13 Fatty Acid Catabolism 2014-2015

7/24/2019 13 Fatty Acid Catabolism 2014-2015

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Fatty acid catabolism

- Fatty acid is an excellent energy source- Fatty acids are packaged as triglycerides (= triacylglycerols)

CH3(CH2)14COOH + 23O2 16CO2 + 16H2O

Example: Palmitic acid C16 saturated fatty acid

G' = -2340 kcal/mol

(This is coupled to formation of 106 ATPs)

- Fatty acid oxidation releases a tremendous amount of energy

- Fatty acid oxidation generate reduced electron carriers and acetyl-CoAs

- Fatty acids provide 80% of the energetic needs in heart and liver

A triacylglycerol

Glycerolbackbone

acyl chain


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Digestion of triacylglycerol

Fatty acids

Lipase


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Conversion of glycerol to glycolytic metabolites:

(DHAP)


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Fatty acid activation

- The acyl chain of fatty acid must be joined to co-enzyme A to becomesubstrates of the -oxidation enzymes in mitochondria

- Enzyme: acyl-CoA synthetase


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Transport of fatty acyl CoA into Mitochondria


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-Oxidation of saturated fatty acids

= acetyl CoA


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Palmitic acid+ CoA-SH (Coenzyme A)

-Oxidation of palmitic acid (C16:0)

12

12

1

2

3

QH2 Complex III

Complex I


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- Once the -ketone backbone is formed, it is possible for CoA-SH to attackthe carbonyl carbon, releasing acetyl-CoA:

Next -oxidation cycle

4

12

34


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Overall changes:

C16Fatty acid 7 -oxidation cycles 8 Acetyl-CoA

- The product of each cycle of reactions become a substrate for the next cycle- A spiral pathway- Final cycle of -oxidation:

CH3(CH2)2CO-S-CoA + CoA-SH 2 acetyl-CoA

C 16


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ATP Accounting for completion oxidation of C16:0

- For each cycle of -oxidation: 1 FADH2 (1.5 ATP) + 1 NADH (2.5 ATP)= 4 ATPs

- For palmitic acid (C16 saturated), 7 cycles of -oxidation are requiredto produce 8 acetyl-CoA

- Number of ATPs derived from -oxidation: 7 x 4 = 28

- For each acetyl-CoA entering the citrate acid cycle, 10 ATPs aregenerated (1 GTP, 1 FADH2, 3 NADH)

- Number of ATPs derived from oxidation of acetyl-CoA: 8 x 10 = 80

- Total number of ATPs from complete oxidation of palmitic acid: 108


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CH3(CH2)14COOH + 23O2 16CO2 + 16H2O

Example: Palmitic acid C16 saturated fatty acid

(This is coupled to formation of 106ATPs) Why only 106 ATPs?

- Fatty acid oxidation releases a tremendous amount of energy

-ATP-consuming step:

Palmitic acid + ATP + CoA-SH Acyl-CoA + AMP + 2Pi

- Free energies of hydrolysis:G'

ATP + H2O AMP + PPi -45.6

PPi + H2O 2Pi -19.2

_________________________________

ATP + 2H2

O AMP + 2Pi -64.8

vs

ATP + H2O ADP + Pi -32.8

- Thus, energetically, the hydrolysis of 1 ATP to AMP is equivalent to the

hydrolysis of 2 ATP to 2 ADP


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ATP generation glucose vs fatty acids

If we start from glucose:

- Glycolysis to 2 pyruvate yields:2 ATP2 NADH

- Conversion of 2 pyruvate to 2 acetyl-CoA:

2 NADH

- Oxidation of 2 acetyl-CoA in the TCA cycle:2 x 10 = 20 ATP

Net yield = __________ ATP for complete oxidation of glucose to CO2

[2 X 2.5 = 5 ATP]

[2 X 2.5 = 5 ATP]

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96 ATP for 3 glucose (18 carbons)


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-For a C18 saturated fatty acid (18:0):

8 cycles of -oxidation are required to produce 9acetyl-CoA

-For each series of -oxidation: 1 FADH2(1.5 ATP); 1 NADH (2.5ATP)

-Number of ATPs derived from -oxidation: 8x 4 = 32

-For each acetyl-CoA entering the citrate acid cycle, 10 ATPs aregenerated (1 GTP, 1 FADH2, 3 NADH)

