Fatty acid metabolism

Functions of fatty acids
Nomenclature of different fatty acids
Fat burning (Fat demolition)
Fat build up (Fatty acid synthesis)

Fatty acids have four important functions in the body:

- As building blocks. Fatty acids are the building blocks of phospholipids and glycolipids (constituents of cell membranes).
- As a targeting molecules. Fatty acids are attached to many proteins. In this way proteins are directed to their appropriate place in membranes.
- As a fuel molecules. Fatty acids are stored as a triacylglycerols (esters of glycerol and fatty acids). Triacylglycerols are also called triglycerides or neutral fats.
- Messenger molecules (messengers). Products of fatty acids function as hormones and as an intracellular messenger molecules (messengers).

The yields of completely burning fatty acids is approximately 9000 calories per gram. The yield of burning carbohydrates and proteins is approximately 4000 calories per gram only. This is the result of the fact that fatty acids are more reduced than carbohydrates and proteins.
Fatty acids are because of their a-polar character (not soluble in water) stored in a water free form. Carbohydrates and proteins in contrast, do bind water when stored. Because of this 1 gram of fat contains six times more energy then 1 gram glycogen in which water is bound.


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The systematic name of a fatty acid has been derived from the name of the carbohydrate molecule with the same number carbon atoms with the supplemental word -acid. Because of the pH in the body fatty acids are ionised (hydrogen atom are split off) and that is why fatty acids are called after their acid rest ion molecule. The supplemental -acid is than replace by -ate. (see the table below)
The carbon atoms of fatty acids are numbered with as first the carbon atom of the carboxyl group (COO^-). The carbon atoms 2 and 3 etc. are also indicated as respectively, etc. The methyl carbon atom at the end of the chain is also called the omega () carbon atom. The place of a double bond in the fatty acid can be indicated to count back from the -carbon atom (for instance omega-3-fatty acids).

The place of the double bond is indicated mostly by the symbol followed by a number in superscript. For instance cis -⁹ means that there is a cis double bond between carbon atoms 9 and 10. Trans ² means that there is a trans double bond between the carbon atoms 2 and 3.
In the table below the most occurring fatty acids in biological systems with their number C atoms, double bonds, common name, systematic name and the molecular formula are indicated.

In the table above only natural occurring animal fatty acids are indicated. Mostly in biological systems fatty acids contain an even number of carbon atoms (almost always between 14 and 24). The fatty acids with 16 or 18 carbon atoms are most common. Animal fatty acids have almost always an unbranched carbohydrate chain. The fatty acid may have been saturated (containing no double bonds) or contain one or more double bonds. The configurations of the double bonds in the most unsaturated fatty acids is cis. The double bonds in plural unsaturated fatty acids are at least one methylene (CH2) group from each other apart.

The properties of fatty acids are dependent on their chain length and saturation degree. Fatty acids with shorter chains have lower melting points then the longer chains. Unsaturated fatty acids have a lower melting point then saturated fatty acids with the same chain length. The melting points of plural unsaturated fatty acids are even lower.
In other words, a short chain length and unsaturation (containing double bonds) promote the liquidity of fatty acids.


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Because the breakdown of fats is a complicated process, this part is divided in a number of different parts. Below the different parts are indicated.

Triglycerides are hydrolysed by cyclical AMP-regulated lipases

Fatty acids are bound to coenzyme A before they become oxidised

Carnitine transports long-chain activated fatty acids the mitochondrial matrix in

Fatty acids are broken by splitting-off of always two carbon atoms

For the oxidation of unsaturated fatty acids yet an isomerase and a reductase are necessary

If the fat breakdown dominates acetyl CoA keton bodies are formed

Acetylacetate is an important fuel in some tissues

Triglycerides become hydrolysed by cyclical AMP-regulated lipases.

The first event in the use of fat as energy source is the hydrolysis (= break down by water) of triglycerides by the enzymes that are called lipases. This process is also called lipolyse. Lipases convert triglycerides into glycerol and fatty acids, see the figure below.

