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Fatty acids are an important energy substrate for many cells/tissues in the body as they can be used in metabolic processes to yield large quantities of energy in the form of ATP. Most of the fatty acids come from our diet and are released into the circulation from the digestive system or from the breakdown of adipose tissues stores.
Under some conditions and in tissues such as the liver, muscle, adipose tissue and mammary glands it is possible for fatty acid synthesis (also known as de novo fatty acid synthesis) to occur from the metabolic intermediate Acetyl CoA, which is primarily derived from carbohydrate metabolism.
The process of fatty acid synthesis is analogous to fatty acid degradation (see Beta-Oxidation pathway) but in reverse. However, fatty acid synthesis occurs in the cytosol, whereas oxidation occurs in the mitochondria. Synthesis and degradation of fatty acids also use different enzymes that allow for separate regulation of these two opposing processes.
Key points:
The long chain fatty acid, Palmitate (16C) (also known as Palmitic acid or Palmitoyl-CoA) is the final product of fatty acid synthesis. Further elongation and changes to the long chain fatty acid can occur by other enzyme systems.
Elevated levels of this end-product can feedback to allosterically inactivate Acetyl-CoA Carboxylase (ACC) to prevent a build-up of fatty acids in cells.
Malonyl CoA is an important substrate of fatty acid synthesis.
It also plays an important role in the regulation of fatty acid oxidation, where it acts to inhibit the enzyme Carnitine Palmitoyltransferase 1 (CPT1), which prevents fatty acids from entering the mitochondria for oxidation (See Beta-Oxidation pathway). In doing so, it acts as a switch that controls the balance between fatty acid synthesis and oxidation.
Acetyl-CoA , or Acetyl Coenzyme A, is an important substrate for fatty acid synthesis. The process of fatty acid synthesis occurs in the cytosol, however, the majority of Acetyl-CoA is produced in the mitochondria (see Citric Acid Cycle pathway) from carbohydrate and fat metabolism.
Fatty acid synthase is the enzyme complex or system that catalyzes the synthesis of long-chain fatty acids from Acetyl-CoA, Malonyl CoA, and NADPH. The process uses repeated cycles of enzymatic steps that for each cycle elongate the fatty acid by 2-carbon units. Elongation by the fatty acid synthase complex continues until the eventual production of the most abundant acid, palmitate (16 carbons).
Acetyl-CoA + 7 Malonyl-CoA + 14(NADPD + H+) + 7ATP → Palmitate + 8CoA + 7 (ADP + Pi) + 14NADP+ + 6 H2O
The enzyme, Acetyl CoA Carboxylase (ACC), regulates the conversion of Acetyl-CoA into Malonyl CoA.
Acetyl-CoA + HCO3 + ATP → Malonyl-CoA + ADP + Pi
This reaction is the rate-limiting step in fatty acid synthesis and as such is regulated through complex phosphorylation and allosteric mechanisms.
Activated by:
Inhibited by:
In the cytosol, citrate is converted back into Acetyl CoA where it can then act as a substrate for fatty acid synthesis.
Acetyl-CoA is an important substrate for fatty acid synthesis. However, the mitochondrial membrane is impermeable to CoA (see Beta-Oxidation pathway), so Acetyl CoA cannot be directly transported out of the mitochondria. It must first be converted to citrate (see Citric Acid Cycle pathway), and then is moved out of the mitochondria via the citrate/malate transporter.