Download Lec 11: Fatty acid degradation

Lec 11: Fatty acid degradation
Unsaturated & Odd carbon length
Regulations
Reference material
Biochemistry 4th edition, Mathews, Van Holde, Appling, Anthony‐Cahill. Pearson ISBN:978‐0‐13‐800464‐4
Lehninger Principles of Biochemistry 4th edition, David L. Nelson, Michael M. Cox. W. H. Freeman ISBN:978‐0716743392
Lipid metabolism
The topic of this chapter is focused on:
1. How lipids are broken down to
provide energy
2. How energy (organic carbon and
NAD(P)H) is stored in cells as lipids
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β‐oxidation…
β‐oxidation removes two carbons (in the form of acetyl‐CoA) out of a fatty acid at a time. Central
metabolism
= R
• What if fatty acid is unsaturated (recall that natural unsaturated fats are cis‐
configuration)?
• What if fatty acid is not even‐number carbon chain length? If fatty acid is odd
carbon chain length, then propionyl‐CoA (3 carbons) is left. How is propionyl‐CoA
utilized and converted into central metabolism?
Enoyl‐CoA isomerase converts cis‐fat to trans‐fat
General method to metabolize cis‐
unsaturated fatty acids:
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Example: Oleate (a common monounsaturated fatty acid) oxidation
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Poly-unsaturated fatty acids
2,4-dienoyl-CoA reductase is needed for degrading
poly-unsaturated fatty acids
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At the end of β‐oxidation of odd‐numbered fatty acid, propionyl‐CoA is left. (3 carbons)
Last step of β‐oxidation of odd numbered Fatty acid
3 carbon acyl‐CoA cannot undergo another round of β‐oxidation
Pathway for catabolism of propionyl‐CoA:
To metabolize propionyl‐CoA, it is converted into succinyl‐CoA, which enters TCA cycle.
The three enzymes required are:
1. propionyl‐CoA carboxylase
2. methylmalonyl‐CoA epimerase
3. methylmalonyl‐CoA mutase
Here, 3 carbon metabolite becomes 4 carbon. However, there is no redox change.
CO2 is fixed into the molecule by the help of energy from ATP hydrolysis.
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Coenzyme B12 assisted mutase
Exchange of hydrogen with an alkyl group without mixing with the hydrogens in the solvent.
This mutase is different from other mutases we have seen so far. What is the difference? This type of mutase utilizes coenzyme B12 (vitamin B12 or cobalamin). B12 refers to a collection of compounds with difference in the group attached to Co3+. α‐oxidation
α‐oxidation occurs when the β‐carbon is substituted (with methyl group).
βα
This is a common process taking place in peroxisome
where α‐oxidation is used to degrade phytol (part of chlorophyll). 1. Hydroxylase functionalizes α‐carbon to hydroxyl‐
group
2. Lyase cut the C‐C bond between CoA‐thioester and
α‐carbon. Electrons go with the CoA‐thioester, forming formyl‐CoA, which is essentially formate (one step reduced CO2).
3. The resulting aldehyde is oxidized to an acid with an aldehyde dehydrogenase. This acid can
then be activated to acyl‐CoA and degrade with β‐
oxidation until reaching another substituted β‐
carbon…
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ω‐oxidation (omega = the end)
While majority of fatty acid degradation occurs through β‐oxidation in mitochondria, another minor pathway called ω‐oxidation occurs in endoplasmic reticulum.
Steps of this ω‐oxidation pathway:
1. P450 dependent oxidation of ω‐ carbon (no
functional groups) with O2 into hydroxylated
carbon.
2. Then this hydroxyl‐group can be oxidized to
aldehyde
3. Then this aldehyde group can be oxidized to
acid
4. The result of ω‐oxidation is the formation of
di‐carboxylic acid.
Mitochondria vs. peroxisome
Mitochondria is the major site of fatty acid degradation. However very long fatty acids and other less‐common fatty acids are degraded in the peroxisome (like α‐oxidation for phytol)
Key difference:
1. Instead of passing electrons from FADH2 to ETC, electrons are passed to O2, forming H2O2. Since H2O2 is strong oxidizing agent, it is immediately cleaved to O2 and H2O by catalase.
2. Since peroxisome does not contain ETC, ATP
generated is dissipated as heat.
For plants, when seeds are germinating, they will use glyoxysome (same as peroxisome) to break the lipid stored in seeds to acetyl‐CoA.
Acetyl‐CoA can then used glyoxylate pathway to make OAA, which then is converted to pyruvate.
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Ketogenesis and ketone bodies
• Recall that Fatty acid cannot convert to sugars in humans and most
mammals.
• acetyl‐CoA formed in the liver can go to TCA cycle for direct energy
generation, or can be used to make ketone bodies which is then
transported to other tissues for utilization. (acetone is not utilized, it is a
degradation product of acetoacetate)
• Ketone bodies refers to:
• Acetone
• acetoacetate
• 3‐hydroxybutyrate
• Ketone bodies are formed during low food intake and starvation.
• Because sugar level is low, OAA level also becomes low. As OAA level
becomes low, flux to TCA cycle decreases and acetyl‐CoA level increases.
This increase in acetyl‐CoA promotes the generation of ketone bodies.
Ketone bodies generation
Essentially 2 acetyl‐CoA is combined to form acetoacetate. Acetoacetate can then be reduced to 3‐hydroxybutyrate
or decarboxylated to acetone.
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Ketone bodies utilization
After ketone bodies are transferred to other tissues, these tissues can turn them back into acetyl‐CoA
Acetyl‐CoA can then enter TCA cycle for generation of energy.
Coordinated regulation of Fatty acid metabolism
Malonyl‐CoA (the activated form of acetyl‐CoA) is a key repressor for fatty acid degradation (because it inhibits fatty acid transport to mitochondria for degradation).
Malonyl‐CoA is also the building block intermediate for fatty acid biosynthesis..
So think about the relationship between carbohydrates and fats…
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Sugars
FATS
TAG storage
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Breakdown to acetyl‐CoA
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