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BB10004 > β-oxidation of fatty acids > Flashcards

β-oxidation of fatty acids Flashcards

1
Q

What experiment did Knoop carry out

A
  1. Published 1904- before radio labelling
  2. Fed fatty acids labelled at the methyl end with phenyl group to dogs (phenyl group blocks degradation)
  3. Criticism that phenyl group could be interfering- big artefact
  4. Some fatty acids had odd number of carbons eg Phenyl propionate
  5. Some had even numbers of carbons eg Phenyl butyrate
  6. Examined the excretion products in the urine
    7)
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2
Q

What was the result of Knoops experiment

A
  1. Discovered with odd chain lengths- benzoate or benzoate derivative in urine
  2. Even chains- phenyl acetate in urine
  3. Where there is a β carbon it can be oxidised and then the bond between the α and β carbons can be broken
  4. Needs to be 2 ch2 groups taken away together
  5. If enzyme which removes carbon attacks alpha carbon- can do one at a time- benzoate
  6. If enzymes recognise beta carbon then that explains how two carbons removed at a time
  7. Beta carbon is c3 from carboxyl end in fatty acid
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3
Q

What are the 3 stages of beta- oxidation

A
  1. Activation
  2. Transport
  3. Oxidation
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4
Q

Where does activation occur

A
  1. In the cytosol on the outer surface of the mitochondrial membrane
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5
Q

What is the enzyme involved in activation

A
  1. Acyl-CoA synthetase (thiokinases)
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6
Q

What is the equation for activation

A
  1. RCOO- + CoA + ATP ACYL-CoA +AMP + PPi

2. RCOO- = fatty acid

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7
Q

What is the purpose of the activation step

A
  1. Ensures subsequent reactions can occur as negative delta G
  2. Combined hydrolysis of ATP and combination of coA to acyl group- delta G almost 0 so is freely reversible
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8
Q

How is the reaction diven

A
  1. Being reversible is not helpful if want to drive reaction to right
  2. Reaction is driven to the right by removal of a product 3. Pyrophosphatase- breaks pyrophosphate into two phosphates- is ubiquitous found all over mitochondria
  3. Cleave different phosphodiester bond to form pyrophosphate and adenosine monophosphate
  4. Hydrolysing pyrophosphate to two inorganic phosphates- removes components from right of reaction and no substrate to go back the other way
  5. RCOO- + CoA + ATP + H2O –> Acyl-CoA + AMP + 2Pi + 2H+
  6. Because got to AMP would need to be phosphorylated again twice- used up two ATPs
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9
Q

Why does transportation need to occur

A
  1. Fatty acid is in cytosol In surface of mitochondria

2. Acyl groups need to enter mitochondrion to be metabolised (oxidised)

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10
Q

Describe how fatty acyl-CoA is transported across the membrane

A
  1. Acyl group attached to coenzyme A outside mitochondria
  2. Long-chain fatty acyl-CoA cannot directly cross the inner mitochondrial membrane
  3. Its acyl portion is first transferred to carnitine
  4. CoA on outside stays outside
  5. Utilises carnitine as intermediate to carry acyl group through facilitated diffusion through a pore in the inner mitochondrial membrane
  6. Acyl CoA can easily go through outer- inner is problem
  7. Acyl carnitine goes in
  8. Then acyl group is transferred back to CoA releasing carnitine
  9. Carnitine returns to the cytosol
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11
Q

Who discovered that fatty acids are oxidised in the mitochondrion

A
  1. Lehninger and Kennedy
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12
Q

Describe the structure of carnitine

A
  1. Has a hydroxyl group
  2. Acyl group becomes attached in place of hydroxyl and releases Coenzyme A
  3. Ester linkage rather than thioester linkage
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13
Q

Where does beta-oxidation occur

A
  1. In the mitochondrial matrix
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14
Q

Outline the first step of beta-oxidation

A
  1. Formation of a trans-alpha,beta double bond through dehydrogenation by acyl-CoA dehydrogenase
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15
Q

Outline the second step of beta-oxidation

A
  1. Hydration of the double bond by enoyl-CoA hydratase to form a 3-L-hydroxyacyl-CoA
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16
Q

Outline the third step of beta-oxidation

A
  1. NAD+ dependent dehydrogenation of this Beta-hydroxy-acyl-CoA by 3-L-hydroxyacyl-CoA dehydrogenase to form the corresponding beta-ketoacyl-CoA
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17
Q

