporters that shuttel metabolites across the inner memebrane

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20
Q

Two faces of inner mitocondrial memebrane

A
  1. Matrix side – N side (Negitive)
  2. Cytoplasmic side – P (Positive)
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21
Q

Bacterial ETC

A

Electron proton pumps + ATP are synthesizing complexes are on on the cytoplasmic side

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22
Q

Where is ETC and ATP synthesis

A

In the mitocondria
***ETC = in the inner memebrane of mitocondria

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23
Q

Where is TCA cycle

A

In the mitocondrial matrix

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24
Q

What does TCA produce

A

NADH + FADH2 –> They both go to ETC

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25
Q

Sections of ETC

A

Split into 4 sections
- Complexes pump Hydrogen into the intermemebrane space –> THEN ATP synthase brings Hydrogen back

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26
Q

Charge of inside of cells

A

Negitive –> Need to bring in positive charge

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27
Q

Purpose of ATP synthase (overall)

A

Maintain Homeostasis

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28
Q

Defect in mitocondria

A

Have disease –> usually die

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29
Q

How are mitocondrial diseases passed on

A

Usually from mother to Son
(Only need 1 X in son = more likley to get it)

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30
Q

Second name for ETC

A

Oxidative Phosphorylation

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31
Q

Why does the inner membrane need complexes

A

Because it is impermeable to most molecules

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32
Q

ETC (Overall)

A

ETC = a series of coupled redox reactions that transfer electrons from NADH to FADH2

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33
Q

What does NADH and FADH2 reduce

A

NADH and FADH2 are used to reduce O2 to H2O
***Highly exergonic reaction – done by electron transfer reaction that takes place in ETC

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34
Q

How do we measure electron transfer potentail

A

Meausre Electron transfer potential based on redox potentoal

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35
Q

The electron transfer potential conversion of NADH and FADH2 in ETC

A

In oxidative phosphorylation – the electron trasnfer potential of NADH and FADH2 is converted into posphoryl trasnfer potential of ATP

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36
Q

Redox example

A

Have X –> X-
Have something that can oxidized or reduced
***THe reduction potential can be measired using electron motive force generated by sa,ple half cell connected to 2 standrad refernce cells

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37
Q

Measuring reduction potential

A

The reduction potential can be measured using electron motive force generated by sample half cell connected to 2 standard reference cells
- The reduction potential (redox potential) is the measure of a molecule’s tendancy to dinate or acceot electrons

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38
Q

Measure of HPTP

A

Delta G

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39
Q

Measure of ETP

A

E’ – reduction potential

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40
Q

Strong reducing agent

A

Readily donates electons
***VERY negitive E0

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41
Q

String oxidizing agent

A

Readliy acceopts electrons
***Has a positive E0

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42
Q

Free energy change is related to the change in reduction potential (equation)

A

Delta G = -nFdEo
n = number of electrons transfer
F = Faraday constant

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43
Q

Charge of strong oxidizers and reducers

A

Slide 7

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44
Q

What does electron flow from NADH to O2 power

A

Powers the formation of proton gradient

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45
Q

Delta G for reactions of NADH + O2

A

1/2 O2 + 2H+ + 2 e- –> H2O E = POS
NAD+ + H+ + 2e- –> NADH E = NEG

COMBINED REACTIONS: 1/2O2 + NADH + H+ –> H2O + NAD+ Delta G = -220.1

Overall: The oxidation of 1 NADH can be coupled with the rephosphorylation of MULTIPLE ADP molecules

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46
Q

Driving force of Oxidative Phosphorylation

A

The electron transfer potential of NADH/FADH2 relative to O2

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47
Q

What is release of energy in reduction of O2 used for?

A

Release of energy = used to generate H+ gradient that is THEN used for synthesis of ATP and the trasnprot of metabolites across the membrane

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48
Q

Quanatative energy associated with H+ gradient

A

Delta G = RTln(C2/C1) + ZFdV
- c1 = concentration of the protons on one side of the mebrane AND c2 is the concetration of protons on the side opf the gradient to which the protons are moving
- pH is 1.4 lower than inside –> ln(c2/c1) = 3.2
- dV is the voltage potential across the mebrane –> Memrane potential is 0.14 V
- Z (charge of the proton) = +1 because outside is positive
- R = teh gas constant
- T = temperature (in kelvin)

Overall – dG = 21.8 kJ

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49
Q

What is dG for each H+ transproted out of the matrix

A

dG = 21.8 kJ

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50
Q

How to calculate Kelvin

A

Celcius + 273

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51
Q

What makes up the respiratory chain?

A

4 Comlexes

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52
Q

Four complexes of the respiratory chain

A
  1. NADH Oxidoreductase
  2. Q-cytochrome c oxidoreductase (Complex 3)
  3. Cytochrome c oxidase (complex 4)
  4. Succinate Q-reudctase (Complex 2)
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53
Q

How do electrons flow from NADH to O2

A

Electron flow through three large protein complexes embedded in the inner mitocondrial membrane

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54
Q

What does electron flow through complexes generate?

A

Electron flow through complexes = exergonic –> powers the transport of H+ across the inner membrane

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55
Q

Succinate Q-reductase (overall)

A

Contains Succinate dehydriogenase that generate FADH2 in the TCA
***It does NOT pump H+

 - Succinate Q - Red. deleivers electrons from FADH2 to Complex 3
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56
Q

Complexes 1,2,3

A

Appear to be super molecular complex = faccilitates rapid transfer of substrate + prevents the release of intermediates

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57
Q

Purpose of the complexes?

A

The complexes pump protons out of the mitocondrial matrix = genrates H+ gradient
***Protons then move back through ATP synthatse to generate ATP

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58
Q

What is ATP used for

A

ATP is used for active transport (Low –> HIGH)

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59
Q

What carreies electrons from one complex to the next?

A

Two special electron carriers:
1. Coenzyme Q
2. Protein Cytochrome C

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60
Q

Coenzyme Q

A

Hydrophob Quionone that diffises rap[idly within inner mitochondrial memebrane

Electrons are carried from NADH-Q to Q-cytochrom OR by reduced form of Q

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61
Q

Flow of elerctons from FADH2

A

Electrons from FADH2 are transfered first to Q THEN Q-cytochrome

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62
Q

Coenzyme Q (Overall)

A

Quinonine deriavtive with long tail of 5 Carbon isporene units
***Most mammales = have 10 isoprene units
- Q – binds to protons and electrons
- Can exist in several oxidation states

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63
Q

Purpose of the isporene units in Coenzyme Q

A

Give hydrophobic nature

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64
Q

Oxidation states of Quinone

A

Quinone = can exist in several oxidation states
START – Fully Oxidized (Q) –> ADD E- AND H+ – GET Semiquinone (QH) –> ADD H+ – GET Semiquinone radical (Q.-) -OR if ADD H+ and e- to QH –> GET QH2 (reduced form of Q)

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65
Q

Protein Cytochrome C

A

Cyt C = an electron carrier that employs an Oron incprportated into a heme
Small solluble proteon shuttle
**Shuttles elevctrons from Q-Cytochrom C To Cytochrom C Oxidase (Complex 3 –> 4) AND catylyzes reduction of Oxygen in the last part of ETC
**Uses heme prostetic groups

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66
Q

ETC Overall

A

NADH –> Complex 1 –> e- goes to COmplex 3 –> e- goes to Complex 4 –> Oxyegn is reduced to water
***All of the complexes require Iron

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67
Q

Requirmnet for Cytochrome C

A

Requires Iron

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68
Q

Protestic groups of Complex 1

A
  1. FMN
  2. Fe-s
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69
Q

Protestic group of complex 2

A
  1. Heme Bh
  2. Heme Bl
  3. Heme C1
  4. Fe-s
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70
Q

Prostetoc group of Comlex 3

A
  1. Heme a
  2. Heme a3
  3. CuA and CuB (Requires COPPER NOT Iron)
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71
Q

Prosthetioc group of complex 4

A
  1. FAD
  2. Fe-s
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72
Q

Where are e- passed to in the protein complexes

A

The e- are passed to electron carriers in the protein complexes

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73
Q

Q pool

A

Oxidized and reduced Q are present in the inner Mitocondrial memebrane

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74
Q

Cytochromes generally

A

Cytochromes are electron transfering proteins that contain a heme group

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75
Q

Heme in Cytochrome C

A

The Heme iron cycles between Fe2+ and Fe3+ as it accepts and donates electrons

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76
Q

Common part of the ETC

A

Iron-sulfur clusters

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77
Q

Iron Sulfur clusters

A

aka “non-heme iron proteins” – prominent electron carries

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78
Q

Purpose of Fe-s

A

Electron carriers

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79
Q

Types of Fe-S known

A
  1. 1Fe –> 1 Fe that is tetrahedrally coordinated to 4 S groups of 4 Cysteins
  2. 2Fe-2S –> 2 iron and 2 Sulfides + 4 Cysteins
  3. 4Fe-4S –> 4 Iron and 4 Sulfars + 4 Cysteins
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80
Q

Iron in Fe-S clusters

A

Cycles between Fe2+ and Fe3+ – as it accepts and donates electrons

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81
Q

What does NADH Q Oxidoreduc contain?

