10 - Fatty Acid oxidation

Question 1

What do fatty acid transporters do? Name one.

Answer 1

Activates and increases solubility (eg. coenzyme A)

Question 2

What are the two stages in the capture of energy from fatty acids?

Answer 2

1. Oxidation to 2-carbon fragments (acetyl-CoA)
2. Oxidation to CO2 (TCA cycle)

Oxidation takes place in the mitochondrial matrix; activated to cross the inner membrane

Question 3

Where are long chain and short chain fatty acid ligases found?

Answer 3

Long chain: outer mitochondrial membrane

Short chain: mitochondrial matrix

Question 4

What do you need for the activation of a fatty acid with ATP to form acyl-CoA and AMP?

Answer 4

You need the hydrolysis of pyrophosphate

Question 5

Gives the broad steps of beta oxidation

Answer 5

1. Transesterification to carnitine, mediated by carnitine acyltransferase I (CATI) occurs in the intermembrane space
2. Acylcarnitine is then transported into the matrix by the acylcarnitine/carnitine transporter in the inner mito membrane (RLS) where the transesterification reaction is reversed by CATII to regenerate fatty acyl-CoA and carnitine after 4 reactions
3. Carnitine is transported back to the intermembrane space
4. There are two different, non-equilibrating pools of CoA: mito matrix CoA is involved in oxidative processes, cytosolic is involved in fatty acid biosynthesis

Coupled to electron transport chain

Enzyme is stereospecific for the trans- isomer and does not act on cis-enoyl-CoA. Important for oxidation of polyunsaturated and monounsaturated fatty acids which are largely cis-.


Question 6

GIve detailed steps of beta oxidation of saturated fatty acids

Answer 6

Overall goal is to break a stable C-C bond by introducing an adjacent carbonyl group, which is a good target for nucleophilic attack

1. Dehydrogenation – to produce a trans- double bond between the alpha- and beta- carbons (C2 and C3) of the fatty acyl-CoA (a trans-2-enoyl-CoA)
   - catalysed by acyl-CoA dehydrogenases (isoenzymes exist specifically for short, medium or long chain fatty acids)
   - uses FADH as prosthetic group; electrons immediately enter the electron transport chain

2. Hydration – to produce beta-hydroxyacyl-CoA
- catalysed by enoyl-CoA hydratase

3. Dehydrogenation – to produce a beta-ketoacyl-CoA
   - electrons lost are donated to NADH dehydrogenase
   - catalysed by beta-hydroxyacyl-CoA dehydrogenase
4. Acyltransfer to CoA – to release acetyl-CoA and CoA ester of original fatty acid minus 2-carbon fragment
   - catalysed by thiolase (acyl-CoA acetyltransferase)

Recall the same type of bond break by succinate dehydrogenase in the TCA cycle

Question 7

How many ATP are yielded from the beta oxidation of palmitoyl-CoA?

Answer 7

129 ATP

2 are expended to generate acyl-CoA

Question 8

Describe beta oxidation of odd numbered carbon saturated fatty acids

Answer 8

Recall the same type of bond break by succinate dehydrogenase in the TCA cycle

Propionyl-CoA enters a distinct pathway prior to entry into the TCA cycle as succinyl-CoA. It is first carboxylated to form D-methylmalonyl-CoA by propionyl-CoA carboxylase (biotin cofactor) and then converted to epimer L-methylmalonyl-CoA by methylmalonyl-CoA epimerase. This then rearranges to succinyl-CoA in reaction catalysed by methylmalonyl- CoA mutase (uses derivative of cobalamin, vitamin B12)

Question 9

Describe the beta oxidation of unsaturated fatty acids

Answer 9

Most of the fatty acids in triacylglycerols and phospholipids are unsaturated at one or more positions and in the cis- conformation

These double bonded acyl groups are not substrates for the 2-enoyl-CoA hydratase (only acts on trans- conformation)

Isomerization by the enzyme enoyl-CoA isomerase changes double bond from cis- to trans-

For polyunsaturated fatty acids an additional enzyme is required to reposition double bonds that are not in the trans-Δ2 position. 2,4- dienoyl-CoA reductase converts the double bond to cis-Δ3 and the action of enoyl-CoA isomerase converts this intermediate to trans- Δ2.The resulting product can then re-enter the normal oxidation pathway.

Question 10

Describe peroxisomal beta oxidation

Answer 10

In peroxisomes the FAD-linked acyl-CoA dehydrogenase transfers electrons to oxygen, rather than the electron transfer system of mitochondria

The product is peroxide, H2O2, which is then degraded by catalase with the generation of heat, but no ATP

This pathway is mostly involved in initial oxidation of very long chain (>20C) FAs

Once oxidized to a length of C4-C6, the acyl-CoA is then released to mitochondria for final oxidation

Question 11

Describe alpha oxidation of fatty acids

Answer 11

Alpha-oxidation is a minor pathway of fatty acid oxidation
Used to degrade the phytanic acid, which contains a methyl group at C3 that prevents beta- oxidation

Alpha-oxidation of phytanic acid generates pristanic acid which can be degraded by beta- oxidation

Pathway is defective in Refsum’s disease where phytanic acid accumulates