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Components of Cells
The Macromolecules
Fatty Acid Synthesis

Role of Acetyl-CoA

Fatty acids are made two carbon atoms at a time. Many of the metabolic processes taking place in cells, including the breakdown of carbohydrates for energy, result in the production of a two-carbon molecular fragment called an acetyl group (CH3-CO-). This is a very tiny molecular fragment that could easily get lost in the soup of similar tiny molecules which pack the cytoplasm of all metabolically active cells, so it is joined to a much larger molecule called CoEnzyme A (CoA).

This hybrid molecule, acetyl-CoA, is a central player in the synthesis of all fatty acids.

Acetyl-CoA is first made in the mitochondria either by the removal of hydrogen from a molecule pyruvate or by the oxidation of other fatty acids. This is a delicate balancing act. When the cell needs lots of ATP energy, all the pyruvate and oxidized fatty acids are broken down further in the tricarboxylic acid (TCA) cycle so as to make more and more ATP.

However, if the need for energy supplies decreases, the cells switch off these breakdown reactions and switch over to those metabolic pathways that join acetyl units together to form fatty acids, lipids and fat. These lipids are then stored and used as long-term fuel supplies as and when they are needed.

However, all of these two-carbon acetyl units are in the wrong place. Before they can be used in fatty acid synthesis, they have to be moved into the cytoplasm of the cell, where the fatty acids will be made.

Acetyl-CoA is moved through the mitochondrial membrane, and enters the cytoplasm of the cell, as the molecule citrate. In the cytoplasm, these citrate molecules are once again converted back to acetyl-CoA. This reaction requires that the cell use up some energy by breaking down an ATP molecule.

Elongation

Fatty acids are made by repeatedly joining together the two-carbon fragments found in acetyl-CoA and then reducing the (-CO-) part of the molecule to (-CH2-). In this way, the hydrocarbon chain, which will become the hydrophobic, energy storing part of the fatty acid, grows two-carbons at a time as the cycle of joining reactions is repeated over and over again.

Most of these reactions take place in and on the membranes of the endoplasmic reticulum (known as microsomal membranes) and takes place in several stages.

Step One In step one, some of the acetyl-CoA is converted to malonyl-CoA by the addition of a carboxyl group
(-COO-).
Step Two In step two, one acetyl-CoA molecule and one malonyl-CoA molecule are joined to two different, but close, acyl-carrier sites on a large, complex polypeptide called Fatty Acid Synthetase (FAS). One of these acyl-carrier sites involves an amino acid called cysteine, which has an -SH group as part of its structure, and the other site is a large phosphopantetheine, which also has an -SH group as part of its structure. It is these -SH (thiol) groups that bind to the acetyl- and malonyl- groups during the joining reactions.
Step Three

In step three, an acetyl-group is attached to the cysteine-SH carrier site on the FAS complex and a malonyl-group is attached to the pantethine-SH carrier site. In a joining reaction, the acetyl-group is transfered to and joined to the malonyl-group with the simultaneous expulsion of a CO2 molecule. This is the elongation reaction (called a condensation reaction) and the hydrocarbon part of the new fatty acid is now four-carbons long.

Step Four In step four, in a multi-stage process the (-CO-) part of the molecule is reduced (hydrogen added) to a (-CH2-) with the elimination of a water (H2O) molecule.
Step Five In step five, the new, growing hydrocarbon chain is transfered from the pantethine-SH carrier site to the cysteine-SH carrier site so the process can start all over again and another malonyl-group be joined to the now vacant pantethine-SH carrier site.

When the hydrocarbon chain of the new fatty acid is 16 carbon atoms long the bond joining the fatty acid to the pantetheine-SH carrier site is finally broken and the 16-C saturated fatty acid palmitate is released.


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© 2005, Professor John Blamire