Last updated on March 11, 2020 at 17:53
- Formation of saturated fatty acids with 16 carbons or less happens in cytosol
- Formation of longer or unsaturated fatty acids happens in mitochondria, ER
- During synthesis, ACP is used to activate acyl groups instead of CoA in degradation
- Uses NADPH
- Citrate is transported from the mitochondria to the cytosol via the citrate shuttle
- In the cytosol ATP citrate lyase will convert citrate to acetyl-CoA
- Acetyl-CoA carboxylase (ACC) then initiates fatty acid synthesis by converting acetyl-CoA to malonyl-CoA
- Several enzymes in the mitochondria are involved in fatty acid synthesis
- Citrate synthase
- Malate dehydrogenase
- Pyruvate carboxylase
- Pyruvate dehydrogenase complex
Procedure of fatty acid synthesis
Synthesis is performed by many enzymatic activities of a large protein called fatty acid synthase. These enzymatic activities act like enzymes on their own.
Fatty acid synthesis requires cytosolic acetyl-CoA. Acetyl-CoA is mostly found in the mitochondrial matrix as a result of the pyruvate dehydrogenase complex. However, for fatty acid synthesis, we need acetyl-CoA in the cytosol. Acetyl-CoA cannot cross the mitochondrial membranes. To transport acetyl-CoA from the mitochondra to the cytosol, it’s converted into citrate in the mitochondria, transported across the membrane, then converted back.
This is done by citrate synthase enzyme in the mitochondria, which synthesises citrate from oxaloacetate (OAA) and acetyl-CoA. Citrate can be transported over the mitochondrial membranes, and when it is in the cytosol, ATP citrate lyase reverses the previous reaction to yield OAA and acetyl-CoA. The OAA molecule is then reduced to malate, and transported back into the matrix, to not waste an OAA molecule.
Once in the cytosol, Acetyl-CoA carboxylase will convert acetyl-CoA into malonyl-CoA. The enzyme malonyl-CoA-ACP-acyltransferase will then convert malonyl-CoA into malonyl-ACP.
It begins by condensing (combining) one acyl-ACP (2 or more carbons) and one malonyl-ACP. This creates a keto-acid (actually ketoacyl-ACP), a reaction which produces CO2. A keto acid is an acid which has a double bond to an oxygen in the middle of the carbon chain (a keto-group).
This keto group is then reduced so that it becomes a hydroxyl group (-OH). Then, we remove this OH group and one hydrogen atom from the carbon next to the one OH is attached to. This OH and H go out as water (which is why the enzyme that does this is called dehydratase).
We are now left with a trans-enoyl fatty acid, which means there’s a double bond between two carbon atoms. This double bond is then reduced (by inserting 2 hydrogen atoms into the molecule to make it go away), and we’re left with a fatty acid that’s 2 carbons longer than what we started with. We have basically added 2 of the carbons from malonyl-ACP onto the acyl-ACP, and the third carbon from malonyl-ACP has left as CO2. This cycle may then be repeated if necessary.
Because we elongate fatty acids with units of 2 carbons, and we begin the synthesis with a similar unit, most fatty acids have an even number of carbons. Odd chain fatty acids are produced when the enzyme acetyl-CoA-ACP-acyltransferase mistakenly uses a proprionyl-CoA (3 carbons) instead of a malonyl-CoA.
The NADPH needed for fatty acid synthesis comes from the pentose phosphate pathway and malic enzyme.
Desaturation of fatty acids is done by cytochrome P450 reductase reactions in the liver. Animals can only put the double bond before the 10th carbon. This is why fatty acids with double bonds near the ends, like omega-3 acids, are essential.
Elongation past 16 carbons is done in the ER. The elongation reaction happening there is similar to the one in the cytosol, except CoA is used as the acyl carrier instead of ACP.
Acetyl-CoA carboxylase is the rate-limiting enzyme of fatty acid synthesis, and is therefore the point of regulation. In addition to the factors shown below, ACC is also regulated covalently by phosphorylation. Phosphorylation is done by AMPK, which inactivates it when energy supply is low, and PP2A activates it in response to insulin.
How ACC, and therefore fatty acid synthesis, is regulated. Note that it is not complete.
5. Regulation and disorders of carbohydrate metabolism
7. Synthesis of complex lipids