The activity of lipase in fat cells is regulated by hormones like epinephrine and glucagon.
These hormones activate the enzyme adenylate cyclase. This enzyme converts ATP in cyclical AMP. This cyclical AMP activates the enzyme protein kinase A (PKA). The enzyme PKA phosphorylyse the lipase enzyme and becomes because of this phosphorylation activated. Like in the break down of glycogen cyclical AMP is here "the second messenger". The hormone insulin inhibits the hydrolysis of triglycerids.

Glycerol, that by the break down of triglyceride arise, becomes phosphoriled by glycerolkinase and then oxidised by glycerol phosphate dehydrogenase to dihydroxyacetone phosphate. This is an intermediary of the glycolysis and will be broken down further in this glycolysis.


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A fatty acid reacts with ATP and coenzyme A to form acyl CoA, AMP and pyrophosphate. This reaction is catalysed by acyl CoA synthetase.
The enzyme acyl CoA synthetase has been bound at the outer membrane of the mitochondria.
The balance of the total reaction lies in the direction of acyl CoA because of the fast hydrolysis of pyrophosphate (a returning patron in the biochemistry).


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Fatty acids are activated at the outer membrane of the mitochondria, but are oxidised inside the mitochondria. Because long-chains fatty acids are not easily going through the outer membrane of the mitochondria a special transport mechanism is necessary to transport these fatty acids into the mitochondria.

Activated long-chain fatty acids are combined with carnitine. The acyl group is transferred by the sulphur atom of coenzyme A on the hydroxyl group of carnitine under formation of acylcarnitine. This reaction becomes catalysed by carnitine acyltransferase I, that is bound at the outer membrane of the mitochondria.

Acylcarnitine is then moved through the outer membrane by a translocase enzyme (membrane protein). The acyl group is transferred back to coenzyme A at the matrix side (in the mitochondria) by the membrane. This reaction is catalysed by carnitine acyltransferase II. Ultimately carnitine is transported back into the cytoplasm by the enzyme translocase in exchange for a coming in of acylcarnitine.

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Fatty acids are broken down by repetitions of separations of parts of two carbon atoms. The reactions that repeat are oxidation, hydration, oxidation (dehydrogenation) and thiolyse. See the figure below.

The three reactions from acyl CoA to 3-ketoacyl CoA are comparable to the reactions of Succinate to Oxalacetate in the citric acid cycle.
The break down of fatty acids with a chain of an odd number of carbon atoms leads to the formation of propionyl CoA in the last thiolyse reaction step. In the last reaction step of the fatty acid break down 3-ketopentanoyl CoA (5 carbon atoms) is split up in propionyl CoA (3 carbon atoms) and acetyl CoA (2 carbon atoms). Propionyl CoA is converted in methylmalonyl-CoA by the enzyme propionyl-CoA carboxylase. This enzyme needs biotin as an assistant-factor (and bicarbonate and ATP) to catalyse the reaction. Methylmalonyl-CoA is converted in succinyl-CoA by the enzyme methylmalonyl-CoA mutase. This enzyme needs coenzyme B12 (a product of vitamin B12) to catalyse this reaction. Succinyl CoA can be further broken down in the citric acid cycle.


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The first reaction in the cycle of the break down (-Oxidation) of a fatty acid under formation of an enoyl CoA with a trans double bond between carbon number 2 is the oxidation of an acyl CoA and 3, see the figure above.
By the break down of an unsaturated fatty acid, the presence of a double bond between C-3 and C-4 prevents the formation of a trans double bond between C-2 and C-3. A trans double bond is necessary for the formation of L-3-hydroxyacyl CoA, because the enzyme dehydrogenase is specific for this. An isomerase changes a double bond between C-3 and C-4 into a trans double bond between C-2 and C-3.