A

Has 2Fe2S + 4Fe-4S – Fe in these complexes cycle

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82
Q

How do Fe-S undergo redox

A

Undergo redox without releasing or binding H+

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83
Q

Frataxin

A

Small mitondrial protein that is crucial for Fe-S synthesis

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84
Q

Frataxin definceiney

A

results in Freidrweich’s ataxia – affects the nervous system + Heart + Skelotal systems

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85
Q

Freidrich’s ataxia

A

Affects nervous + heart + Muscle
- Genetic Autosmal Recessive
- metabolism disorder
- Symton – bottom of feet is heard = feet roll
- heart probelm –> have hypertrophic cardiomyopathy = large cells = large heart – blood = fills and the nervous syetm is activated = heart contracts = the blood goes to the body BUT with the bigger cells = thick blood vessels = less blood held in the heart = have less blood being pumped
- Antiseption disorder – means the next generation will get it younger and young – younger generations get the disease faster
- Have GAA repeats in Frataxin gene = abnormal DNA

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86
Q

Where do High-potential Electrons of NADH enter the respiratory chain?

A

e- enter ETC at NADH Q Oxidoreductase

Electrons get passed form NADH –> Q = forms QH2 (passed by complex 1)
***Electrons carries between NADH and Q uses Flavin Mononumcleotoide and Fe-S proteins

Q –> QH2 THEN the QH2 leaves the enzyme for the Q pool in teh hydrophic ineterior of the inner memebrane

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87
Q

Flow of e- from NADH –> Q

A

Uses FMN and Fe-S

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88
Q

Protons in Complex 1

A

4 H+ are pumped out of matrix into memebrane space

NADH + Q + 5H+ –> NAD+ + QH2 + 4H+

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89
Q

Flow of H+ in ETC

A

Matrix –> Inner membrane space

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90
Q

Reaction of FMN in complex 1

A

FMN Oxidized –> FMNH2
**Adding 2e- and 2H+

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91
Q

Electron Flow through Complex 1

A

NADH –> FMN –> Fe-s clusters –> Q = get QH2

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92
Q

What codes for H+ pump?

A

Encoded by genes in the mitocondria and the nuclues

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93
Q

Shape of NADH Q OR

A

L-Shaped – horizontal arm lying in the membrane + verticle arme that projects into the matrix

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94
Q

Reaction at Complex 1

A
  1. Binding NADH and transfer of 2 e- to FMN –> Get FMNH2
  2. e- go form FMNH2 –> Fe-S clusters
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95
Q

Structural elements required for proton pump

A
  1. Memebrane embded part – has 4 H+ half chanels consisting iof verticle helicies
    • one set of half chanels are exposed to the matrix and the other half are exposed to the inner memebrane space
  2. Encloded Q chamber
  3. Hydrophobic funnel conects Q chamber and Water chanel – extends the entire length of the memebrane part
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96
Q

Verticle helices in H+ pumps

A

Linked on matrix side by a long horitonzal helix that connects the metrix half chanels

THE intermemrane space half chanels are joined by a speries of B-hairpin helix connecting elements

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97
Q

Connection of Intememebrane space half channels

A

Intermemrane space half chanels are joined by a speries of B-hairpin helix connecting elements

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98
Q

What happens when Q acceps e-

A

The Q exiits near junction of hydrophillic protion and memebrane embedded protion

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99
Q

How do the strucutral elements cooportae to pump H+ into the matrix?

A

Q accepts 2 e- = generates Q2- –> negitive charge on Q2- interacts electrostatsically with negtive Amino Acids on memebrane embeded arme – the interaction causes confirmational change in long horizontal helix in B-helix elememy –> Confirmational change alters the structure of the verticle helizes -= have a chnage in pKA of Amino acids = allows H+ from the matrix to bind to the Amino Acids and THEN dissocaite into the watert linked chanel –> THEN can enter the intermmebrane space –> THEN Q2- tajes 2 H+ from matrix –> forms QH2 and QH2 leaves Q pool and another cycle can occur

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100
Q

Affect of QH2 forming

A

removes H+ = contributes to the formation of Proton Motive Force

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101
Q

Other ways to synthesize NADH

A
  1. FA degradation
  2. e- from cytoplasmically generated NADH
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102
Q

What is the entry point for FADH2

A

Ubiquinol

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103
Q

Where is Succinate Dehydrogenase

A

Succinate Dehydrogenase = part of Complex 2

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104
Q

FADH2 in ETC

A

FADH2 –> Fe-2 – reduces Q –> QH2 – QH2 then enters the Q pool

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105
Q

Difference in Complex 2

A

Complex 2 is NOT a proton pump – means that less ATP is formed in oxidation of FADH2

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106
Q

e- flow from Ubiquinol to Cty C

A

Electrons flow from ubiquinol to Cyt C through Q-cytochrom c Oxidoreductase

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107
Q

Q-cytochrom C Oxidoreductase

A

Cataylyzes flow of electrons from QH2 –> Cytc (reduces two molecules of cytochrome C)
***Complex 3 = also a proton pump

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108
Q

Cytochromes in Complex 3

A
  1. cyt b
  2. Cyt c1
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109
Q

Reaction in Complex 3

A

QH2 + 2CytCox + 2H+ (matrix) –> Q + 2cytcred + 4H+

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110
Q

Net protons pumped in Complex 3

A

2 protons – smaller because smaller driving force

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111
Q

Hemes of Complex 3

A

Heme c1 – Uses Cys + Met
Heme BL – Uses His
Heme bH – uses His
Rieske Fe-S – Uses His + Cys

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112
Q

Cytochrome

A

Electron transfering protein taht contains a heme group

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113
Q

Heme in Cyt b1, C, and C1

A

iron-Protophorin – Iron in the cyt alternates between + 2 and +3 state
***2 Cyt subunits = have 3 hemes
2 hemes in B (bL and bH)
1 heme in C1

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114
Q

What does Cyt have besides hemes?

A

In Addition to hemes –> Cyt has 2 fe-2S in center

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115
Q

Center of Complex 3

A

Has reike Center – unula in that one fe is coordinated by 2 His
Coordination = stabilizes center in reduced form = increases the reduction potential to accept the elerctons from QH2

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116
Q

Why do identical hemes have diffrent electron affinitys?

A

Identical hemes have different electron affinities because they are in diffreent envirnments

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117
Q

Mutations in Succinate Dehydrigenase

A

Result in increase in Succinate = facilitates in the development of cancer

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118
Q

Purpose of the Q cycle

A

The Q cycle funnels electrons from two electron carrier to a one elercton carrier and pumps protons

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119
Q

Electrons in QH2 Vs. cyt C

A

QH2 – carries 2 e-
cyt C –> Carries 1 e-

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120
Q

Q cycle overall

A

QH2 –> Cyt C

Q Cycle = Mechanism for coupling of e- transfer from Q to Cyt C to Transmemebramne proton pump

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121
Q

How many types of Q cycle exist?

