6. Fatty acid synthesis (with elongation and desaturation)

From greek.doctor

Learning objectives

  • Where does fatty acid synthesis take place?
  • What are the limitations of fatty acid synthesis in the cytosol of human cells?
  • What are the limitations of fatty acid synthesis of human cells overall?
  • How are odd-chained fatty acids produced?
  • Which substrates and how much of each are required for synthesis of one molecule of palmitate?
  • How is acetyl-CoA transported from the mitochondria to the cytosol?
  • Describe one cycle of fatty acid synthase
  • Describe desaturation of fatty acids
  • Describe elongation of fatty acids
  • What is the rate-limiting enzyme of fatty acid synthesis?

General

Fatty acid synthesis refers to the synthesis of fatty acids from acetyl-CoA or malonyl-CoA. Synthesis itself takes place in the cytosol, but this synthesis (in animal cells) can produce saturated fatty acids which are at most 16 carbons long. The 16 carbon long saturated fatty acid is called palmitic acid, or palmitate.

If the cell requires longer fatty acids or unsaturated fatty acids they must be further modified in the ER or mitochondria.

Most fatty acids synthesised are even-chain, meaning that they contain an even number of carbons. This is because the beginning substrate acetyl-CoA has 2 carbons, and the fatty acids are elongated by 2 carbons at a time. Odd-chained fatty acids, which contain an odd number of carbons, are only synthesised when the synthesis mistakenly uses propionyl-CoA as a substrate instead of acetyl-CoA. Propionyl-CoA has 3 carbons.

Fatty acid synthesis occurs mainly in three organs – the liver, adipose tissue, and lactating mammary glands.

Fatty acid synthesis uses NADPH for energy instead of NADH. Recall that during beta-oxidation (degradation of fatty acids), the intermediates are bound to CoA. In fatty acid synthesis, the intermediates are bound to acyl carrier protein (ACP) instead. The only exception is acetyl, which is still bound to CoA like always.

The synthesis of one palmitate requires 8 acetyl-CoA, 7 ATP, and 14 NADPH.

The citrate shuttle

Fatty acid synthesis takes place in the cytosol. 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 into the cytosol, then converted back into acetyl-CoA. This is called the citrate shuttle.

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.

Procedure of fatty acid synthesis

Synthesis is performed by a large protein called fatty acid synthase (FAS). This large protein has many enzymatic activities, which act like independent enzymes. Each cycle of fatty acid synthase elongates the fatty acid by 2 carbons.

Synthesis begins when ketoacyl synthase condenses (combines) one acyl-ACP (2 or more carbons) and one malonyl-ACP. If this is the first cycle the acyl-ACP in question is acetyl-CoA. This creates a keto-acid (actually ketoacyl-ACP), a reaction which releases 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 by ketoacyl reductase so that it becomes a hydroxyl group (-OH). This consumes one NADPH.

Then, hydroxyoacyl dehydratase will 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.

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 enoyl reductase. This enzyme inserts 2 hydrogen atoms into the double bond, converting it to a single bond. We’re now 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.

If the cell requires fatty acids shorter than 16 carbons it will just stop repeating the cycle when the fatty acid has reached the required length.

Because we elongate fatty acids with units of 2 carbons, and we begin the synthesis with a 2 carbon substrate, 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 instead of a malonyl-CoA.

Desaturation and elongation

Desaturation of fatty acids is done by cytochrome P450 reductase reactions in the liver. The P450 system is found in the ER and in the mitochondria. Animal cells can only desaturate fatty acids before the 10th carbon. This is why fatty acids with double bonds near the ends, like omega-3 acids, are essential fatty acids which must be acquired through diet. Desaturation requires NADPH.

Elongation past 16 carbons is done in the ER by an enzyme called fatty acid elongase. The elongation reaction happening there is similar to the one in the cytosol, except CoA is used as the acyl carrier instead of ACP.

Regulation

Regulation is covered in topic 10

Summary

  • Where does fatty acid synthesis take place?
    • In the cytosol
  • What are the limitations of fatty acid synthesis in the cytosol of human cells?
    • Can only synthesise saturated fatty acids up to 16 carbons long
  • What are the limitations of fatty acid synthesis of human cells overall?
    • Can not put double bonds beyond the 10th carbon
  • How are odd-chained fatty acids produced?
    • When malonyl-CoA-ACP-acyltransferase mistakenly uses a proprionyl-CoA instead of a malonyl-CoA
  • Which substrates and how much of each are required for synthesis of one molecule of palmitate?
    • 8 acetyl-CoA, 7 ATP, 14 NADPH
  • How is acetyl-CoA transported from the mitochondria to the cytosol?
    • By the citrate shuttle
    • In the mitochondria, acetyl-CoA and oxaloacetate form citrate
    • Citrate is shuttled into the cytoplasm
    • Citrate is converted back into acetyl-CoA and oxaloacetate
  • Describe one cycle of fatty acid synthase
  • Describe desaturation of fatty acids
    • Performed by cytochrome p450 in the mitochondria and ER
    • Can’t desaturate beyond the 10th carbon
  • Describe elongation of fatty acids
    • Performed by fatty acid elongase in ER
    • Uses CoA instead of ACP
  • What is the rate-limiting enzyme of fatty acid synthesis?
    • Acetyl-CoA carboxylase