Reference Work Entry

Encyclopedia of Cancer

pp 1380-1383

Date:

Fatty Acid Synthase

  • Weiling ZhaoAffiliated withDepartment of Radiation Oncology and Brain Tumor Center of Excellence, Wake Forest University School of Medicine Email author 

Synonyms

FAS; FASN

Definition

Fatty acid synthase is a key enzyme which regulates the de novo biosynthesis of long-chain fatty acids.

Characteristics

Structure and Function

Fatty acid synthase (FAS) is a key enzyme that regulates the de novo biosynthesis of long-chain fatty acids from acetyl-CoA and malonyl-CoA in the presence of NADPH. There are two types of FAS. FAS II, found in prokaryotes, plants, and mitochondria, consists of an acyl carrier protein (ACP) and seven structurally independent monofunctional enzymes. Each of these enzymes is encoded by a separate gene that produces a unique protein which catalyzes a single step in fatty acid synthesis. Mammalian FAS, named FAS I, consists of two identical multifunctional polypeptides. Each monomer of FAS I contains seven distinct catalytic domains starting from the N-terminal. These catalytic domains including β-ketoacyl synthase (KS), malonyl/acetyltransferase (MAT), dehydrase (DH), enoyl reductase (ER), β-ketoacyl reductase (KR), acyl carrier protein (ACP), and thioesterase (TE).

Two models have been proposed for the structure of FAS. The conventional model is based on cross-linking studies with the bifunctional reagent, 1, 3-dibromopropanone (DBP). In this model, two identical monomers are arranged in a head-to-tail orientation that allows functional interactions across the monomer interface (Fig. 1a). The second model is based on functional mutant complementation and improved DBP cross-linking studies. These studies suggest that the FAS monomers form a coiled conformation that allows for a variety of intra- and intermonomer functional domain interactions (Fig. 1b). In this model, both of KS and MAT domains are located in the center of the FAS dimer and can interact with the ACP groups on either of the monomers.
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Fatty Acid Synthase. Fig. 1

Two models for the organization of FAS [1]

FAS in Normal Tissues

FAS I plays an essential role during embryonic development and a key role in energy homeostasis in adult mammals. Most normal tissues preferentially use circulating dietary fatty acids for the synthesis of new structural lipids. Thus, FAS expression is generally low to undetectable in most human normal tissues and is high only in the lipogenic tissues, such as liver and adipose tissues. In liver and adipose tissues, fatty acid synthesis occurs when it is necessary to store excess calories from carbohydrates as triglycerides. FAS expression is tightly controlled by nutrients through transcriptional induction and regulated by insulin, glucagon, glucocorticoids, and thyroid hormone. During starvation, fatty acid oxidation is activated to produce free fatty acids for survival, and FAS activity is rapidly downregulated. The effect of nutrients and hormones on the expression of lipogenic genes is mostly mediated by the sterol regulatory element-binding protein-1 (SREBP-1). In adipose tissue, the transcription factor, peroxisome proliferator-activated receptor γ PPARγ, is critical for regulating both adipogenesis and lipogenesis. Activation of PPARγ stimulates fatty acid synthesis and storage.

FAS and Cancer

Elevated expression of FAS has been observed in many human tumors, including carcinoma of the breast, prostate, colon, ovary, endometrium, mesothelium, lung, thyroid, and stomach. Moreover, overexpression of FAS in breast, prostate, and thyroid cancers has been associated with more aggressive malignancies. The differential expression of FAS in normal and tumor tissues has led to FAS being considered as a target for anticancer therapy. Abnormally active endogenous fatty acid metabolism appears to be important for cancer cell proliferation and survival. The data from clinical studies and animal models indicate that tumor cells constitutively express high levels of FAS and undergo significant endogenous fatty acid biosynthesis. In contrast to liver and adipose tissues, the function of elevated endogenous synthesis of long-chain fatty acid in most human cancers is not for energy storage; the new synthesized fatty acids are converted into phospholipids, not triglycerides. In cancer cells, overexpression of FAS seems to be independent of the regulatory signals found in normal tissues. Recent studies indicate that mitogen-activated protein kinases (MAPKs) and PI3 kinases pathways (PI3K signaling) are likely involved in FAS regulation via SREBP-1c. Inhibition of MAP and PI3 kinases downregulates SREBP-1 levels, thereby reducing FAS expression and fatty acid synthesis in transformed human cancer cells. Deletion of the major SREBP-binding site from the FAS promoter abrogates the transcription activity of FAS. The constitutive activation of the MAPK and PI3 kinase AKT signaling pathways in cancer cells leads to elevated levels of FAS and sustained fatty acid synthesis.

