TCA cycle Flashcards

wk 7

1
Q

How are kinase and phosphatase regulated?

A

Via changes in NADH, acetyl-CoA, pyruvate and Insulin.

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2
Q

How is the pyruvate dehydrogenase complex regulated?

A

Covalent modification using specific kinase and phosphatase

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3
Q

What is covalent modifcation?

A

Where the structure of an enzyme is modified by adding special groups to specific locations. In regulation - the addition of these groups is reversible.

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4
Q

What are the cofactors used in the regulation of pyruvate dehydrogenase

A

Thiamine, Lipoate and FAD+

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5
Q

What are the activator Allosteric regulators of pyruvate Dehydrogenase?

A

F1,6BP

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6
Q

What are the inhibitory Allosteric regulators of pyruvate Dehydrogenase?

A

ACoA

NADH

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7
Q

What are the consequnces of pyruvate Dehydrogenase deficiency?

A
  • Progressive neurodegenerative disease
  • Intermittent ataxia
  • Poor muscle tone
  • Lethargy
  • Seizures
  • Abnormal eye movements
  • Lactate buildup
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8
Q

What are the intermediates of the TCA cycle?

A

Citrate

Isocitrate

A-ketoglutarate

Succinate

Fumarate

Malate

Oxaloacetate

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9
Q

What is the role of anaplerotic reactions

A

replenishes oxaloacetate in the citric acid cycle after been consumed AND maintain adequate levels of ATP to allow for the uninterrupted continuation of cellular respiration.

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10
Q

What are anaplerotic reactions?

A

Chemical reactions that form the intermediates for the TCA cycle.

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11
Q

What is the chemical make-up of Oxaloacetate?

A

an Asparate transaminase

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12
Q

What is the only mitochondrial enzyme capable of ATP production and how?

A

Syccinyl-CoA Synthetase

via substrate level phosphorylation (anaerobic)

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13
Q

What is the role of Syccinyl-CoA Synthetase?

A

conversion of Succinyl CoA –> Succinate

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14
Q

What is Cataplerotic vs anaplerotic

A

C= exit point
A = Entry points

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15
Q

What occurs when there is high ADP?

A

Faster respiration

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16
Q

What occurs when there is low ADP?

A

Slower respiration

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17
Q

How is the rate of respiration controlled?

A

By the amount of ADP

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18
Q

What does electron flow cause?

A

transport of protons from mitochondrial matrix into inner membrane

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19
Q

What does the electron transport chain create?

A

proton concentration gradient

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20
Q

What is chemiosmosis?

A

Process of ATP synthesis using free energy from electrons when they are passed to several carriers

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21
Q

How does the TCA cycle link to glucose oxidation and ATP production?

A

Link reaction connects glycolysis to TCA by creating aCoA

Electron transporters used to generate a proton motive force and generate ATP via chemiosmosis

Oxidative phosphorylation

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22
Q

What are the 5 major exit points of the TCA cycle?

A

Citrate, Ketogluctarate, Succinyl CoA, Malate and OAA

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23
Q

What are the 5 major entry points (anaplerotic reactions)

A

Ketoglutarate, succinyl-CoA, Fumarte, malate and OAA

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24
Q

What is the linking reaction in the TCA cycle?

A

Pyruvate + CoASH + NAD –> CoA + NADH2 + CO2

(occurs twice)