A

2 types

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122
Q

Two halves of the Q cycle

A

Part 1 – One electron from QH2 reduces Cyt C and reacts with Q to form Q-
QH2 –> CytC + Q THEN Q –> Q-

Part 2 – Another QH2 reduces Cty C and Q-
QH2 –> cyt C + Q-

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123
Q

Protons in Q cycle

A

In one cycle – 4 protons are pumped out of the matrix and two are

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124
Q

Reaction of Q cycle

A

2QH2 + Q + 2Cty c oxd + 2 H+ (matrix)–> 2Q + QH2 + 2cty C red + 4H+ (ims)

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125
Q

Issue in Q cycle (

A

QH2 – pases 2 e- to Cyt c BUT Cyt C can only accept 1 electron

Solution: Mechanism for coupling of e- transfer from Q to Cyt C to Transmemebramne proton pump

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126
Q

Q cycle (depth)

A

2 QH2 molecules bind to complex at the same time –> each give 2 e- and 2H+ –> THE H+ GET RELEASED TO INTERMEMBRANE SPACE

 - The first QH2 to exit the pool binds to the first Q binding spot (Q0) and its 2 e- travel through the complex to diofferent destinations -- 1st e- flows to Rieske center THEN to C1 THEN to molecule of oxidized Cyt C = converts cty C to reduced form 
                    2nd e- passes through 2 heme groups of cty b to an oxidize Q in second binding site (Qi) --. reduces the Q to Q radical -- fully oxidizes Q leave the first site and enters the Q pool 
    - Second molecule of QH2 binds to Q0 site of Ctc C and reacts in the same way at the first -- 1 e= goes to partially rediced Q in Qi --> the radical takes up 2H+ from the matric to form QH2

END: 4 H+ are released into IMPS and 2 H+ are removed from the matrix (removal still contributes to the gradient)

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127
Q

Result of 1 Q cycle

A

2 QH2 molecules are oxidized to from 2Q molecules –> THEN one Q Molecule is reduced to QH2

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128
Q

Purpose of Q cycles

A

Solves the problem of funneling elerctons from a 2 e- carrier to a 1 e- carrier

IN essence – its a recycling system that makes use of both electrons effectively

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129
Q

Cytochrome C Use

A

Catylzyes the reduction of O2 to water

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130
Q

Cytochrom C Oxidase (overall)

A

Cty C Oxodase acceots 4 electrons from 4 molecules of cyt C to catylyze the reduction of O2 to 2 molecules of water
E- go from Cty C –> Cty C oxidase

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131
Q

Protons in cyt C oxidase

A

Eight proteons are removedfrom the matrix
- 4 H+ = the chemical proton – REST go to the IMPS

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132
Q

Chemical protons

A

Protons used to reudce O2

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133
Q

Cyt C Oxidase reaction

A

4CytCred + 8H+ (matrix) + O2 –> 4Cytc Oxd + 2water + 4H+

END – pump 4 protons into the IMS + use 4 protons to reudce Oxygen

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134
Q

Heme requirements in Cyt C oxidase

A

Heme a – His
Heme a3 – His
CuA/CuA– uses Cys + His
CuB – His + Tyr

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135
Q

Structure of Cytochromse C Oxidase

A

Conatins 13 Subunits

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136
Q

Requirments of Cty C Oxidase

A
  1. Two heme A Moeities – Heme A and A3
  2. Two copper ions – the two centers contain 3 Cu ions
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137
Q

Two copper ions in Cyt C Oxidase

A
  1. Copper A – have 2 copper ions – the Cu ions are linked by bridging Cysteine residues
    - Copper A = intially accepts elecrtons from reduced Cyt C
  2. Copper B – has three His –> One Histidine residue is linked to tyrosine
    ***Copper centers alternate between reduced Cu and Oxd Cu2+ as they accept and donate e-
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138
Q

Electron flow in Cyt C Oxidase

A

Cty C –> CuA/CuA –> Heme a –> Heme a3 –> CuB
***Adding two more electrons and 4 H+ generates two molecules of water

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139
Q

What happens when the Fe in heme a3 and CuB are rediced

A

Bind to oxygen as a peroxide bridge between them

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140
Q

What disease in Tyr associated with?

A

PKU

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141
Q

Cytochrome C Oxidase

A

Last of the H+ assemblies – it catylizes the transfer of electrons from reduced Cyt C to O2

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142
Q

What makes ETC aerobic

A

Requirement of O2 for rxn in complex 4 – reason that humans need to breath

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143
Q

How many electrons are used to reduce O2

A

4 e- –> 4 e- are funneled to O2 to completeley reduce it to water

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144
Q

What happens when O2 is reduced

A

H+ are pumped from matrix to teh IMPS

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145
Q

dG of Complex 4

A

Reaction is thermodynamically favorable – dG = -231.8
***Want to capture as much of the dG as possible in form of the proton gradient for ATP sytnthesis

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146
Q

Heme A in Complex 4

A

Different than heme in C and C1

Has:
1. A formyl Group instead of CH3
2. A C17 hydrocrabon chain replaces Vinyl Group
3. heme is not covalentley attatched to protein

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147
Q

Complex 4 Mechinsm

A
  1. Two molecules of cyt C transfer e- to reduces CuB and Heme A3
    • electrons from 2 molecules are red cyt C flow down ETC within Complex 4 – one e- stops at CuB and one at heme a# –> THEY BOTH bind to O2 molecule
  2. Reduced CuB and Fe in heme a3 bind O2 = forms perpxide bridge
    • As O2 binds to e- peroxide bridge forms
  3. The addition of 2 more e- and 2 more H+ cleaves the peroxide bridge
    • Two more e- of Cyt C bind and release e- that travel to active center
    • The addition of an e- as well at H+ to each Oxygen reduces the 2 oxugens to Cub2+-OH and Fe3+-OH
  4. The addition of 2 H+ leads to release of H2O
    - reactions with more H+ ions allow the release of 2 molecules of water and resets enzymes to oxidized form
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148
Q

Affect of Oxidizing Cytochrome C

A

Also converts Oxygen to water

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149
Q

Heme a and Heme a3

A

Have distict redox potentoals bevause they ate located in different envirnments within Complex 4

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150
Q

Active center in Complex 4

A

Heme a3 and CuB –> Forms active center at O2 at with O2 –> goes to water

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151
Q

Protons in Complex 4

A

4H+ come from the matrix = consumtion of 4H+ contibutes to gradient

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152
Q

dG in complex 4

A

Each H+ moving = 21.8kJ –> 4 = 87.2 kJ –. LESS than the dG avalable from reducihng water – what is the fate of the missing dG –> Cty C Oxidase uses the energy to pump 4 additional H+ from matrix to intermemebrane space = 8H+ are removed from the matrix

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153
Q

Two things that affect Complex 4 mechanism

A
  1. Charge nuertrality – is mainatined in the interior of proteins -> THIS adding e- to site = favors H+ binding
  2. Confirmational Change occurs (espcially for a3-Cub) –> in one confirmation the H+ can enyter prtein from matrix side and in another confirmation they exit to the intermembrane space
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154
Q

Where is most of the ETC organized into

A

Most of the ETC is organized into the Respirasome Complex

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155
Q

Respirasome

A

Protein that coordinates complex – reserach shows that the three componenet are arranged in a large comples
***Complex = resparasome

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156
Q

Human Respirasome

A

Consists of:
1. 2 Complex 1
2. 2 Complex 4
3. 2 Complex 3
4. 2 Cyt C
**The Complex 1 and 4 surrodound the copies of complex 3
**The two copies of cyt C are on the surface of Complex 3

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157
Q

Purpose structure of respirasome

A

Structures allow for Complex 2 to associated in a gap between Complex 1 and 4

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158
Q

What does respsirasome show

A

Shows multienzyme system used to increase efficiency

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159
Q

Where is cyt C located in mitocondria

A

Sits on the external size of the inner membrane

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160
Q

Solution for Toxic derivatives of O2

A

The toxic derivatives are scavenged by protective enzymes

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161
Q

Toxic derivatives of O2

A

Superoxide Ions + Peroxide

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162
Q

Partial reduction fo O2

A

Generates highly reactive Oxygen derivatives – Creates ROS

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163
Q

ROS

A

reactive oxygen species – made by the partial reduction of O2
***ROS = implicated in a lot of pathological conditions

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164
Q

Types of ROS

A
  1. Superoxide Ions
  2. peroxide Ions
  3. Hydroxyl Radical

O2 -+ e- –> O2.- (Superoxide ion) + e- –> O22- (peroxide)

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165
Q

Affect of alcholol

A

Kills nuerons = decreases intellegence

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166
Q

Emphysema

A

Bronchitus –> COPD – Chronic Absurtutice Pulminary disorder
- Get small cell cracino/Co-cell carcinoma because of Emphysiomia
- 6 months to live
***Casued by ROS

167
Q

Duchene Muscular

A

Lose skeoltal muscle and replace it with fatty tissue
- Sympton = cow manuver to get upo
- Die by 11/12 – die because of lung infections
- genetic – X-linked recessive

168
Q

Diseases associated with ROS

A
  1. Emohysema
  2. Duchene Muscular Dystrophy
  3. Alcohol Liver disease
169
Q

Alcholol Liver dieases

A

Get cirrosious = get cancer
- Live longer but eventually die
- Luver becomes hard –> need liver transplants

170
Q

Super Oxide Dismutase + Catalse

A

Help protect against ROS Damage

SOD – 2O2.- + 2H+ –> O2 + H2O2
Catalase – H2O2 –> O2 + H2O

171
Q

Two forms of SOD in Eukaryots

A

1 – Magnese containing Mitocondrial from
2 – Copper and zinc containing Cytoplasmic form

172
Q

Exersize + SOD

A

Exercise is associated with increased SOD expression

173
Q

O2 as terminal acceptor

A

O2 = ideal terminal acceptor because of its high affinity for electrons = provides a large thermodriving form BUT danger lurks in reduction of O2

