|Lecture Notes: 2 February||
Fatty acid metabolism is regulated both hormonally and via feed-back inhibition and feed-forward activation. Thus mobilization of free fatty acids from the adipose tissue results from low insulin levels. The free fatty acids are then transported through the blood to the rest of the body including the liver. In the liver fatty acid oxidation and ketone body synthesis is activated by glucagon. Note that glucagon and insulin levels are opposite: high insulin =low glucagon and vice-versa. So for low insulin will also have high glucagon, thus fatty acids will be released from the adipose and will be converted in the liver into ketone bodies.
The regulation of fatty acid oxidation, fatty acid synthesis and ketone body synthesis in the liver is summarized in the figure:
Note that a LACK of insulin results in a release of fatty acids from adipose.
The Glyoxylate Cycle
As we've seen fats are only used in biosynthesis for lipids in animals. Plants, on the other hand can use fats for biosynthesis of carbohydrates, amino acids, etc. Of course plants don't generally store lots of energy as fat, except in their mobile forms, such as seeds. Seeds then use this fat, which is a dense form of energy storage, to manufacture the carbohydrate and protein needed to sprout. So how do seeds use fat for biosynthesis?
Plants add two new enzyme activities to the set seen in the TCA Cycle to create a new pathway, the Glyoxylate Cycle or Pathway. The stoichiometry of this pathway is:
The pathway can be represented by a simple cycle with two acetyl-CoA's added with succinate as the product, the Glyoxylate Cycle.
In actuality, the pathway is broken up into two parts by being compartmentalised in the mitochodria and a specialized organelle, the Glyoxysome. The two new reactions occur in this organelle:
The acetyl-CoA required for this synthesis is generated in the glyoxysome from fatty acids via a modified -oxidation pathway using NAD+ molecular oxygen (instead of FAD) as oxidants (text Figure 16-22).
Triglycerides are synthesized from DHAP (cytosol) or glycerol-3-P (mitosol) and fatty acyl CoA (activated fatty acid) via the pathway outlined in Figure 21-17 on p 805 of your text. Note that either starting reactant leads first to the monacylglycerol phosphate, Lysophosphatidate:
A second fatty acyl CoA is then added to give Phosphatidic acid, which is then hydrolyzed to the diacylglycerol and a third fatty acyl CoA to give the final product (text Figure 21-18 on p 805). Note that 2-monoacylglycerol from the intestinal track may also be used to make triglycerides by adding two fatty acyl CoA's.
These phospholipids generally tend to have a saturated fatty acyl group on the C1 position while they mostly have an unsaturated fatty acyl group on the C2 position. The biosynthesis of phosphatidylethanolamine and phosphatidylcholine (lecithin) are outlined in your text (text Figure 21-23 on p 809 & text Figure 21-23 on p 809). For phosphatidylcholine:
Choline + ATP Phosphocholine + ADP
Phosphocholine + CTP CDP-choline + PPi
CDP-choline + Diacylglycerol Phosphatidylcholine + CMP
Phosphtidylserine is then made by exchanging serine (using the side chain -OH group) for ethanolamine on a phosphatidylethanolamine.
Finally note the synthesis of ceramide, a sphingolipid, as outlined in Figure 19-31 on p 597 of your text.
Cholesterol is an essential molecule, not only in its own right where it modifies membrane fluidity (e.g. red blood cells), but also as a precursor for the various steroids (e.g. estrogens and androgens for determining secondary sexual charecteristics, corticosteroids to promote healing etc., salt balance etc.), vitamin D, and bile salts.
Cholesterol and the steroids are all based on the so-called Steroid Nucleus shown below:
Cholesterol is ultimately constructed from acetyl CoA units, as shown by the red circles on the cholesterol molecule below:
Now we want to look at how the synthesis of cholesterol from acetyl CoA results in this pattern.
Last modified 2 February2009