BIOCHEMISTRY AND HUMAN NUTRITION

Module 3. Metabolism

Lesson 21
BIOSYNTHESIS OF FATTY ACIDS

21.1 Introduction

• Fatty acid synthesis in animal/yeast cells occurs in cytosol and in case of plant cells in chloroplast stroma.
• Biosynthesis of fatty acids involves stepwise addition of two carbon units. The two carbon units are supplied by acetyl-CoA, which in turn is derived from the oxidation of glucose.
• Acetyl-CoA formed in the matrix of mitochondria cannot cross the inner mitochondrial membrane, and an acetyl CoA shuttle system is required to transport the two-carbon units out of the mitochondria and into the cytosol.

21.2 Fatty acid Synthesis

21.2.1 Carboxylation of acetyl CoA

• The formation of malonyl coenzyme A is the speed determining step in the fatty acid synthesis.

Fig. 21.1 Carboxylation of acetyl CoA

• 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.

21.2.2 The cycle of the chain extension in the fatty acid synthesis.

• The enzyme system that catalyses the synthesis of saturated long-chain fatty acids from acetyl CoA, malonyl CoA and NADPH are called the fatty acid synthase.
• Fatty acid synthase (FAS) carries out the chain elongation steps of fatty acid biosynthesis. FAS is a large multienzyme complex. In mammals, FAS contains two subunits, each containing multiple enzyme activities. In bacteria and plants, individual proteins, which associate into a large complex, catalyze the individual steps of the synthesis scheme.
• 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:
  

The four reactions of the chain extension in the fatty acid synthesis are a condensation, reduction, dehydration and a reduction.

Fig. 21.2 Fatty acid synthesis

• Acetyl-ACP and malonyl-ACP condense to acetoacetyl-ACP under influence of the enzyme acyl-malonyl-ACP condensing enzyme. In this condensation reaction, a C4-unit is formed from a C2- and a C3-unit while a CO₂-group is split off.
• 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.
• Here the 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 in synthesis, 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 is dehydrated to crotonyl-ACP. In the last step, crotonyl-ACP is reduced to butyryl-ACP, with which the first extension 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.

21.3 Citrate Transports Acetyl Groups from the Mitochondria to the Cytoplasm

• Fatty acids are formed from acetyl CoA in the cytoplasm, while acetyl CoA from pyruvate is anabolised in the mitochondria. Acetyl CoA is transported from the mitochondria to the cytoplasm in the form of citrate and involves an additional enzyme, citrate ATP-lyase.

Fig. 21.3 Acetyl CoA shuttle system

21.4 Stoichiometry of the Synthesis of Palmitate

7 Acetyl CoA + 7 CO₂ + 7 ATP + 7 H₂O → 7 Malonyl CoA + 7 ADP
Acetyl CoA + 7 malonyl CoA + 14 NADPH → Palmitate + 7 CO₂ + 14 NADP⁺ + 6 H₂O
Sum: 8 Acetyl CoA + 7 ATP + 14 NADPH + H₂O → palmitate + 7 ADP + 14 NADP⁺