Outline the fourth step of beta-oxidation

A
  1. Calpha-Cbeta cleavage in a thiolysis reaction with CoA as catalysed by Beta-ketoacyl-CoA thiolase (just thiolase)
  2. forms acetyl CoA and a new acyl-CoA containing two less C atoms than the original
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18
Q

When do the fourth steps of beta-oxidation repeat

A
  1. If 4 or more carbons long undergo 4 reactions again
  2. Keeps repeating
  3. E.g. Seven cycles to reduce a 16 carbon fatty acid into eight 2 carbon units
19
Q

Describe the first step of beta-oxidation

A
  1. Reduces number of hydrogens present- dehydrogenation reactions
  2. 3rd carbon from carboxyl end- beta carbon-is attacked
  3. Why Knoop saw no oxidation with phenyl groups- if beta carbon is carbon in phenyl group it can’t be oxidised
  4. Double bond forms between beta and alpha carbon
  5. FAD receives 2 hydrogens
  6. Produces a trans-delta2-Enoyl-CoA
  7. Oxidation
20
Q

Describe the second step of beta-oxidation

A
  1. Enoyl-CoA oxidised further by water
  2. Enzyme- enoyl-CoA hydratase
  3. Double bond is attacked and broken down
  4. Hydroxyl group attaches to beta carbon
  5. Alpha carbon regains a hydrogen
  6. Forms beta-3-hydroxy-acyl-CoA
  7. Hydration
21
Q

Describe the third step of beta-oxidation

A
  1. Removal of 2 hydrogens
  2. Carrier- NAD
  3. Start with hydroxy acyl Co-A
  4. Enzyme hydroxy acyl Co-A dehydrogenase
  5. Hydrogens removed from hydroxyl group and beta carbon
  6. Forms a ketone group- Beta-ketoacyl-CoA
  7. Oxidation
22
Q

Describe the fourth step of beta-oxidation

A
  1. Enzyme- acyl-CoA-acetyltransferase (thiolase)
  2. CH2CO group is removed and forms acetyl-CoA
  3. The C=O of the remaining molecule reattaches to CoA forming Acetyl-CoA -Most will go into citric acid cycle
  4. The acyl-CoA now has 2 less carbons
  5. These 4 steps are repeated each time removing 2 carbons
23
Q

What is the overall equation for beta oxidation of a fatty acid and give an example using palmitoyl-CoA

A
  1. Cn-ACYL-CoA + FAD + NAD+ + H2O + CoA –> Cn-2-ACYL-CoA + FADH2 + NADH + H+ + ACETYL-CoA
  2. E.g. Palmitoyl-CoA + 7 FAD + 7 NAD+ + 7 H2O + 7 CoA –> 8 acetyl-CoA + 7 FADH2 + 7 NADH + 7H+
  3. 7 repeats of 4 step process
24
Q

What happens to the acetyl-CoA produced

A
  1. Enters the TCA cycle
  2. Made into ketone bodies
  3. Most goes into the TCA cycle unless there is a shortage of carbohydrate/a lot of fatty acid metabolism
25
Q

What is the overall equation for the citric acid cycle

A
  1. Acetyl-CoA + 3 NAD+ + FAD + GDP + Pi + 2H2O ->CO2 + 3 NADH + 3H+ + FADH2 + GTP + CoA
26
Q

How much NADH, FADH2 and GTP molecules are formed from the acetyl-CoA produced from oxidation of palmitate in TCA

A
  1. As there are eight acetyl-CoA from palmitate the total production in TCA
  2. 8 x 3 = 24 NADH + H+
  3. 8 x 1 = 8 FADH2
  4. 8 x 1 = 8 GTP
27
Q

How much NADH, FADH2 and GTP is produced from the beta oxidation of palmitate

A
  1. The steps of β–oxidation produce some FADH2 and NADH + H+
  2. For palmitate that is:
  3. 7 FADH2
  4. 7 NADH + H+
  5. No GTP
28
Q

What is the total production of NADH, FADH2 and GTP from the beta oxidation of palmitate including TCA

A
  1. 24 + 7 = 31 NADH + H+
  2. 8 + 7 = 15 FADH2
  3. 8 = 8 GTP
29
Q

What is the relation between GTP and ATP

A
  1. GTP + ADP–>ATP + GDP

2. So 8 GTP make 8 ATP

30
Q

How much ATP does NADH + H+ and FADH2 produce in oxidative phosphorylation

A
  1. NADH + H+ - theoretical- 3.0 but measured 2.5
  2. FADH2 - theoretical- 2.0 but measured 1.5
  3. Either can calculate theoretical amount- more comparable but may not be strictly accurate- mainly stick with theoretical amount
31
Q