FAS Inhibitors as Potential Cancer Chemotherapeutic Agents

Several FAS inhibitors have been developed to study the loss of FAS function in tumor cells. These inhibitors include cerulenin, the cerulenin derivative, C75, the β-lactone, orlistat, and the green tea polyphenol, epigallocatechin-3-gallate (EGCG). Cerulenin, C75, and orlistat are selective inhibitors of tumor cell growth.

Cerulenin, (2R, 3S)-2, 3-epoxy-4-oxo-7, 10-trans, trans-dodecadienamide, was the first identified “specific” inactivator of FAS. It is a natural antibiotic product of the fungus Cephalosporium ceruleans. Cerulenin irreversibly inhibits FAS by binding covalently to the active site cysteine thiol in the β-ketoacyl-synthase domain. Cerulenin is selectively cytotoxic to a number of established human cancer cell lines including leukemias, breast, colon, brain, ovary, and prostate. The inhibition of fatty acid synthesis by cerulenin has been shown to be dose-dependent. The cytotoxic effect generally parallels the level of endogenous fatty acid synthesis in human breast tumor cells. FAS inhibition by cerulenin leads to apoptotic cell death in breast cancer, Prostate Cancer, brain cancer, and colon cancer cells. However, cerulenin’s chemical instability renders it ineffective as a systemic anticancer agent.

C75, a potent derivative of cerulenin, is a more stable FAS inhibitor. Structurally, it is a cell-permeable α-methylene-γ-butyrolactone, designed to be less reactive and potentially safer than cerulenin. In vivo and in vitro studies have confirmed the selective toxicity of C75 against tumor cells. C75-mediated inhibition of FAS increases malonyl-CoA levels and inhibits carnitine palmitoyltransferase 1 (CPT-1) activity, preventing the oxidation of newly synthesized fatty acids. High levels of malonyl-CoA and low levels of CPT-1 may represent mechanisms whereby FAS inhibition leads to tumor cell death. C75 treatment of mesothelioma and prostate tumor (Prostate cancer, clinical oncology) xenografts in nude mice leads to significant inhibition of tumor growth. Subcutaneous xenografts of MCF-7 breast cancer cells in nude mice treated with C75 showed fatty acid synthesis inhibition, apoptosis, and reduced tumor growth with no normal tissue toxicity. C75 has also been used as an antiobesity treatment in animal models. Treating obese mice with C75 produces a profound reduction in body weight and food intake.

Orlistat (also known as Xenical or tetrahydrolipstatin), a US Food and Drug Administration (FDA)-approved drug used for treating obesity, is a saturated derivative of lipstatin and works by inhibiting pancreatic and gastric lipases in the lumen of the gastrointestinal tract to decrease systemic absorption of dietary fat. Orlistat is also a rather potent and selective inhibitor of FAS. It inhibits the thioesterase domain of FAS which is responsible for releasing palmitate from the ACP of the enzyme. Orlistat has been reported to have antitumor activity in many tumor cell models because of its ability to block the activity of FAS. Cell cycle arrest induced apoptotic cell death and downregulation of the HER2/​Neu (erbB-2) oncogene have been observed in orlistat-treated breast cancer cells. Orlistat is also able to effectively inhibit the growth of prostate tumor (prostate cancer, clinical oncology) xenografts implanted in nude mice.

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© Springer-Verlag Berlin Heidelberg 2011
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