Synthesis of Fatty acids

Glucose ingested in excess of our immediate energy need and storage capacity is converted by glycolysis into pyruvate and then into acetyl CoA form which Fatty acids are synthesized.

These fatty acids then form Triacylglycerols (TAGs), which have higher energy content than polysaccharides.

These TAGs are then stored in adipose tissues.

Biosynthesis of Saturated Fatty acids

Biosynthesis of Saturated Fatty acids is done from the precursor, Acetyl CoA, prominent in liver, adipose tissue and mammary glands of higher animals.

The process of synthesis is significantly different form β-oxidation of fatty acids.

It occurs in cytosol while β-oxidation occurs in the mitochondria.

Presence of citrate is necessary for the maximum rate of synthesis (not required for oxidation).

CO₂ is essential for the fatty acid synthesis.

FA synthesis has a totally different set of enzymes.

Source of C-atoms is Acetyl CoA formed in mitochondria by:

Oxidative decarboxylation of pyruvate.
Oxidative degradation of some amino acids.
β-oxidation of long chain fatty acids.

Fatty acid Synthesis - The Citrate Shuttle

High carbohydrate meal leads to increased glycolysis leading to increased formation of Pyruvate.

So more Acetyl CoA is formed.

Acetyl CoA accumulates in the mitochondria as TCA cycle is not running due to high NADH.

Now this Acetyl CoA takes up the first reaction of of TCA cycle and forms citrate by combining with oxaloacetate (OAA).

Now citrate accumulates and passes out of the mitochondrial membrane through Citrate shuttle.

Once outside in the cytosol, citrate is acted upon by the enzyme citrate lyase with addition of coenzyme A and is converted into OAA and Acetyl CoA.

Acetyl CoA formed is then acted upon by a highly regulated enzyme Acetyl CoA Carboxylase (Biotin and CO₂is added), and Malonyl CoA is formed.

Acetyl CoA is 2-C compound and by addition of one more carbon in the form of CO₂, a 3-C Malonyl CoA is formed.

Malonyl CoA is the precursor of fatty acids.

Factor favouring FA Synthesis

Fed state/high carbohydrate meal.

Increased glucose leading to increased insulin in blood.

Increased ATP production.

Cofactors needed

NADPH, ATP, Mn⁺⁺

Biotin & HCO3 (as a source of CO₂).

Acetyl CoA is the immediate substrate & Palmitate is the END PRODUCT.

Fatty acid Synthesis - next steps

Fatty acids grow by 2C in each step.

To start with we must have one 3C molecule i.e. Malonyl-ACP and a 2C molecule (Acetyl-ACP).

The 3rd substrate required is an enzyme Fatty Acid Synthase (FAS) – it is a multifunctional dimeric enzyme.

Each FAS monomer is a multicatalytic polypeptide with 7 different enzymic activities plus a domain that covalently binds a molecule of 4′ phosphopantheine (derivative of pantothenic acid), carries an acyl unit on its terminal SH group.

FAS is a multienzyme complex and its 4′ phosphopantheine domain is a separated protein referred as ACP (Acyl Carrier Protein). ACP has SH groups attached to it.

Fatty acid synthesis does not use Acetyl CoA. It starts with Acetyl CoA but gets replaced by ACP (Acyl Carrier Protein).

Steps

Precursors – NADPH, Malonyl CoA, FAS, Acetyl CoA.
Step 1:
- Acetyl CoA is added on to ACP end – enzyme is Acetyl transacylase to form Acetyl-ACP.
Step 2:
- 2 Carbon residue or Acetyl CoA is transferred to a temporary holding site – thiol group of cysteine – Acetyl-KS. Enzyme is Acetyl KS-ACP synthase.
Step 3:
- Malonyl CoA is added on the ACP end by the enzyme Malonyl transacylase to form Malonyl-ACP.
Step 4:
- Acetyl-KS group condenses (ACP condensing enzyme) with malonyl group on ACP. CO2 originally added by ACC is released forming a 4C β-Ketone molecule called β-Ketoacyl-ACP.
Step 5:
- Keto group is reduced to alcohol, NADPH is added – it gives electrons to β-ketone to add hydroxyl group to the β-ketone to form D-3-Hydroxyacyl-ACP.snd the enzyme is β-Ketoacyl-ACP reductase.
Step 6:
- Dehydration step – the OH group is taken out, a double bond is created. Enzyme is 3-Hydorxyacyl dehydratase to form trans Δ²Enoyl-ACP.
Step 7:
- NADPH adds hydrides and reduces the enoyl group. The double bond is reduced and we have a fully saturated fatty acid. Enzyme is Enoyl-ACP reductase and the fatty acid formed is Butyryl-ACP (4C).
This completes ONE cycle.
After Step 7, these steps are repeated 6 more times until 16-C Palmitate is formed.
Palmitoyl thioesterase then cleaves the thioester bond, releasing a fully saturated molecule of Palmitic acid.

Acetyl CoA Carboxylase (ACC)

Acetyl CoA carboxylase is the only regulated enzyme in Fatty acid synthesis, puts on a carboxyl group on Acetyl CoA to produce Malonyl CoA.

Acetyl CoA is highly regulated by 2 ways:

By phosphorylation (inactivated) and dephosphorylation (activated).

Allosteric regulation – it is turned off by the end product of the pathway i.e. Palmityl CoA (feedback inhibition) and Turned ON by Citrate (some citrate is broken down to form Acetyl CoA while remaining turns on the enzyme).

Insulin and Citrate have +ve effect on the reaction while Glucagon, LCFAs, Epinephrine, norepinephrine inhibit ACC.

Malonyl CoA also inhibits (apart from FA synthesis) the CAT I enzyme required for FA translocation into the mitochondria for β-oxidation.

Regulation of Fatty acid synthesis

All depends on Acetyl CoA Carboxylase which is highly regulated
It is regulated at all three levels:

1. At genetic level.
2. By phosphorylation/dephosphorylation.
3. Allosterically.

Regulation by Insulin

Insulin activates Acetyl CoA Carboxylase:

1. At genetic level.
2. By Phosphorylation/dephosphorylation of the enzyme.

Insulin also turns ON glycolysis
It turns on glucokinase, PFK2 after high carbohydrate meal,
All the glucose enters the liver (GLUT2) and insulin increases glycolysis.

Allosteric regulation

The enzyme Acetyl CoA Carboxylase is also turned on allosterically by Citrate
- Citrate turns ON the enzyme
- Glucagon turns it OFF.

Metabolism of Lipids 9 Sections27 LessonsLifetime

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