How much ATP is generated in the Beta-oxidation of palmitate including the TCA

A
  1. 31 NADH+H+ * 3 = 93 ATP [77.5]
  2. 15 FADH2 * 2= 30 ATP [22.5]
  3. 8GTP = 8 ATP
  4. Overall = 131 ATP [108 ATP]
  5. BUT- this is just from palmitate-CoA need to remember ATP used to convert palmitate to palmitate CoA
  6. Used 1 atp but took 2 phosphates from it = 2 ATP
  7. So OVERALL = 129 ATP [106ATP]
32
Q

How much is the energy captured per mole of ATP

A
  1. Energy captured is 129 times the Free energy of hydrolysis of one phosphate from ATP
  2. 129 x -31kJ/mole = -3999kJ/mole
33
Q

What is the efficiency of beta oxidation of palmitate

A
  1. Standard Free energy of oxidation of palmitate is -9790kJ/mole
  2. Calculated by burning it in calorimeter
  3. Proportion of energy captured = -3999 / -9790= ~40%
34
Q

What is the yield of ATP per carbons oxidised to CO2

A
  1. No. of ATP/ No. of carbons = 129 / 16 = ~8.2
  2. Equivalent figure for glucose is ~6.3
  3. Fats can generate more atp per carbon than carbohydrates
35
Q

Describe storage of energy in fats compared to carbohydrates

A
  1. Fats aren’t stored with water- less volume taken up than with carbohydrates
36
Q

Describe need for oxaloacetate

A
  1. Oxaloacetate is needed for entry of acetyl-CoA into the TCA cycle
  2. Not always present in large enough quantities e.g. during fasting
  3. TCA not 100% efficient- not all molecules come back as oxaloacetate
  4. Need anaplerotic reactions- regenerate or reproduce oxaloacetate so can continue around
37
Q

What is the ketotic state

A
  1. Ketotic state- some acetyl CoA can’t go into TCA cycle
  2. So have to form ketone bodies
  3. When not enough carbohydrate
38
Q

What happens when Acetyl-CoA cannot enter TCA cycle

A
  1. When it cannot enter the TCA cycle: Acetyl-CoA –>acetoacetate + D-3-hydroxybutyrate
  2. Acetoacetate + D-3-hydroxybutyrate- both ketone bodies
39
Q

Where does the formation of ketone bodies mainly occur

A
  1. Mostly occurs in liver as undergoes gluconeogenesis
  2. Oxaloacetate is being withdrawn in those cells for synthesis of glucose- gluconeogenesis
  3. Key enzymes found in liver
40
Q

What are the properties of ketone bodies

A
  1. energy rich
  2. Water soluble – so easily transported in the blood- unlike fats
  3. Heart and renal cortex are major users of ketone bodies- use them as preferred fuel
41
Q

How are ketone bodies formed

A
  1. Reaction is reverse of last step of beta oxidation
  2. 2 acetyl-CoA react with thiolase producing acetoacetyl-CoA
  3. In mitochondria
  4. Reforms acetoacetyl-CoA or never forms acetyl-CoA from acetoacetyl-CoA in beta oxidation
  5. SHORTAGE of Co-A also keeps it as acetoacetyl CoA
42
Q

How is the build-up of acetoacetyl-CoA prevented

A
  1. HMG-CoA synthase takes another acetyl-CoA and combines with acetoacetyl-CoA to form hydroxy-methylglutaryl-CoA
  2. HMG-CoA also used to synthesis cholesterol- normal function
  3. But liver also has HMG-CoA lyase which removes a acetyl CoA forming acetoacetate
43
Q

What happens to the acetoacetate

A
  1. Can diffuse through mitochondrial membrane- water soluble
  2. Can be reduced by H+ +NADH- Concentration gradient to form beta-hydroxybutyrate by beta-hydroxybutyrate dehydrogenase
  3. Acetoacetate decarboxylase- take carboxyl carbon (CO2) from acetoacetate to give acetone
44
Q

How are ketone bodies used

A
  1. Beta-hydroxybutyrate can be used to produce acetoacetate- reverse of other reaction
  2. Acetoacetate can be turned to acetoacetyl-CoA using Succinyl-CoA to succinate
  3. Formation of Succinyl-CoA requires energy input
  4. Acetoacetyl-CoA converted to 2-acetyl-CoA by thiolase these enter TCA cycle to give more ATP
  5. Utilisation of ketone bodies reverse of formation

BB10004 (14 decks)

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