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MET1 > The Tricarboxylic Acid Cycle > Flashcards

The Tricarboxylic Acid Cycle Flashcards

1
Q

What is Krebs cycle? Where does it occur?

A
  • Continuation of glycolysis to release further ATP from oxidation of carbon to produce carbon dioxide and convert ADP to ATP in the process.
  • Occurs only in the mitochondria.
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2
Q

What is the starting point of Krebs?

A
  • Starting point is Acetyl Co-A (the product of pyruvate metabolism from glycolysis) and oxaloacetate.
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3
Q

What is Krebs cycle dependent on?

A
  • Completely dependent on the presence of oxygen.
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4
Q

What is Krebs cycle central to the metabolism of?

A
  • Central to the metabolism of glucose, fatty acids and amino acids since different substrates of each can feed into the TCA cycle.
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5
Q

What is the most important step in Krebs and why? What catalyses this reaction? What does it result in?

A
  • The conversion of pyruvate to acetyl co-A is the most important step in the Kreb’s cycle since once acetyl co-A is produced, the following reactions are all irreversible.
  • This reaction is catalysed by the pyruvate dehydrogenase complex (3 enzymes which catalyse 3 reactions in the conversion)
  • Uni-directional reactions (due to loss of CO2) with many intermediates.
  • Also result in reduction of NAD to NADH.
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6
Q

What family are all of the enzymes in the formation of Acetyl Co-A a member of?

A
  • All the enzymes and co-enzymes of this reaction are members of the B-vitamin family, including thiamine pyrophosphate (TPP: vit B1) (so very important part of nutrition to keep TCA cycle going).
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7
Q

What is the net equation of the formation of Acetyl Co-A?

A

Pyruvate + CoA + NAD+ -> acetyl CoA + CO2 + NADH

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8
Q

What are the pros and cons of multi-enzyme complexes?

A
  • Multi-enzymes complexes are efficient but means its intermediates cannot be used for anything else
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9
Q

Which enzymes and cofactors are involved in the pyruvate hydrogenase complex reactions?

A
  • Pyruvate dehydrogenase (E1)
  • Dihydrolipoyl transacetylase (E2)
  • Lipoamide
    FAD/FADH2
  • NAD+
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10
Q

In which two ways is pyruvate dehydrogenase (PDH) regulated?

A
  1. De-/ Phosphorylation by kinases and phosphatase enzymes.
    o Kinases inhibit PDH by adding a PO4
    o Phosphatases activate PDH by removing a PO4
  2. Allosterically either on the PDH itself or the kinase/phosphatase that control the PDC (pyruvate dehydrogenase complex)
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11
Q

What substances can inhibit PDH or PDH kinase?

A
  • Inhibition:
    o NADH and Acetyl CoA inhibit pyruvate dehydrogenase
    o Pyruvate and insulin inhibit the PDH kinase thereby keeping PDC active
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12
Q

Which substances can activate PDH kinase/phosphatase?

A 
-	Activation:
o	ATP, acetyl CoA, NADH activate PDH kinase thereby switching pyruvate dehydrogenase off
o	Calcium (muscle) activates the PDH phosphatase thereby switching it on.
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13
Q

How is excessive production of acetyl Co-A prevented?

A
  • Negative Feedback inhibition by the products of the reaction prevents excessive production of acetyl Co-A.
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14
Q

Which hormones affect the PDC?

A

Insulin has a positive effect on phosphatases and a negative effect on kinases
Adrenaline, glucagon (and cAMP?) increase gluconeogenesis

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15
Q

Where does the TCA cycle occur?

A

Mitochondrial matrix

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16
Q

What are the end products of the TCA cycle? What does this mean for the energy in the products?

A
  • The end products of the TCA cycle are:
    o 1 GTP/ATP by substrate level phosphorylation (about 10kcal of energy)
    o 3 molecules of NADH (50kcal of energy per NADH)
    o 1 molecule of FADH (40kcal of energy)
  • So the reduced products of the TCA cycle (NADH and FADH) still have a lot of energy in them which can be converted to ATP. (1 mole glucose = 684kcal)
  • This occurs in the Electron Transport Chain (ETC) where these products are oxidized to release energy.
  • ETC occurs in the inner membrane of the mitochondria.
17
Q

What does one cycle of the TCA cycle produce? What about two? Why is this relevant?