-Number of ATPs derived from oxidation of acetyl-CoA: 9x 10 = 90

-Net profit of ATPs from complete oxidation = 32 + 90 2 = 120

vs. 96 ATP for 3 glucose (18 carbons)

O id i f d f id


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Oxidation of unsaturated fatty acids

(substrate for enoyl-CoAhydratase)

23

4

- 2 additional enzymes are required: enoyl-CoA isomerase, 2, 4-dienoyl-CoA reductase

(1) Oxidation of monounsaturated fatty acid:

Acetyl-CoA

oxidation(last 3 steps)

oxidation(4 full cycles)

5 Acetyl-CoA

1

2

3

4

(cis-3 to trans- 2 conversion)

O id ti f t t d f tt id


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Oxidation of unsaturated fatty acids

(substrate for enoyl-CoA hydratase)

2

34

- 2 additional enzymes are required: enoyl-CoA isomerase, 2, 4-dienoyl-CoA reductase

Acetyl-CoA


oxidation(4 full cycles)

5 Acetyl-CoA

1

2

3

4

TCA cycle 3 x 10 = 30 ATPs

3 x 4 = 12 ATPs

4 1.5 = 2.5 ATPs

Step 1 is skipped(no FADH2 formation)

4 x 4 = 16 ATPs


TCA cycle 5 x 10 = 50 ATPsNet ATP yield = 120.5 -2 (formation of acyl-CoA) = 118.5

(1) Oxidation of monounsaturated fatty acid:


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(2) Oxidation of polyunsaturated fatty acids:

C

O

SCoA

10

4

cis-4

(substrate for enoyl-CoA hydratase)2

3

4 Acetyl-CoA


4


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C

O

SCoA

10

4

cis-4

First step of -oxidation cycle

(acyl-CoA dehydrogenase)

FAD

FADH2


1

2

3

4Acetyl-CoA


More oxidation cycles (full cycles)


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(2) Oxidation of polyunsaturated fatty acids:

C

O

SCoA

10

4

cis-4

(substrate for enoyl-CoA hydratase)2

3

4 Acetyl-CoA



3 x 4 = 12 ATPs

cis-3 to trans- 2 conversion

4 1.5 = 2.5 ATPs

TCA cycle 1 x 10 = 10 ATPsStep 1 is skipped(no FADH2 formation)

4


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C

O

SCoA

10

4

cis-4

First step of -oxidation cycle

(acyl-CoA dehydrogenase)

FAD

FADH2


1

2

3

4Acetyl-CoA


[3 -oxidation cycles + releases of 4 acetyl CoAs]More oxidation cycles (full cycles)

1.5 ATP

-2.5 ATP [equivalent to 1 NADH]

trans-3 to trans- 2 conversion

4 1.5 = 2.5 ATPs

TCA cycle 1 x 10 = 10 ATPsStep 1 is skipped(no FADH

2formation)

O id i f dd f id


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Oxidation of odd fatty acids

- Fatty acids with odd numbers of carbons are rare in mammals, but manyplants and bacteria do contain these lipids

- Substrate of the last -oxidation is a 5-C acyl-CoA, giving rise to oneacetyl-CoA and one proprionyl-CoA (3-C unit)


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How can succinyl-CoA be completely oxidized for ATP formation?

F ti f k t b di


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Formation of ketone bodies- During starvation, TCA cycle intermediates in liver are depleted by

gluconeogenesis.- Acetyl-CoA released from fatty acid oxidation will be in excess- Ketone bodies are then formed


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Ketone bodies: acetoacetate, acetone, -hydroxybutyrate


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Ketone body formation and export from the liver:

starvation


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Utilization of ketone bodies

- In non-hepatic tissues (brain, heart, kidney, skeletal muscle)

- Under starvation conditions

- Depletion of glucose supply

absencein liver

O id ti d l l t l i l t d


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-Oxidation and glyoxylate cycle in plant seeds- In glyoxysomes organelles in developing seeds (fat reserves)- Plant mitochondria do not contain -oxidation pathway enzymes.- Acetyl-CoA produced by -oxidation enters the glyoxylate cycle to makesuccinate.

- Succinate is exported to mitochondria for use as a TCA cycle intermediate or agluconeogenesis precursor.


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The glyoxylate cycle

- Most enzymes are same as thoseof the citric acid cycle

- Two unique enzymes

- One unique metabolite- Not in animals or humans


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Conversion of lipids tocarbohydrates in plant seeds

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13 Fatty Acid Catabolism 2014-2015