174
Q

Dangers in Reductions of O2

A

4 e- = leads to safe prodycts BUT partial reduction generates hazardous compounds
***Transfer of a single e- or 2 e- is bad –> both potentiall destructive

175
Q

Stradegy for safe reduction of O2

A

Catalysts do not release reactive intermediates – cty C does this by holding O2 tightley between Fe and Cu

Issuse – small amounts of ROS

176
Q

Implications of ROS

A

ROS have been implicated in the aging process + a growing list of diseases

177
Q

Cellular defense stradegies against ROS

A
  1. Enzyme SOD –> scavenges superoxide radicals and catylezed them to H2O2 and O2
178
Q

SOD

A

Superoxide radicals –> H2O2 + O2
- Enzymes preform dismutation reactions – oxidized form of enzyme is reduces by the superoxide to form O2
- reduced form of the enzyme reacts with a second superoxide ion to form peroxide –> takes up 2H+ along the reaction path to make H2O2

179
Q

Fate of H2O2 formed by SOD

A

H2O2 is scavenged by catalase

180
Q

Catalase

A

Heme protein that catylyzes the dismutation of H2O2 into H2O and O2

181
Q

Efficiencey of SOD and Catalase

A

They are very efficient – near diffusion limit

182
Q

Gluyayhone peroxidase

A

Also plays a role in scavenging H2O2

183
Q

Excersize + SOD (depth)

A

Increase in aerobic metabolism = increse in ROS –> in response rge cell sythesized more protective enzymes – net effect = protection because increase in SOD = protects cells during periods of rests

184
Q

New use of ROS

A

Recent evidence suggests that under certain circumstances the controlled generation of ROS = may be implicated imn signal transduction

Exampple – growth factprs have shown to increase ROS levels as part of their signalling pathway + ROS regulates chanells and transcription fcatoprs
***ROS have been implicated in the control of cell diferentation + immuresponse + Autophase

185
Q

Other cell defense against ROS

A

Antoxidants E and C – because lipophillic unit L is usefule in protecting memebranes from lipid peroxidation

186
Q

Proton Motive Force

A

The proton gradient generated by the oxidation of NADH and FADH2
***Energy rich unequal distrobution = PMF

187
Q

Used of PMF?

A

Proton motive force powers the synthesis of ATP

188
Q

Parts of the proton Motive Force

A
  1. Chemical Gradient – pH gradient
  2. Charge Gradient – created by postive on H+
    ***Chemiostatic hypothesis = proposes that both components power ATP Synthesis
189
Q

How did we confirm that the proton gradients can power ATP Sythesis?

A

Using Heterologous experimental systems

190
Q

dG of red o2 vs dg of ADP

A

NADH –> O2 dG = Exo
ADP –> ATP dG = Endo

***The reactions are coupled to drive the synthesis of ATP

191
Q

Complex that carries out ATP synthesis

A

Mitocondrial ATPase OT F1/F0 ATPase –> Named like this because it was discovered through the reverse mechanism

192
Q

How is oxidation of NADH coupled to the Phosphorylation of ATP

A
193
Q

Two proposals about How oxidation is coupled to phosphorylations

A
  1. e- transfered leads to formation of high covalent intermediate that serves as a compud with HPTP (likes generation of ATP in glycolysis)
  2. That the e- transfer aids in the formation of an activated protein confirmatyion –> THEN drives synthesis – NO such intermediate has been found
194
Q

Peter Mitchell

A

Suggested the Chemiosomatioc Hypothesis

195
Q

Chemiosomatioc Hypothesis

A

Suggests that e- transprot and ATP synthsies are coupled by a proton gradeint across the inner mitocondrial memebrane – the transfer of e- through the resporatory chaon leads to the pumping of protons from the matrix to the IMPS –> THEN the H+ flow back into the matrix to establish equillibrium

Idea = that the flow of protons drives ATP synthesis by ATP synthase

196
Q

Support of Chemiostatsic hypothesis

A

NOW supported by a lot of evidence

NOW KNOW – the e- transoprt dies geenrate a H+ gradinet + the TMP is 0.14v

197
Q

pH gradient generated

A

The pH outside if 1.4 units lower than inside

198
Q

Demonstrating the Chemiosomatic hypothesis

A

It was demonstrated using Artifical system – used Bacteriarhodposin

***Synthetioc vesicles with bacteria Rhodopsin and Mitocondrian ATP were sythesized and purofied –> when vesicles were exposed to light ATP was formed –> Showed that the resporaty chain and ATP synthesis are seprate systems that are linked by PMF

199
Q

What drives ATP synthesis?

A

Proton motive force

200
Q

Proton Motive Force Equation

A

dP (PMF) = Chemical gradients (dpH) + Charge Gradient (dPsi)

201
Q

What makes up ATP synthase?

A
  1. Proton conducting unit
  2. Catalytic Unit
202
Q

How is NADH coupled to ATP synthesis?

A
  1. e- transport generates PMF
  2. ATP synthesis by ATPsynthast is powered by PMF
    ***Coupled by PMF
203
Q

How is PMF converted into HPTP?

A
204
Q

Structure of ATP synthase (overall)

A

Large complex enzyme resembling a ball on a stick
- Stick = F0 subunit (in inner mitocondrial memebrane)
- Ball = F1 Subunit (protrudes into the matrix)

205
Q

F1 Subunit

A

Subunit in ATP synthase with catalytic activity – F1 isolated has ATPase activity
- Conatins 3 active sizes ;ocated on the three Beta Subunits
***F1 protrudes into the mitocondrial matric

206
Q

Where are the active sites on F1

A

The active sites are located on the three Beta subunits

207
Q

F1 Subunit (depth)

A

F1 unit = has 5 types of PP chains with identical stoicheometry
- Alpha + beta make up most of F1 –> arranged alternativley in a hexameric ring
- Both Alpha and beta bind nucleotides BUT onl Beta has catalytoc actitovity
- Below alpha and beta –> have central Stalk

208
Q

Central Stalk of F1

A

HAS Y AND E proteins
- Y –> long helical coil coil that goes through the center of a3b3 hexamer –> y breakls the symetry of the a3b3 hexmoer

209
Q

Why is each Beta subunit distinct

A

Each beta Subunit is distinct by virtue of its different interaction with Y
***Distuguishing the three beta subunits = criticakl for understanding sythesis

210
Q

F0 Subunit of ATP Synthase (depth)

A

F0 = the hydrophibic segment that spanns inner mitocondrial memebrane
- F0 = have H+ chanel

211
Q

Chanel in F0

A

Has a ring of 8-14 Carbon subunits that are embedded in the membrane –> A single subunit binds to the outside of the ring

212
Q

Ways that F0 abnd F1 are connected

A
  1. By the central Stalk
  2. By exterior colum –> have one of alpha Subunit and 26 of delta subunit
213
Q

ATP synthates interaction

A

ATP SYnthases interact with one another to form a dimer –> The dimers then associate to form larger oligiomers of dimers
- Associtiona stabilizes the individual enzumes to rotational forces required for catalysis

214
Q

Affect of forming dimers

A

Association of ATP synthase enzy,mes stabilizes the individual enzymes to rotational forces that are required for catalyasis + facilititases the curvature of the inner mitocondrial memebrane

215
Q

Formation of Cristea

A

Allows proton pumps of ETC to localize H+ gradinet in vicinity of substrates = higher efficieney

216
Q

Where are the substartes for ATP synthesis located?

A

Located at the tips of cristae
***The formation of cristea allows the proton pumps of the ETC to localize the H+ gradient at the tips wherte the substrates are found

217
Q

Where is the F0 compartment

A

Embedded in the inner mitocondrial Memebrane

218
Q

What does F0 have?

A

Has a proton chanel

219
Q

What connects F1 and F0?