A 
-	One cycle produces:
o	3 NADH
o	1 FADH2
o	1 GTP
-	Two cycles produce
o	6 NADH
o	2 FADH2
o	2 GTP
-	Cycle goes round twice as 2 acetyl CoA are produced from one glucose molecule
18
Q

How are reduced co-enzymes, NADH and FADH , (electron carriers produced during glycolysis, TCA cycle, fatty acid metabolism, etc) used in the electron transport chain?
What does this generate?

A
  • Reduced co-enzymes, NADH and FADH, (electron carriers produced during glycolysis, TCA cycle, fatty acid metabolism, etc) are used to create a proton gradient across the inner membrane of the mitochondria whilst getting oxidised.
  • Electrons from these reduced co-enzymes are transferred down an energy gradient which is exploited to pump protons (H+) outside of the inner membrane, creating a proton gradient between the matrix and the inter membrane space.
  • This proton gradient can then be used to generate ATP.
19
Q

What are the four complexes (enzymes found in the inner membrane of the mitochondria) that make up the ETC?
How do they work to generate ATP?

A
  • Complex 1: Oxidises NADH to NAD+ and transfers its electrons to an electron carrier called ubiquinone (Q)
  • Complex 2: Oxidised FADH to FAD and transfers electrons to Q (the diagram is incorrect!).
  • Complex 3: Transfers electrons from Q to a mobile carrier in the membrane: cytochrome C (C)
  • Complex 4: Transfers electrons from cytochrome C to oxygen to produce water.
  • Complexes 1,3 and 4 can transfer protons from matrix to the intermembrane space, creating proton gradient.
  • ATP is then generated when protons are allowed back in matrix through the ATP synthase enzyme on the membrane.
20
Q

How does oxidative phosphorylation occur in the ETC?

A
  • Proton gradient exists across the membrane
  • Protons flow back to the matrix through ATP synthase
  • This drives phosphorylation of ADP to ATP
  • Oxidative phosphorylation involves membrane –bound enzymes and transmembrane proton gradients
  • (Substrate-level phosphorylation involves soluble enzymes and chemical intermediates)
  • Ultimately, one glucose produces 30 – 32 ATPs
21
Q

What happens when the two reactions of the ETC are uncoupled?

A
  • In some cases, the two reactions can be uncoupled, resulting in a proton gradient that is not used to create ATP.
  • Used in non-shivering thermogenesis in infants.
  • Proton gradient is used to generate heat at the expense of less ATP produced.
  • Uses a specialized protein in the membrane called thermogenin or uncoupling protein (UCP) found in brown adipose tissue.
  • Some antibiotics work by uncoupling the ETC.
  • Ex. Gramicidin, nigericin, oligomycin, valinomycin.
22
Q

How does dinitrophenol (DNP, a chemical used in bombs) work as an uncoupler? How does cyanide work similarly?

A
  • Dinitrophenol (DNP) is a chemical used in bombs, that is also an uncoupler, it disrupts the interaction between the ETC and the proton pump resulting in a proton gradient that does not generate ATP.
  • Also used as a weight-loss drug! Caused lethal reactions in some users.
  • Cyanide is lethal also by blocking the terminal cytochrome and un-coupling the production of ATP.
23
Q

How is the TCA cycle controlled?

A
  • Controlled mostly by end-product inhibition (ATP and NADH) that feedback on two dehydrogenase enzymes in the cycle.
  • These enzymes are activated by calcium in skeletal muscle in response to work (contraction) to generate more ATP.
  • Substrate regulation also occurs since the cycle depends on the availability of oxaloacetate, acetyl Co-A and NAD+.
24
Q

Which organic molecules can be generate by the Krebs Cycle?

A
  • Although many organic molecules feed into the TCA cycle (glucose, fats, proteins), Krebs cycle can also generate other organic molecules such as fatty acids and glucose.
  • The TCA cycle forms a focal point in the network of organic molecules
  • Since many organic compounds feed into the cycle and many also feed out of the cycle.
25
Q

What can happen when electrons are not transported efficiently in the TCA cycle? How can the TCA cycle be affected by hypoxia?

