Fatty acid synthesis plays a vital role in homeostasis within the human body. The process of fatty acid synthesis regulates energy metabolism and provides fuel in times of starvation1. This process also synthesizes biomolecules that are important to life during embryonic development and lactation in mammary glands2. An overproduction of synthesized fatty acids is implicated in disease states such as obesity, liver disease, and cancer3.
The fatty acid synthase (FAS) complex performs a vital role in fatty acid synthesis. While there are two FAS complexes known, FAS I is the complex present in eukaryotes and higher prokaryotes4. Despite the difference in complexes utilized, the steps of fatty acid synthesis are, for the most part, conserved in all life4. FAS I is a homo dimer of ~272-kd subunits and contains three N-terminal active domains, each comprising a number of catalytic sites2,5. There are seven known catalytic sites in the FAS I complex, linked together by a polypeptide chain2,5. These include β-ketoacyl synthase (KS), malonyl/acetyltransferase (MAT), dehydrogenase (DH), enoyl reductase (ER), β -ketoacyl reductase (KR), acyl carrier protein (ACP) and thioesterase (TE)6. These sites facilitate the reactions necessary for fatty acid synthesis to occur (see fig 1).
Figure 1. Diagram of the FAS I complex showing each of the seven catalytic sites6
Overexpression of FAS I is common in some types of cancers. Therefore, inhibition of FAS I is of significant note because anti-cancer therapies targeted to inhibit FAS I have the possibility of being an effective cancer treatment. This review will discuss the regulation of fatty acid synthesis, examine the biochemical reactions involved in fatty acid synthesis, and highlight the area of research that involves inhibition of FAS I in cancer treatment.
Regulation of Fatty Acid Synthesis
While regulation of mammalian fatty acid synthesis is not completely understood, basic experimental models for mechanisms of regulation have been established. FAS I transcription is activated by insulin7. After a meal in which higher levels of insulin are present, utilization of fatty acids is repressed and the accumulation of triacylglycerols by muscle and adipose tissue is stimulated. Insulin stimulates the activity of protein phosphatase, which, in turn, activates acetyl CoA carboxylase, a pre-FAS I enzyme, through dephosphorylation7. The reaction catabolized by Acetyl CoA carboxylase is the committed step in fatty acid synthesis and so activation of this enzyme is essential for fatty acid synthesis to take place2. It is also thought that insulin acts to stimulate Akt, which phosphorylizes AMP-activated protein kinase (AMP-K) and deactivates it8. AMP-K suppresses acetyl CoA carboxylase and so its deactivation results in active acetyl CoA carboxylase8.
Inhibitors of FAS I include the hormones glucagon and epinephrine. When large quantities of these hormones are present, they increase...