Fatty acid synthase is a multi-enzyme protein that catalyzes fatty acid synthesis. It is not a single enzyme but a whole enzymatic system composed of two identical 272 kDa multifunctional polypeptides, in which substrates are handed from one functional domain to the next.
Fatty acid synthase (FAS) is a homodimeric enzyme, with each 250 kDa monomer containing a polypeptide sequence of all seven enzyme activities of FAS along with an acyl carrier protein (ACP). The monomers are deployed in a head-to-tail configuration, held together by two thio-disulfide bonds. The seven active catalytic functions of FAS, listed in order of when they are utilized in the fatty acid elongation sequence are: acetyl/malonyl transacylase, 3-ketoacyl synthase, 3-ketoacyl reductase, 3-hydroxyacyl dehydratase, enoyl reductase, and thioesterase. The FAS-catalyzed chain elongation sequence is fuelled by NADPH, which is primarily provided by the pentose phosphate pathway.
FAS functions as a dimer and catalyzes the synthesis of palmitate from the substrates acetyl CoA, malonyl CoA and NADPH. In normal tissue, FAS is expressed mainly in liver, adipose and lactating breast, where it converts excess carbohydrates to fatty acids. Because dietary lipids generally satisfy the requirement of fatty acids for growth, development, and survival of normal cells, they are less dependent on endogenous fatty-acid synthesis. There are however three main functions of FAS in normal tissues of well-nourished adults: 1) maintaining energy homeostasis by storaging excess energy as fat; 2) when the diet is low in fat, de novo synthesis of fatty acids from carbohydrate or protein to provide the substrates for synthesis of cell membrane and signaling molecules and 3) synthesis of medium-chain fat for lactation.
Fatty acid synthase and cancer
Fatty acid synthase (FAS) has been thought as a novel metabolic oncogene. This enzyme is specifically overexpressed in a variety of human cancers including colon, breast, prostate and ovarian carcinoma. The overexpression of FAS confers growth advantage to tumors in the micro-environment of hypoxia and high acidity. The role of FAS in human cancer cells has been found to be more important than that in normal tissues. In the 1980s, 14C glucose studies have shown that de novo synthesis of fatty acid by the tumor cells accounted for more than 93% of triacylglycerol fatty acids in the tumor cells despite adequate nutritional supply. Also, in the 14C glucose labeled tumor model, all esterified fatty acid in the tumor was found to be derived from de novo synthesis. These data indicate that FAS may have particular functions that are important for survival of the tumor cells regardless of the supply of dietary fatty acids. Moreover, FAS plays a crucial role in growth and survival of human cancer cells and the treatment of tumor cells with FAS inhibitors has been shown to be selectively cytotoxic to tumor cells. Therefore, FAS is considered to be an ideal therapeutic target for cancer treatment.
FAS as a therapeutic target for cancer treatment
After the report of high FAS expression in breast cancer, numerous studies demonstrated the association of FAS expression with clinically aggressive cancers. In breast cancer, a nine-fold increased risk of death was associated with a phenotype of high levels of FAS expression and high proliferative index. Similarly, in prostate cancer, high levels of FAS expression were shown to be associated with aggressive disease. Importantly, with the high levels of FAS in cancer cells, FAS has been identified in the blood of cancer patients, suggesting that FAS can be used as a diagnosis or prognosis marker. Treatment of tumor cells with pharmacological inhibitors of FAS leads to cell growth arrest and apoptosis of breast tumor cells both in vitro and in vivo. Several in vivo studies demonstrated that inhibition of FAS was selectively cytotoxic to human cancer cells in vivo.
Zhan, Rui. The Role of Fatty Acid Synthase in Breast Cancer Cells. ProQuest, 2006.
Lau, Dominic Sze Yan. Fatty Acid Synthase and Cancer: Expression and Interaction with Conjugated Linoleic Acid. ProQuest, 2007.