By the break down of a plural unsaturated fatty acid, a cis-4 double bond forms another problem. Through dehydrogenation of this part, a 2,4-dienoyl intermediate product is raised, that is no substratum for the following enzyme in the -Oxidation. This problem is solved by the enzyme 2,4-dienoyl CoA reductase that with NADPH as coenzyme reduces the intermediate product to a cis-³-Enoyl CoA. The earlier called isomerase converts cis-³-Enoyl CoA in the trans form, see the figure below.

Odd numbered double bonds become processes by the isomerase and even numbered double bonds by the combination of the reductase and the isomerase.


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All by the fatty acid break down formed active acetyl CoA can only sufficient fast in the citric acid cycle further be broken when it sufficient oxalacetate is present. By fasting or by diabetes oxalacetate becomes used for the gluconeogenesis. There is then insufficient oxalacetate available to react with acetyl CoA.

Under these circumstances, from two molecules acetyl CoA one acetoacetyl CoA is forms and become that the keton bodies formed: acetylacetate (diacete), D-3-hydroxybutyrate and acetone.

The enzymes that accelerate these reactions in the liver are (1) 3- ketothiolase, (2) hydroxymethylglutaryl CoA synthetase, (3) hydroxymethylglutaryl CoA junctions enzyme and (4) the mitochondrial enzyme D-3-hydroxybutyratedehydrogenase. Acetylacetate decarboxylate (= carbon atom there from) spontaneously to acetone. Acetone is a volatile compound and one smells the smell of acetone in the breath of men with diabetes or with people that fast.

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The keton bodies appear to be important energy sources, it is the primary fuels for the heart muscle and the kidney salt marsh. By fasting or diabetes the brains change from the use of glucose to the use of acetylacetate as fuel.

Acetylacetate is activated by the transfer of the CoA of succinyl CoA to acetylacetate. Acetoacetyl CoA becomes then thiolysed to two molecules acetyl CoA that go into the citric acid cycle.

The liver can supply acetylacetate (not thiolysed) to other organs because the liver itself has not the enzyme CoA transferase. Other tissues do have this enzyme.
Acetylacetate has a regulating role. High concentrations in the blood are a signal for an excess of acetyl-units and lead to a delayed lipolyse (fat breakdown) in fat tissue (negative feedback).

Humans and animals cannot convert fatty acids into glucose. Humans and animals can not convert fatty acids into glucose because they cannot use the acetyl CoA to make pyruvate or oxalacetate. The both carbon atoms are taken up in the citric acid cycle, but is formed by two decarboxylations per balance no extra oxalacetate (no gluconeogenesis).
Plants can do that with help of the glyoxylate cycle.


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The chain extension stops after the formation palmitate (C16). A further chain extension and the inserting of double bonds is catalysed by other enzyme systems and occur in the peroxisomes.

The fatty acid synthesis begins with the carboxylation of acetyl Coa to malonyl CoA by the enzyme acetyl CoA carboxylase with biotin as help group. The carboxyl group of the formed malonyl CoA originates from a bicarbonate-ion. This irreversible reaction determines the speed of the fatty acid synthesis. The reactions is comparable to the carboxylation of pyruvate (gluconeogenesis).

The enzyme system that catalyse the synthesis of saturated long-chain fatty acids from acetyl CoA, malonyl CoA and NADPH are called the fatty acid synthase. The enzymes of the fatty acid synthase are separated from each other when the cells breaks. The availability of these loose enzymes have simplified the clarification of the steps in the fatty acid synthesis.
The intermediate products in the fatty acid synthesis are bound to an acyl transport protein (ACP = acyl carrier protein). The extensions phase of the fatty acid synthesis begins with the formation of acetyl-ACP and malonyl-ACP by respectively acetyl transacylase and malonyl transacylase:

Acetyl CoA + ACP Acetyl-ACP + CoA
Malonyl CoA + ACP Malonyl-ACP + CoA

The synthesis of fatty acids with an odd number of carbon atoms begins with a specific enzyme acetyl transacylase with the formation of propionyl-ACP from propionyl CoA.
The four reactions of the chain extension in the fatty acid synthesis are a condensation, reduction, dehydration and a reduction.