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25
Where does the linking reaction occur?
Mitochondrial matrix
26
How is the linking reaction regulated?
Via Allosteric activity and inhibition
27
What are the components that are allosterically activated involved in linking reaction regulation?
NAD+, ADP, Pyruvate, CoASH and Ca
28
How are active allosteric enzymes activated?
by dephosphorylation
29
What are the allosteric inhibitors involved in regulation of linking reaction?
NADH2, acetyl CoA and ATP
30
How are allosterically inhibited components inhibted?
via phosphorylation
31
What steps in the TCA cycle are regulated?
Citrate Synthase, Aconitase, Isocitrate DH, a-KG DH, Succinate DH and malate DH
32
How is citrate synthase regulated?
allosterically activated by citrate.
33
How is aconite regulated?
inhibited by fluroacetate
34
How is Isocitrate DH regulated?
Allosteric activated: ADP, NAD, CA Allosteric inhibited: ATP, NADH2 and Succinyl CoA
35
How is a-KG DH regulated?
Allosteric activated: ADP, NAD, CA Allosteric inhibited: ATP, NADH2 and Succinyl CoA
36
How is Succinate DH regulated?
Inhibited by malonate (competitive inhibitor)
37
What is the purpose of the ETC?
recycle NADH2 and FADH2 into NAD+ and FAD+
38
What is the site of reactions in the ETC?
transmembrane proteins in the inner mitochondria membrane
39
what are the two entry reactions to the ETC?
1- NADH2 at complex 1 (NADH-Q reductase) (oxidised to NADH+) 2- FADH2 at complex 2 succinate DH) (oxidised to FAD)
40
What are the 4 large protein complexes for ETC?
I = NADH-Q Reductase II- Succinate Dehydrogenase III - Cytochrome C Reductase IV- cytochrome c Oxidase
41
What is the first step in the electron transport chain? (electron movement)
NADH2 oxidised at complex I
42
What is the second step in the electron transport chain? (electron movement)
Complex I transfers electrons to CoQ
43
What is the third step in the electron transport chain? (electron movement)
FADH2 oxidised to FAD+ at complex II
44
What is the fourth step in the electron transport chain? (electron movement)
electrons are transferred from CoQ --> cytochrome c --> complex IV
45
What is the fifth step in the electron transport chain? (electron movement)
O2 reduced at complex IV
46
What are the four steps that allow the ETC to produce ATP?
1. electron flow causes complexes I-IV to pump protons into intermembrane space 2. proton movement creates a proton gradient across the inner mitochondrial membrane 3. protons diffuse down the gradient through an ATP synthase channel 4. ATP synthase catalyses ATP synthesis
46
How many ATPs synthesised per NADH2?
pumps 10 protons = 4 protrons per ATP = 2.5 ATP
46
What is meant by coupling?
the electrochemical gradient couples the rate of ETC with the rate of ATP synthesis
46
How many ATPS synthesised per FADH2?
pumps 6 protons (4 protons per ATP) = 1.5 ATPs
46
What is uncoupling?
ATP synthesises and electron flow is disconnected electron transport no longer regulated by intact chemiosmotic gradient
47
Where do protons come from?
ADP-ATP translocate, H+ pyruvate symporter, shuttles, fatty acid oxidation, NADH2 and FADH@ oxidation and water
47
How does ATP:ADP affect the rate of ETC?
decreased ADP:ATP slows down the rate Increased: speeds it up
48
What are the consequences of uncoupling?
increased ADP:ATP = increased electron flow = O2 consumption increased heat production as energy stored in proton gradient is released. ATP use greater than formation = metabolic acidosis with compensatory respiratory alkalosis
49
50
How does ATP affect ATP synthesis?
Respiratory Rate Determines avaliability of O2
51
What is the effect of dinitrophenol?
dissipates proton gradient by transporting protons across inner mitochondrial membrane via simple diffusion-mediated transport
52
What is the effect of thermogenin?
promotes heat generation (non-shivering thermogenesis)
53
What is thermogenic?
Physiological uncoupler (in brown fat)
54
What is the main (general) action of ETC inhibitors?
Prevent electrons from being passed from 1 carrier to the next
55
What are the ETC inhibitors?
Antimycin Cyanide and carbon monoxide ogliomycin atratyloside rotenone
56
What is the effect of antimycin?
Inhibits the electron transfer from III to Cytochrome C Inhibits NADH2/FADH2 dependent O use inhibits ATP synthase
57
What is the effect of cyanide and carbon monoxide?
prevents the docking of O2 Inhibits complex IV Inhibits ATP synthesis
58
What is the effect of oligomycin?
Inhibits proton passage through ATP synthase --> proton concentration acts as a barrier to the export of more proteins = decreased electron flow
59
What is the effect of atractyloside?
Blocks ADP-ATP transolcase Cytosolic protons accumulation arrest the ETC inhibits O2 Consumption
60
What is the effect of Roteone?
Inhibits electron transfer from I to CoQ Restricts NADH2 oxidation inhibits generation of proton gradient, O2 consumption and ATP synthesis
61
In the TCA cycle, how many ATPS are produced per glucose?
32
62
How do cells produce energy in the absence of oxygen?
Using lactic acid fermentation (glycolysis alone)
63
What happens to the pyruvate in glycloysis in aerobic conditions?
it is converted to acetyl CoA --> enters the TCA --> electrons enter ETC
64
What happens to the pyruvate in glycolysis under anaerobic conditions?
Converted into lactate then enters the Cori cycle
65
What does AMPK mean?
AMP- activated protein kinase - used to regulate cellular metabolism.
66
What is the role of AMPK in regulation?
1. Shuts off anabolic pathways (ATP using) 2. Turns on catabolic pathways (ATP making)
67
What factors activate the regulator: AMPK?
increased ADP:ATP increased AMP:ATP
68
What is the mechanism of action for metformin?
inhibits complex I → decreased NADH2 oxidation → decreases proton-driven ATP synthesis → increases ADP:ATP and increases AMP:ATP → inhibits glucagon-induced cAMP synthesis and activates AMPK
69
What are the actions of metformin in glycolysis?
increased glucose uptake increased glucose transporter translocation increase insulin receptor activity increase insulin-mediate glucose uptake in skeletal muscle stimulates glycolytic enzymes
70
What is the role of gluconeogenesis?
- $\downarrow$ uptake of gluconeogenic substrates (alanine, lactate) - inhibits gluconeogenic enzymes - enhances insulin-mediated suppression of gluconeogenesis - opposes the gluconeogenic action of glucagon
71
What does ETC do to NADH2 and FADH2?
recycles it back to NAD and FAD
72
What happens to the energy in the ETC?
As the electrons are transported along the chain, they lose energy. Some of this energy is conserved by forming a proton gradient in the inner mitochondrial membrane
73
Where does cytochrome carry electrons to?
complex IV
74
What carrier picks up electrons from complexes I and II and where does it take them?
Ubiquinone Q, takes them to Complex III
75
what does dinitrophenol do?
dissipates proton gradient via transport of protons across inner mitochondrial membrane increased CHO and lipid metabolism
76
What are the ETC inhibitors?
Antimycin cyanide and carrbon monoxide oligomycin atractyloside rotenone
77