A

The Y subunit

220
Q

What is the outcome of Protons flowing through ATP Synthase

A

Protons flowing through ATP synthase leads to the release of Tightly bound ATP

221
Q

What is the name of the ATP synthase mechinsm

A

The Binding-Change Mechanism

222
Q

ATP synthase role

A

Catalyzes the formation of ATP from ADP + Pi

Reaction: ADP3- + HPO42- + H+ –> ATP4- + H2O

223
Q

What is needed for ATP and ADP to function as substrates

A

ATP and ADP must be bound to MG2+ to function as substrates
- ATP and ADP in ATP synthase need to be bound to Mg2+

224
Q

Intermediate in ATP synthase mechinasm

A

Pentacovalent intemedeiate

225
Q

ATP synthase mechanism

A

ADP + Pi + H+ –> Pentacovalent INtermediate –> ATP + H2O

**Slide 48

226
Q

Binding Charge Mechanism

A

Accounts for the Synthesis of ATP in response to proton Flow

227
Q

Confirmations of the three Beta Catalytic Subunits of F1

A
  1. O form
  2. L form
  3. T form
228
Q

O form

A

Nucleatoirs can bind to or be released form the Beta subunit

229
Q

L form

A

Nucleotides are trapped in teh Beta Subunit

230
Q

T form

A

ATP is synthesized from ADP and Pi in the absence of a proton gradient BUT can’t be released from the enzyme
***Responsible for produces the ATP

231
Q

What releases the Newly synthesized ATP

A

Proton flow releases the newly synthesized ATP
- The T form makes the ATP without the proton gradient BUT it can’t release the ATP unless there is a gradient

232
Q

What is needed for ATP to be formed vs. needed to be releases

A

ATP forms without H+ flow (without PMF) BUT it will not be released without PMF – need PMF in order to release ATP

233
Q

Mechanism of ATP formations

A

Terminal Oxygen atom on ADP attacks the phosphate of Pi to form ATP + H2O

234
Q

How does the flow of protons drive the synthesis of ATP?

A
235
Q

Isotope Exchange experiments

A

Showed that enzyme bound to ATP can be found in absence of PMF – when ADP and Pi are added to ATP synthase in the presence of H2O(18) –> the O18 was incorporated into the Pi through ATP synthase
- Experiments showed equal amounts of ATP and ADP are bound in equillibruim at cataluytic site even in the abdence of teh H+ gradient

BUT – it showed that ATP does not leave until teh H+ gradient flows through the enzyme

OVERALL – shows that the role of the H+ is not to form ATP BUT it is to release ATP from the substrate

236
Q

What is teh role of the H+ grandient?

A

To release ATP from the sythase – NOT to make ATP

237
Q

Three cataylytic units on F1 at a given point

A

The 3 beta subunits in F1 – all orefron one of three functions at any given time

238
Q

PMF and ATP symthase beta units

A

The PMF – causes the three active sites to sequnetially change functions as the H+ flows through the memebrane mebded part of the enzyme

239
Q

How do the three Beta subunits respond to H+ flow

A
240
Q

What causes the Beta subunits to change function?

A

The three beta subunits can preform each of the three steps by chnage in confirmations

241
Q

Steps preformed by the Beta subuit for ATP synthesis

A
  1. ADP + Pi binding
  2. ATP synthesis
  3. ATP release
242
Q

F1 parts

A
  1. Moving part – rotor –> consists of C ring and gamma stalk
  2. Stationary part
243
Q

ATP synthesis (depth)

A

Rotation of the Gamma subunit = drives the conversion of the 3 forms

***Gamma rotates =
1. T –> O
2. L –> T = enables the transformation of ADP –> ATP

ATP in O = can leave the enzyme and is replaced by ADP – then can rotate again

244
Q

Rotation of Beta subunits

A

T –> O –> L – no two are ever present in the same confirmation
***Mechanism suggests that ATP can be synthesized and released by driving gamma subunit in the right direction
- Each subunit cycles through the three confirmations

245
Q

What turns the gamma subunit?

A

Proton flow moves the gamma subunit = powers interconversion of forms

246
Q

Angle and direction of Beta subunit movement

A

120 Degrees counter clockwise
***120 Degrees = 1ATP

247
Q

Which beta form produces ATP

A

T Form – produced if there is a turn –> then it is released and there can be another turn

248
Q

Rotational Catalysis is…

A

The worlds smallest motor

249
Q

Studying ATP sythase

A

Used experiments using A3B3G
- Beta subunits were engineered to have an amino terminal Poly histidine tag –> have affinity for Nickle = allows teh A3B3 to immobilize on a glass surface that was coated with Nickle
- Gamma subunit was liked to actin filamirs to see it under floruecnce

–> When added ATP = it caused the Actin filaments to rotate clockwise –> the gamma subunit was rotating = driven by hydrolysis of ATP

250
Q

Clockwise rotation of Gamma subunit

A

Consistent with predicted mechanism for Hydrolysis

251
Q

Efficiency of ATP synthase

A

Near 100% efficiency –> All of the energy released by ATP hydrolysis is converted into rotational movement

252
Q

Requirment for Actin filaments

A

Requires Ca2+

253
Q

Actin vs. Myosin

A

Actin –> Thin filament

Myosin –> Thick filament

***Both found in skeletal muscles

254
Q

What powers ATP synthesis

A

Proton Flow around C ring

255
Q

Use of Clones A3B3G subunits

A

When attached to a glass slide they were able to show the movement of the gamma subunit – visualized ATP hydrolysis

256
Q

Where do protons flow inATP synthase?

A

Protons flow through F0 component of ATP synthase

257
Q

Parts of F0 Subunit

A

Subunit A and C Ring

258
Q

Structure of Subunit A in F0

A

Subunit a has two 1/2 chanels (each reach halfway into the A subunit
1. Opens to the intermemebrane space
2. Opens to the matrix

259
Q

Subunit A and C Ring associatation

A

Subunit A is attached to the C ring (on outside of the c ring)

260
Q

Flow of Protons through ATP synthase

A

H+ enter the half-chanel in SU A that faces the Intermembrane space – in the chanel they bind to a Glutamate or an Aspartate on one of the subunits of the C ring –> Then they leave the C subunit once the C subunit rorates to face the matrix 1/2 chanel –> Then H+ leave into the matrix through the matrix 1/2 chanel

261
Q

Movement of C ring in F0

A

First faces the IMPS 1/2 channel –> Then it rorates to face the matrix Half channel

262
Q

Amino Acids in F0 Subunit of ATPO synthase

A

Requires Glutamate or Aspartate –> The H+ bind to one of the residues on the Subunits of the C ring in F0

263
Q

What rotates the C ring in the F0 Subunit?

A

The proton gradient powers the rotation of the C ring

264
Q

Affect of the rotation of the C Ring

A

The rotation of the C ring powers the movements of the Gamma subunit in F1 –> Alters the confirmations of the Beta subunits

265
Q

What powers the movement of the Gamma subunit in F1?

A

The rotation of teh C ring due to PMF –> the roation of teh gamma subunits = alters the confirmation of the Beta subunits

266
Q

PUT IT ALL TOGETHER (ATP synthase)

A

Gamma subunit rotates such that ATP can be synthesized without proton motive form –> THEN the C ring which moves ONLY because of PMF will move –> The c ring movement due to PMF will cause gamma to move which causes the beta SU to change in confirmation which allows the release of the newly synthesized ATP

267
Q

Movement of protons ion F0

A

Intermebrane space –> Matrix

268
Q

Direction of C ring movement

A

Clockwise

269
Q

Hydrogen that goes into C ring vs. H that leaves

A

NOT the same H
***Look at slide 58

270
Q

Evidence for rotational mechanism for ATP synthesis

A

The direction observation of rotory motion of the gamma Subunit

271
Q

Stationary part of F0?

A

A subunit

272
Q

Structure of A subunit (depth)

A

Has 2 hydrophillic 1.2 chanels that do NOT span the memebrane –> thus H+ can pass BUT it can’t move comp[letley across A in one chanel

273
Q

How is A SU positioned in relation to C ring

A

The A SU is positioned such that each 1/2 chanel directley interacts with one C SU in ring

274
Q

Stucture of C ring (depth)

A

Each polypeptide forms a pair of alpha spanning helicies
***Have Glu or Asp redidue found in the middle of one of the helicies

275
Q

Movment of C ring

A

IF Glu or Asp is charges (unprotinated) –> C SU does NOT move

IN a H+ rich envirnment the H+ will enetr the A SU half chanel and bind to Glu while the H+ poor envirnmemnt of other 1/2 chanel releases an H+

Overall – the C SU binds to H+ –> C SU rotates one C SU –> Rotations brings protinated C form from IMPS chanel to teh deprotinated matrix chanel where it binds to H+ = h+ goes through the chanel
- The movement for H+ through 1/2 chanel from high to low H+ concentration powers rotatioon of C ring

276
Q

What powers rotation of C ring?

A

The moevment of H+ 1/2 chanels from high to low H+ concentration

277
Q

A subunit while the C ring moves

A

Remains stationary

278
Q

Proton rich envirnment Vs. poor

A

Rich (IMPS) – protons enetyers chanel and binds to Glu

Poor (Matrix) – release the protons

279
Q

Rotational movement of C ring (overall)

A

Rotational movement brings the deprotanated C SU form the matrix channel to the proton rich IMPS channel

280
Q

How does rotation of the C ring lead to ATP synthesis?

A

C ring = rightley linked to the gamma and e SU –> THUS as the C ring turns the Gamma and E SU are truned – rotation of the gamma SU promotes the synthesis of ATP through binding change mechanism

281
Q

What prevents the hexemer from rotating in Sympaythy with C?