The shown intermediate products are formed in the first round of the synthesis.

Explanation by the four reactions.
Acetyl-ACP and malonyl-ACP condense to acetoacetyl-ACP under influence of the enzyme acyl-malonyl-ACP condensing enzyme. In this condensation reaction, a C becomes4-units formed from a C2- and a C3-unity meanwhile an CO2-Group is split off.
That not two molecules acetyl-ACP condense has as background that the reaction with malonyl-ACP a larger balances constant has because the decarboxylation an important contribution at the abasement of the going out energy supplies. The going out energy that is conserved by the carboxylation of acetyl CoA through ATP in malonyl CoA is released by the decarboxylation. In the decarboxylation the same carbon atom split off as the one that by the carboxylation is formed and was supplied to Acetyl CoA through the bicarbonate-ion. Thus, the carbon atoms of fatty acids with an even number of carbon atoms are all originating from acetyl CoA.
In the three next reactions of the fatty acid synthesis, the keto-group (C with double tied oxygen) at the third carbon atom is reduced to a methylene group (-CH2-). In the first reaction, acetoacetyl-ACP is reduced to D-3-hydroxybutyryl-ACP. This reaction differs in two respects from the similar reaction in the fatty acid break down:
(1) instead of the L-epimer the D-epimer is formed.
(2) NADPH is the reducing compound, while NAD+ is the oxidising compound in the Beta-oxidation. This difference is an example of the general principle that NADPH is used for synthetic (build up) reactions and NADH is made in energy supplying reactions. Then D-3-hydroxybutyryl-ACP becomes dehydrated to crotonyl-ACP. In the last step, crotonyl-ACP is reduced to butyryl-ACP, with which the first extensions cycle is completed.
After the first round, butyryl-ACP is formed. In the second round, butyryl-ACP condenses with malonyl-ACP. Below go the reactions as in the first round. As to it are added each round 2 carbon atoms. This goes on until palmitate (C16) has been formed. Palmitate then is taken away by ACP and there palmitate and ACP arises.
The net reaction for the synthesis of palmitate is:
8 acetyl CoA + 7 ATP + 14 NADPH + 6 H+ palmitate + 14 NADP+ + 8 CoA +
6 H2O + 7 ADP + 7 Pii

Fatty acids are formed from acetyl CoA become synthesised in the cytoplasm, meanwhile acetyl CoA from pyruvate in the mitochondria.


Acetyl CoA is transported from the mitochondria to the cytoplasm in the form of citrate. At the same time NADH is exchanged for of NADPH by this series of reactions.

For each acetyl CoA that moves from the mitochondria to the cytoplasm one NADPH is generated.
From this we see that by the formation of palmitate eight NADPH are formed as consequence of the transport of eight molecules acetyl CoA to the cytoplasm. The remaining six required NADPH come from the pentose phosphate path.

The fatty acid metabolism is regulated so that the formation and break down of fatty acids strongly react to the need of energy and other compounds. The fatty acid synthesis is at its maximum when carbohydrates and energy are sufficient and fatty acids are scarce.
The speed determining step in the fatty acid synthesis is catalysed by acetyl CoA carboxylase. The enzyme is regulated by the hormones epinephrine, insulin and glucagon. This messenger compound indicates the total needs of the organism. Insulin activates the fatty acid synthesis. Glucagon and epinephrine have the opposite effect.
Also the concentrations of citrate, palmitoyl CoA and AMP in the cell regulate the fatty acid metabolism. Concerning regulation, the key enzyme reacts to the complete organism and to locale regulation.
Acetyl CoA carboxylase becomes activated as a consequence of phosphorylation by an AMP dependent protein kinase. It is activated by the bonding with citrate.

Sources

[1]. Stryer, Lubert;- Biochemistry - fourth edition; New York: W. H. Freeman and Company
(1995). ISBN 0-7167-2009-4