Food Chemistry and Fish in Nutrition

4.3.3. Synthesis of fatty acids in cytoplasm

 The main pathway for the synthesis of fatty acids from acetyl CoA occurs in the cytoplasm. This system is present in many tissues, including liver, kidney, brain, lactating mammary gland and adipose tissues. Its cofactor requirements include NADPH, ATP, Mn²⁺, biotin, and HCO₃ (as a source of CO₂₎. Acetyl-CoA is the immediate substrate, and free palmitate is the end product. The reactions are as follows

1.  Formation of malonyl-CoA.

The first reaction is the formation of malonyl-CoA by the carboxylation of acetyl-CoA in the presence of ATP, biotin and acetyl-CoA carboxylase. Bicarbonate is the source of CO₂. The reaction takes place in two steps:

(1) carboxylation of biotin (involving ATP) and

(2) transfer of the carboxy group to acetyl-CoA to form malonyl-CoA

Acetyl-CoA carboxylase.
Acetyl-CoA + ATP+ biotin + HCO₃^- → Malonyl-CoA + ADP + Pi

Fatty acid synthase

Two types of fatty acid synthase are found to be involved in the synthesis of fatty acids. In bacteria, plants, and lower forms, the individual enzymes of the system are separate, and the acyl carrier protein (ACP). However, in yeast, fish, higher animals and birds, the synthase system is a multienzyme complex and ACP is part of this complex. ACP of both synthase systems has 4’- phosphopantetheine and cysteine -SH group.

2. Reaction of acetyl CoA and malonylCoA with Enzyme

An acetyl-CoA molecule combines with the cysteine -SH group of ACP catalyzed by acetyl transacylase. Then a malonyl-CoA combines with the adjacent -SH on the 4’- phosphopantethenine of enzyme catalyzed by malony1 transacylase, to form acetyl (acyl)-malonyl enzyme.

3. Action of 3-ketoacyl synthase

The acetyl group attacks the methylene group of the malonyl residue, catalyzed by 3-ketoacyl synthase, and liberates CO₂, forming 3-ketoacyl enzyme (acetoacetyl enzyme). This frees the cysteine-SH group, hitherto occupied by the acetyl group. Decarboxylation allows the reaction to go to completion.

4. Reduction of 3-ketoacyl group of Acyl ACP

The 3-ketoacyl-S-enzyme is reduced to form a 3-hydroxyl acyl-S-enzyme. NADPH and H⁺ are needed for the reaction.

5. Dehydration of 3-hydroxyl acyl-S-enzyme by hydratase

A water molecule is removed from the 3-hydroxyl acyl-S-enzyme to form an unsaturated acyl-S-enzyme. This reaction is catalysed by hydratase.

6. Reduction of unsaturated acyl-S-enzyme by enoyl reductase

Unsaturated acyl-S-enzyme is reduced by enoyl reductase to form a saturated acyl-S-enzyme.

Repeat of the sequence of reactions

A new malonyl-CoA molecule combines with the -SH group of the enzyme. The sequence, of the reactions (No 3-6) is repeated 6 more times, a new malonyl residue being incorporated during each sequence, until a saturated 16 carbon acyl radical (palmityl) has been assembled.

It is then liberated from the enzyme complex by the activity of a seventh enzyme in the complex, thioesterase (deacylase).

The free palmitate must be activated to acy-CoA before it can proceed via any other metabolic pathway. Its usual fate is esterification into triglycerides.

The equation for the overall synthesis of palmitate from acety-CoA and is shown below.

   Acetyl CoA                 Malonyl CoA                                                         Palmitate

CH₃COSCoA + 7HOOC.CH₂CO.S.CoA+ 14NADPH + 14H⁺ →CH₃(CH₂)₁₄COOH +7CO₂ + 6H₂O+8CoA.SH + 14NADP⁺

Sources of acetyl CoA-Carbohydrates and glucose

The pathway involves glycolysis followed by the oxidative decarboxylation of pyruvate to acetyl-CoA within the mitochondria and subsequent condensation with oxaloacetate to form citrate, as part of the citric acid cycle.

This is followed by the translocation of citrate into the extra mitochondrial compartment via the tricarboxylate transporter, where in the presence of CoA and ATP, it undergoes cleavage to acetyl-CoA and oxaloacetate catalyzed by ATP-citrate lyase.

The acetyl-CoA is then available for malonyl-CoA formation and synthesis to palmitate.