A

The exterior column formed by 26 chains and 6 SU – prevents hexamer from rotating in sympathy

+

The dimerization and oligiomerization in cristae also stabilize the enzyme from rotational forces

282
Q

Number of C SU

A

usually 8-14 –> Significant because it determines the # of protons that muct be transported tp generate ATP

283
Q

Why is the number of c SU important?

A

Determines the number of protons that are needed in order to generate ATP

Example – 360 degrees generates 3 ATP –> THIS for 10 c SU – each ATP generated requires 10/3 H+

284
Q

360 degree rotation of gamma

A

leads to the synthesis and release of 3 ATP

285
Q

Number of C rings in vertabrates

A

Recent evidence shows that the number of C rings in all vertabrates = 8 –> Makes vertabrate ATP synthesis the most efficient sthase known (only 2.7 H+ required)

286
Q

Assumption for how many H+ flow for 1 ATP

A

3 H+ flow for 1 ATP

287
Q

Another function of resporatory chain

A

To regenerate NAD+ for glycolysis

288
Q

NAD+ issue in ETC

A

The inner mitocondrial membrane is impermeable to NADH and NAD+ – need to have a way to shuttle NAD+ to cytoplasm to be used by glycolysis

289
Q

Solution of NAD+ shuttling issue

A

Muscle –> e- from the cytoplasmic NADH can enter the ETC using the Glycerol-3Phosphate shuttle

Solution: The e- from NADH rather than NADH itself are carried across the mitocindrial memebrane
Example – introducing teh electrons from NADH into ETC using Glycerol-3-Phosphate shuttle

290
Q

Purpose of the Glycerol-3-P shuttle

A

Allows cytoplasmic NADH to enter the ETC

291
Q

Gleycerol-3-P shuttle (Overall)

A

e- are transfered from NADH –> FADH2 –> Q = forms QH2

292
Q

Amount of ATP from NADH

A

2.5

293
Q

Amount of ATP from FADH2

A

1.5 – because DAD is the e- acceptor

294
Q

Where is the Glycerol-3-P shuttle?

A

In the cytoplasm
***Used in Muscle

295
Q

Where does NAD+ go after the Glycerol-3-P shuttle

A

Goes to the cytoplasm to be used in glycolysis

296
Q

Two places with Glycerol-3-Phosphate dehydrogenase

A
  1. Cytoplasm – for glycolysis
  2. In the Mitocondria – for shuttle
297
Q

Glycerol 3 - Phosphate shuttle (depth)

A

DHAP –> Glycerol-3-P –> DHAP
**When DHAP –> G-3-P – have NADH –> NAD+
**When G-3-P –> DHAP – have FAD –> FADH2 – on the process get Q –> QH2

298
Q

Where is the Malate Aspartate shuttle

A

In the heart and liver

299
Q

Use of Malate Aspartate shuttle

A

e- from the cytoplasmic NADH are used to generate mitocondrial NADH – getting NADH to the mitocondria

Cytoplasm NADH + Mitocondria NAD+ –> Cytoplasmic NAD+ + Mitcondrial NADH
(Putting NADH in mitocondria)

300
Q

Parts of the Malate-Aspartate Shuttle

A
  1. Two membrane transporters
  2. Four enzymes
301
Q

Malate Aspartate Shuttle (depth)

A

Malate enters matrix through malate shuttle –> Malate is turned to Ocoloacate (GENERATES NADH – NOW HAVE NADH IN THE MATRIX)– Oxoloacetate is combined with Glutamate –> Oxo + Glutamate forms A-KG + Aspartate –> A-KG and Aspartatae leave thriugh their repective trasnproters –> In the intermemebarne space A-KG and Aspartate are combined –> forms Oxoloacete + Glutamate –> Oxoloacate goes to Malate (in the intermemebrane space) = refroms NAD+ in the intermemebrane space + malate can go through for a new cycle

302
Q

Permeability of the inner memebrane

A

The inner membrane needs to be impermeable to most small molecules BUT also need to have exchange between the cytoplasm and the mitocondria

303
Q

How is exchange done in the inner mitocondrial memebarne

A

using different memebrane spanning transporter proteins

304
Q

How do cytoplasmic electrons from NADH enter mitocndria

A

Using shuttles

305
Q

What NADH is already in the mitocondria

A

NADH from the TCA cycle and Fatty acid synthesis = already in the mitocondria (because those processes occur in the mitocondria)

306
Q

Glycerol-3-P shuttle (textbooks)

A

Overall: Introduces the e- from NADH into the ETC – not intridcuing NADH itself directley

  1. Transfer e- from NADH –> DHAP = forms Glycerol-3-P (USes Glycerol-3-P dehydrigenase)
  2. Glycerol-3-P is rexidized to DHAP on outter surface of innter mitocndria memebrane using isozyme of Glycerol-3-P Dehydrogenase – here an e- pair is transfered from FAD –> FADH2
  3. The reduces FADH2 – transfers e- to G –> e- can enetr the ETC as QH2
307
Q

Glycerol-3-P dehydrigenase

A
  1. Cytoplasmic – Putts e- into DHAP –> forms Glycerol-3-P – forms NAD+
  2. Mitocndria –> Turns Glycerol-3-P into DHAP – forms FADH2 + QH2
308
Q

Why use FAD if it is lower yeild?

A

Because enable e- from NADH to be trasnproted into the mitocodnria NADH gradient
***price of trasnprt is 1 ATP

309
Q

Where is the Glycerol-3-P shuttle + why

A

Found in muscle cells –> enables mucslces to sustain a high rate of Oxidative phosphorylation

310
Q

Some insects + G-3-P shuttle

A

Some insects lack Lacatae Dehydrigenase and are completley dependents on the Glycerol-3-P shuttle for regeneration of cytoplasmic NAD+

311
Q

Use of Malate-Aspartate shuttle

A

Brings e- from cytoplasmic NADH into mitocondria in the heart + liver

312
Q

Malate-Aspartate shuttle (textbook)

A

e- are transfered from NADH into the cytoplasm to oxoloacetate –> Forms malate –> Malate traverses the inner mitocondrial emebrane in exchange for A-KG –> THEN get rexoidation of malate using NAD+. in the matrix (catylyzed by matlate dehydrogenase) – forms NADH –. Oxolooacentat does not readily traverse the memebarne = trannsamainan reaction is needed to form aparttate and A-KG that cab be trasnfered

313
Q

How does Malaate traverse the Inner mitocondrial memebrane

A

By going through trasnproter AND by exchaning it for A-KG – Malatae goes in and. theA-KG leaves

314
Q

Malate Dehydrogenase

A

Malaate –> Oxoloacetente (goes NAD+ –> NADH)
***Oxidizing malate to form Oxoloacetate

315
Q

How can Aspartate go across the Mitochondrial memebrane

A

By exchanging for glutamate

316
Q

Oxoloacate moving across mitocondrial memebrane

A

Oxoloacateate does not teadioly travser the inner memebarne = need a transamianan reaction
- Glutamate donates NH3 group to Oxoloacetate = forms aspartate and A-KG = can cross memebarne –> THEN in the cytoplasm Asparatate is deaminated to go back to oxoloacetate

317
Q

Coupling of enter of ADP into mitocondria

A

The entery of ADP into mitocondria is coupled by the exit of ATP using ATP-ADP Translocase

318
Q

ADP-ATP Translocase (overall)

A

Helps couple the entry of ADP into the mitocodnria and the exit of ATP – enables the exchange of cytoplasmic ADP for mitocndrial ATP
- Brings in cytoplasmic ADP
***Enables ADP and ATP to traverse the inner memebrane
- Couples the flows of ADp and ATP

Reaction – ADP (cyt) + ATP (matrix) –> ADP (matrix) + ATP (cyt)

319
Q

What percent of the inner mitocondria memebrane in ATP-ADP trasnlocase

A

15% of the inner membrane – very abdundent
***Abudnece is manifestation of the fact that humans exchange the equivilant of theoir weight in ATP each day

320
Q

What is needed for ATP to leave

A

ADP much enter the mitocondria

321
Q

Difference in ATP-ADOP translocase and ATP synthase

A

In ATP-ADP trasnlocase neither the ATP or the ADP is bound to Mg2+

322
Q

Energy of ATP-ADp exchange

A

The ATP-ADP exchange is energyetically expensive –> 25% of the PMF generated by the ETC is conssumed by the exchange process

