Fatty Acid Synthesis- Lecture-1 (Quick revision)

Sources of Fatty acids

• Diet
• Adipolysis
• de novo synthesis(from precursors)- Carbohydrates, protein, and other molecules obtained from the diet in excess of the body’s need can be converted to fatty acids, which are stored as triglycerides

De novo Fatty Acid Synthesis

Characteristics

• An extramitochondrial system synthesizes fatty acids
• This system is present in many tissues, including liver, kidney, brain, lung, mammary gland, and adipose tissue.
• Acetyl-CoA is the immediate substrate, and free palmitate is the end product.
• Its cofactor requirements include NADPH, ATP, Mn²⁺, biotin, and HCO₃^– (as a source of CO₂).

Substances required for fatty acid biosynthesis

1. Acetyl CoA

• Acetyl CoA is produced primarily from pyruvate, ketogenic amino acids, fatty acid oxidation, and alcohol metabolism
• It is a substrate of the TCA cycle and a precursor for fatty acids, ketone bodies, and sterols.

2. NADPH

NADPH is involved as a donor of reducing equivalents

• The oxidative reactions of the pentose phosphate pathway are the chief source of the hydrogen required for the reductive synthesis of fatty acids.
• Tissues specializing in active lipogenesis—i.e., liver, adipose tissue, and the lactating mammary gland—possess an active pentose phosphate pathway (Figure 1).

 Figure 1- Reactions 1 and 2 are catalyzed by glucose 6-P dehydrogenase and 6-phosphogluconate dehydrogenase,       respectively.

• Other sources of NADPH include the reaction that converts malate to pyruvate catalyzed by the “Malic enzyme” (NADP malate dehydrogenase) – figure-2 and the extramitochondrial isocitrate dehydrogenase reaction (probably not a substantial source, except in ruminants) figure-3.

Figure 2- It is a reversible reaction; pyruvate produced in the reaction reenters the mitochondrion for further utilization

Figure-3-There are three isoenzymes of Isocitrate dehydrogenase. One, which uses NAD⁺, is found only in mitochondria. The other two use NADP⁺ and are found in mitochondria and the cytosol. Respiratory chain-linked oxidation of Isocitrate proceeds almost completely through the NAD⁺-dependent enzyme.

3. Enzymes and cofactors involved in the process of Fatty acid synthesis

Two main enzymes-

• Acetyl CoA carboxylase
• Fatty acid Synthase

Both the enzymes are multienzyme complexes

Coenzymes and cofactors are-

• Biotin
• NADPH
• Mn⁺⁺
• Mg⁺⁺

Transportation of Acetyl CoA (Figure-4)

• Fatty acid synthesis requires considerable amounts of acetyl-CoA
• Nearly all acetyl-CoA used in fatty acid synthesis is formed in mitochondria
• Acetyl CoA has to move out from the mitochondria to the cytosol
• Acetate is shuttled out of mitochondria as citrate
• The mitochondrial inner membrane is impermeable to acetyl-CoA
• Intra-mitochondrial acetyl-CoA first reacts with oxaloacetate to form citrate in the TCA cycle catalyzed by citrate synthase
• Citrate then passes into the cytosol through the mitochondrial inner membrane on the citrate transporter.
• In the cytosol, citrate is cleaved by citrate lyase regenerating acetyl-CoA.

Figure-4- Transportation of acetyl CoA out of the mitochondria through citrate transporter

The fate of Oxaloacetate (Figure-4)

The other product of Citrate cleavage, oxaloacetate, can be:

• Channeled toward glucose production
• Converted to malate by malate dehydrogenase
• Converted to pyruvate by malic enzyme, producing more NADPH, which can be used for the fatty acid synthesis
• Pyruvate and Malate pass through special transporters present in the inner mitochondrial membrane.

To be continued……