A
  • TCA cycle is very efficient but sometimes electrons are not transported efficiently and result in the formation of reactive oxygen species (ROS), which are high energy molecules that can disrupt molecules and result in damage to lipids, proteins and DNA.
  • Hypoxia is a condition of low oxygen concentration.
  • Hypoxia causes the production of even more ROS since oxygen is not there to mop up electrons and electrons are backed up in the ETC (”overcharging the battery”).
  • Need to take care with reperfusion following ischaemia
  • Cells need to adapt to the lack in oxygen in order to survive with limited damage.
26
Q

How does the cell respond to hypoxia?

A
  • In response to hypoxia the cell:
    1. Limits the amount of ATP needed (since it cannot produce ATP by the ETC)
    2. Improve anaerobic ATP production efficiency (glycolysis, lactate, NAD/NADH etc)
    3. Limit oxidative stress (ROS) to prevent damage to tissues
  • Most of this is achieved by the increased expression of hypoxia –induced factors (HIF) gene and protein.
  • During normal oxygen conditions, HIF1 is broken down
  • During hypoxia, HIF1 is activated and it moves to the nucleus where it acts as a transcription factor, switching on the expression of genes that allow the cell to survive low oxygen conditions (eg. Increases production of glycolytic enzymes, GLUT transporters and pyruvate dehydrogenase kinases)
27
Q

What are the causes of HIF (Hypoxia-Inducible Factor)?

A
  • HIF causes:
    1. Reduction in mitochondria by promoting their degradation (autophagy)
    2. Inhibits the synthesis of new mitochondria by blocking PGC1 activity.
    = reduction in TCA and ETC = less ROS produced
28
Q

How does HIF1 relate to cancer?

A
  • Most tumours live in a low oxygen environment due to the lack of blood supply.
  • HIF1 acts as an oncogene in cancer because it allows them to survive in low oxygen. HIF1 is related to angiogenesis, metastasis and poor prognosis in cancer.
  • Being studied as a target for cancer drug therapy.
29
Q

What is Leigh Syndrome? What are its symptoms and pathology?

A
  • Rare genetic hereditary condition (1-40,000 births; 1-2000 in Quebec
  • and Faroe Islands)
  • Symptoms:
    o Appear usually in first year of life and result in death after 2/3 years
    o Progressive loss of mental abilities and movement
    o Damage to brain, nerves and muscles leads to respiratory death
  • Pathology:
    o Genetic mutations in any of the genes related to the ETC causes loss of oxidative metabolism in the production of ATP, resulting in loss of cell viability and death of cells dependent on ATP, such as brain, nerves and muscles.
30
Q

Summarise the TCA and its relations to biosynthesis and hypoxia.

A
  • The Krebs cycle takes place in mitochondria and needs acetyl CoA and oxaloacetate
  • NADH and FADH2 and GTP are produced
  • NADH and FADH2 donate their electrons to the electron transport chain and ATP is produced via oxidative phosphorylation.
  • The Krebs cycle is controlled by substrate availability and the energy status of the cell.
  • In addition to its role in energy production, the Krebs cycle can also provide intermediates for biosynthesis such as for lipids, amino acids or haem.
  • Krebs cycle and the ETC need oxygen and the cell adapts in hypoxic conditions.
31
Q

Which multienzyme complex is needed to produce acetyl CoA from pyruvate and which vitamin is needed as a cofactor?

A

Pyruvate dehydrogenase. Thiamine (for thiamine pyrophosphate)

32
Q

What is oxidative phosphorylation and how does it differ from substrate level phosphorylation?

A

Oxidative phosphorylation involves membrane –bound enzymes and transmembrane proton gradients whereas substrate-level phosphorylation involves soluble enzymes and chemical intermediates

33
Q

The electron transport chain transfers _________ from one complex to the next, using energy from ___________ to pump ____________ from ___________ to the _____________. The final electron acceptor is __________________. ____________ flow back through ATP synthase to produce ATP from _______ and _______

A

The electron transport chain transfers electron from one complex to the next, using energy from redox reactions to pump protons from the matrix to the intermembrane space. The final electron acceptor is oxygen. Protons flow back through ATP synthase to produce ATP from ADP and inorganic phosphate

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