323
Q

Eversion

A

Two molecules going away from each other

324
Q

Mechanism of ATP-ADP Trabslocase

A
  1. ADP enters Translocase (the AS is facing the cytoplasm)
  2. The Translocase site with ADP flips the other wat – flipes towards the matrix (1st eversion event)
  3. ADP is release – active sit is still facing the matrix
  4. ATP from the matrix can enter
  5. Second eversion occur –> AS flips to face the cytoplasm
  6. The ATP is released into the cytoplasm
    ***When ADP comes in teh ATP can be realsed form the matrix
325
Q

Diffusion of ATP and ADP across inner memebrane

A

They do not diffuse freely

326
Q

Purpose of ATP synthase Vs. ADP-ATP translocase

A

ATP-synthase –> Makes ATp + releases teh ATP intp yje matrix

ADP-ATP translocase –> trasports the ATP from the matrix to cytoplasm and birngs ADP into the matrix to be used by ATP syntahse

327
Q

ATP in mitocondria vs. nucleus

A

Cytoplasm + Nucleus = have more ATP that mitocodnria –> testamenet to the efficiencey of the transprt of ADP-ATP translocase

328
Q

ADP-ATP translocase structure

A

20 kDalton translocase containing a single nucleotide bidning site that alternativley faces the matrix + the Cytoplasmic sides of the memebarne

329
Q

Energy of ADP-ATPtranslocase

A

ATP has one more neg. charge that ADP –> THUS in activatley respiring mitocondria with positive memebrane potential –> ATP trasnprt out of the matrix + ADP in is FAVORED
***ADP/ATP exchage is energetocally expensivce –> 1/4 of the PMF in ETC is consumed in process

330
Q

Inhibition of translocase

A

Leads to inhibition of cell respiration

331
Q

Commonality if Mitocondrial Transporters

A

All have. acommom Tripartite Structure

332
Q

Composition of ATp-ADP translocase

A

ATP-ADP Translocase is composed of three tandom repeating 100 AMino acid domain – each domain conaints two transmemenbarne regions

333
Q

What is on the inner mitocondiral memebrane

A

The inner mitocondrial memebrane has many transporters + carriers –> enable the exchange of ions and charges partciles between the matrix and the cytoplasm

334
Q

Tripartitae structure of Translocase

A

The AA seq has 3 tandom reptease of 100 AA sequence
- Each repeat has 2 Transmembrane regions
***Tripartite structure has been confiormed by the determination of the 3D structure of the tranporter
- The transpemebrane helicies form a teppee like structure with nucleotide binding site laying at the center
- Each of the three repeats have. asimilar structure

335
Q

Phophate carries in Inner membrane

A

Works with ATP/ADP trasnlocase – mediates the electrocal chatge of H2PO4 + OH-
- Combination. ofaction of trasnlocase and Phosphate carrier – leads to exchange of cytoplasmic ADP and Pi for matrix ATP – uses 1 H+
***Transporters PROVIDE ATP SYTHASE with substartes

336
Q

Phosphate craiiers + translocase + ATP synthase

A

Phosphate carriers and Translocase work togther to exchage ADp + Pi for matrix ATP –> PROVIDE ATP synthase with substrates
***The three are associated in a large complex

337
Q

ATP Synthasome

A

Large complex with translocase + ATP synthase + Phophate carriers

338
Q

Dicarboxylate carrier

A

Enables malate + Succinate + Fumarate to be exprote form matrix in exchange for Pi

339
Q

Tricarboxylate carrier

A

Excghanges citrate and H+ for malate

340
Q

How does pyruvate enter mitocondria

A

Uses heterodimer composed of 2 small transmembrane proteins

341
Q

What regulates cell repsirtaion

A

Cell resipiration if regulated primaryly by the need for ATP
***Because ATP is the end product of Cell respiration –> The ATP needs is the ultmate determinate of the rate of repiratory path and its components

342
Q

ATP in Combustion of gluse

A

30 Molecules of ATP are mode –> 26 of those 30 are made in ETC

343
Q

ATP made. inmetalbilsim of glucose

A

Metabolism of glucose to two molecules of pyruvate –> yeilds 4 ATP

344
Q

ATP in fermentation

A

When glucose undergoes fermentation only two molecules of ATP are generated per glucose molecule

345
Q

What determines the rate of ETC

A

The need for ATP

346
Q

When do e- flow through ETC

A

e- ONLY flow if there is ADP avalble to be converted to ATP
***e- do NOT flow through the ETC unless ADP is avalble to be converted into ATP

347
Q

Regulation of OP by ADP is…

A

Repiratory/Acceptor control
***The regulation of OP by ADP is called “Reiratory/Acceotor control”

348
Q

What is repiratory control an example of

A

Respiratory control is an example of control using Energy Charge
***Coordiatoon of the compenents of Cell respiration makes regulation possibel

349
Q

Respiratory control

A

Means that the rate of OP is controlled by. theamount of ADP avalable
- More O2 consumed = more ADP = more converted to ATP

350
Q

What is e- transport coupled to

A

e- transport. ioscoupled to phosphorylation –> means that e- won’t flow thourgh EYC unless ADP is also being phophorylated to ATP

351
Q

Increased ADP concetration

A

Increased ADP = increase the rate of OP to meet ATP needs

352
Q

Rate of oxygen consumption in the mitocondria + ADP

A

The rate. ofoxygen consumption in the mitocondria = increases when ADP is added –> THEN Oxygen l;evel retruns to intial value when ADP is converted to ATP

353
Q

ADP levels + TCA

A

The level. ofADP also affects the rate of TCA – decrese ADP = NADH/FADH2 are not used in ETC –> Makes the TCA slow down because there is less NAD+/FAD+ to feed the cycle
***Low ADP = lower TCA rate

Vs.
Increase ADP –>? Increase OP – NADH and FADH2 are reoxided = increases TCA

354
Q

Regulation of ATP synthase

A

Inhibited by Inhibitory factor 1 (IF1)

355
Q

Inhibitory Factor 1

A

Conserved protein that inhibites ATP synthase
***Inhibits the Hydrolitic activity of ATP synthatse
- IF1 = prevents ATP hydrolysis when Oxygen is not avalable to accept the e- in ETC
- Inhibits the wastful hydrolysis of ATP

356
Q

Overexpression of IF1

A

Overexoressed in some cancers –> facilitates the induction of aerobic glycolysis

357
Q

Function of IF1

A

Inhibits the hydrolitic activoty of F0F1 in ATP synthatse
- Tissues deprived of O2 = have no O2 to accept in ETC = can’t geenrtate a PMF –> leads the ATP to be hydrolyszed by synthatse – ROLE of IF1 = to preveny the watsful hydrolysis of ATP by inhibiting the hydrolysis activity of sythase

358
Q

Result of regulated uncoupling

A

Uncoupling of ETC and ATP synthesis –> Leads to heat

359
Q

NOn-shivering Theromogensis

A

Occurs when the ETC is uncoupled from ATP synetshis –> Generates heat

360
Q

Uncoupliing protein 1 (UCP1)

A

facilitates the uncoupling of ETC and ATP synthesis in a regulated fashion
**It is an Integral prtein in the inner mitocondrial memebnrane
**Aka “Thermogenin”
- It is. adimer that resembles ATP/ADP translocase
- It trasnports H+ from the intermmebrane soace to the matrix using Fatty acids
- Genertaes heat by short circuting the mitocondiral proton natter – the energy of the H+ gradient is normally captured as ATP = NOW releases as heat as the H+ flows through UCP1 into the mitocondrial matrix

361
Q

Where does non-shivering thermogenisis occur

A

In Brown Adipose Tissue (BAT) – adult humans have non-shivering thermogensis in BAT

362
Q

Where does uncoupling occur

A

In BAT

363
Q

BAT

A

Rich in mitochondria + has uncoupling occuring there
- Rich in mitocondira because it needs ATP –> The inner mitocondrial memebrane has large amounts. ofUP1
- Amount of BAT decreases as we age
***BAT = specialized tissue for the process. ofnon shivering thermogenisis

364
Q

Affect of Obesity on BAT

A

Obesity leads to decrease in BAT

365
Q

UCP2 and UCP3

A

Also play a role in energy homeostatis + may be important in regulation of body weight

366
Q

Kid fatty tissue vs. Adult fatty tissue

A

Kids have different fatty tissue than adults –> adult fat smells bad

367
Q

When do you see more BAT

A

After someone is put in cold environment

368
Q

Use of uncoupling reactions

A

Uncoupling reactions are a means to maintain body temperature – espcially in hibernating animals + in some new born animals + in many adult animals (escoailly those adpated to the cold)

369
Q

Snuck Cabbage

A

Usues an analagou uncoupking mechanism to heat its floral spikes in early spring = increase sthe amount of evaportaion of the Odorferous molecule yhat attracts insects to fertilize its flowes

370
Q

Uncoupling in animlas

A

In animlas uncoupling = in BAT

371
Q

White Adipose Tissue

A

Plays. norole in thermogensis BUT serves as energy sourcve + an endocrine gland

372
Q

UCP1 Activation

A

The H+ pathway is activated when the core body temperature is begining to decrease
- Alpha adrehenic hormones stimulate the release. fofree Fatty acids from Triglycerides storyed in cytoplasmic lipis
- The long chain FA bind to the cystolic face of UCP1 + Coo- binds to H+ –> Binding causing tsructural change in UCP1 – so the H+ and the COO- now face teh H+ poor envirnment of the matrix = H+ are released –> release of H+ resets the UCP1 to its intial state

373
Q

Where do humans have BAT

A

Mostley in theor neck and vchest – adult females have more
***BAT is activated by the cold

374
Q

how is BAT activated?

A

Activated by the cold

375
Q

Non-shiveroing thermogenisis in Pigs

A

Ancestors of pigs are believed to have lost UCP-1 20 MYO when they inhabited tropical and subtropical envirnments where they couold survive withoiut the non-shivering thermogensis –> As the range of pigs expanded the kack of UCP1 became a liability
- Pigs = unsual mammales in that they have large litters and are hoofed anima=las that build nests for birth
- Charchaterics= appear to be an adaptation to the absence. ofUCP1 –> pigs need to rely on oyher methods as a means of themroegensis (nsting + large litter + shivering)

376
Q

UCP2 and 3 (textbook)

A

UCP2 – 50% identical to UCP1
- Found in many tissues
UCP3 – 57% ideitical to UCPO 1 and 25% isdetical to UCP2 –> Found in skeletal Muscle and BAT

377
Q

Family of uncoupling proteins

A

All play a role in energy homeostatsis

378
Q

Genes for UPC2/3

A

Genes for UCP2/3 –> map to regions of the human and mouse chromosome that have been linked to obesity –> Supports the notion that they function. asa means of regulating body weight

379
Q

How do posons effct OP

A

Can inihibit by:
1. Inihibition of the ETC by preventing the generation of PMF
2. Inihibition of ATP synthase
3. Uncoupling of ETC and ATP synthsis
4. Inhibition of ATP export

380
Q

2,4 Dinitrophenol

A

Inhibits Oxidative Phophorylation – does so by uncoupling ETC from ATP syntehsis
- Works by carrying protons across the inner mitocodniral membrane down theor concentration gradient and bypassing ATP synthase

381
Q

Sites of ETC inhibitors

A

NADH-Q OcdRed –> QH2 – Blocked by Rotenone + Amytal

Q-cyt C OxdRed –> Cty C – Blocked by Antimycon A

Cyt C Oxidase –> O2 – blocked by CN- + N3- + CO

382
Q

Where do you put CO detector

A

ON the floor – if it is at high level you would due before it beeps

383
Q

Retanone + Amytal

A

Inhibits ETC – block e- transfer
**Amytal = setative
**Retanone = fish + insect poison
- NADH Q OXDRed inhibition = prevents the utilization of NADH as a substrate
- In the presence of Retonones + Amytals –> e- flow form Oxdation of Succinate is impared because e- enter at QH2

384
Q

Retonones + parkinsons

A

Retinoes may play a role in the development of Parkinsons

385
Q

Antimycin A

A

Interferes with e- flow from Cytochrom Bh

386
Q

CN- + N3- Vs. CO

A

CN- + N3- –> react with Ferric acid form of heme a3

CO –> inhibits ferrous forms

**All inhibit ETC = inhibit ATP synthase
**e- flow in Cyt C can be blocked

387
Q

Inhibition of ATP synthase

A

Oligomycon (antifungal AB) + DCC – prevent influx of H+ through ATP synthase by bindinh to COO- group pf C ring
- B;ock on of only one C SU by DCC is suffeicent to inhibit the roation of entire C ring = inhibits ATP synthase
***If activley respiring miticindria are expsoded to inhibitor of ATP synthatse –> ETC stops – shows that the ETC. andATP synthase are coupled

388
Q

Uncoupling of ETC and ATP synthesis

A

Uncoupling usinhg DNP + other acidic Aromatic coumpunds
- Uncouplers = carry H+ across the membrane down the gradinet
- In the presence of uncpuplers e- trasmpry is mormal but ATP is not formed by ATP synthaste because the PMF is continually diseemsinated
***Loss of resporatory control increases O2 consumtion to oxidation of NADH
- Ingestion of uncouplers = increases metabolic fuels but NO energy is made into ATP– RATHER the energy is released as heat
- DNP = in herbacides + fungociedes

389
Q

DNP use

A

Some people take DNP as weight loss uspplement + Russian soldiers were gievn DNP to keep warm in the winter

390
Q

Drugs + uncouplers

A

Drugs are bieng made to function. asmild uncouplers –> to be used for obesity + related pathologeniss

Example – Xanthomoal = prenylated CVhalcone –> shows promise
- Works by scavenging free radicals
- Is used for treatment of cancer
- Found. inBeer

391
Q

Inhibition of ATP trasnport

A

ADP-ATP trasnlocase is inhibited by decrease. inconcentration of atfraftloside + Bonkrekic Acid
***WHen inhibited –> Oxidative phosphorylation stops – shows that ATP/ADP translocase is essntial. formanintingenough ADP to accept energy accoasited with the PMF

392
Q

Atraftolosde

A

Binds to translocase when its nucleotide site faces the intermemebrane soace = inhibits ADP/ATP trasnlocase

393
Q

Bankrekic Acid

A

Binds to ADP/ATP trasnlocase when the nucleotode site faces the moitocndrial matrix – inhibits ATP exort/inhibits ATP/ADP translocase

394
Q

MOst common cause of mitocondrial disease

A

Disruption of complex I

395
Q

Defects in compoenet of ETC

A
  1. reduce ATP synthsis
  2. Increase the amount of reactive oxygen species formed = increases mitocndrial damage
396
Q

Number of diseases that are asociated with mitocondrial mutations

A

Increasing number as we grow our understanding of biuochemistry + genes
- Prevelance. =10-15 per 100,000 people

397
Q

First mitocoindrial disease to be understood

A

Leber Hei Optic Neropathy – (LHON) –> Form of blindness that strikes midline. asa result of mutation in Complex 1

398
Q

LHON

A

Form of blindness that is a result of mutation in complex 1 –> mutaion inpairs NADH utilization + some block of e- transfer to Q

399
Q

Egg Mittocondrial DNA vs. Sperm DNA

A

Egg – has Mitocdnrial DNA BUT the sperm has much less
- because materninity inherited mitodndial disease – is large numbers + not all mutocndria may be affects

400
Q

What Process is the mitocondria also associate with

A

Apoptosis – Mitocondria can control the process of apoptosis
- Mitocondria act as control centers regulating process

401
Q

Apoptosis

A

Progrgrammed cell death –> results in selective cell death

402
Q

Use of programmed cell death

A

Critical for tissue remodneling during development + for the removal of damaged cells

403
Q

What occurs during apoptosis

A

Outter mitocondrial memebrane because highly permable = “mitocondria outter memebrane permabilization”

404
Q

What activates the death pathway

A

Cytochrom C leaving the mitocondria – one of the most potent activators. =Cty C
- Cyc C = exits the mitocondrial and interacts with APAF1 –> leade to formation of Apsome – Aposome recruits Casphase 9 = protease –> Activased the cascdae of other casphases –: Eachh caspahse tyoe destroys a target

405
Q

What makes the Outter memebrane highly permable durong apoptosis

A

Bcl family of proteins (initailly discivered bevcaise of role in cancer)

406
Q

DNAase

A

Frees CAD to cleave DNA –> used in apotpsos

407
Q

Nickname for apoptosis

A

Cascade of proteolitoc enzymes = “detah by 1000 cuts”

408
Q

LHON (overall)

A

Form. ofvision loss due. todeath in optic nuerons

409
Q

hat neuron is affected in LHON

A

Nerve 2 = optic nerve –> it is defected = blind

410
Q

Mutation in LHON

A

Due to mutations in mitocondrial genes that encode Complex 1
Exampple mutaion – Pro –> Lys (lys = positive AA)

411
Q

LHON mice

A

A mouse with mutations was made to allow the phenotype to be sutidies
- Mitocondria in the optic nerve of these mice were dound yo. bean abnormal shape + in higher numbver –> matches what is observed in LHON pateints
- Mitcondria from LHON mice were isolated. ad studies to determine where the LHON phenotuoes results from a decrease in ATP proudctiom or increase in ROS damage

412
Q

Curing LHON

A

It s a metabolism disorder = no cure

413
Q

Cures for mitocindria disoerders

A

NO cures

BIOL304 (4 decks)

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