Fatty acid synthases and

Before closing we should point out that, over an extended period, dietary conditions can alter the levels of enzymes involved in fatty acid metabolism. For example, the concentrations of fatty acid synthase and acetyl-CoA carboxylase in rat liver are reduced four- to fivefold after fasting. When a rat is fed a fat-free diet, the concentration of fatty acid synthase is 14-fold higher than in a rat maintained on standard rat chow diet. Current evidence indicates that the levels of these enzymes are governed by the rate of enzyme synthesis, not degradation. It appears that synthesis of the enzyme, in turn, is controlled by the rate of transcription of DNA into mRNA. A question of current interest is how this transcription of DNA is regulated. 

Menendez JA, Lupu R (2007) Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis. Nat Rev Cancer 7 763-777... 

Another major lipogenic enzyme, fatty acid synthase, is also regulated in the liver by nutritional status, insulin, glucagon and T3. Wilson et al. [78] have found that stimulation of fatty acid synthase requires both thyroid hormones and insulin (40-fold stimulation), whereas T3 or insulin alone had much smaller effects (2.5.-fold). Experiments performed in the presence or the absence of puromycin suggest that a common T3-induced peptide intermediate regulates the level of both fatty acid synthase and malic enzyme mRNAs. 

Keon, B.H., Ankrapp, D.P., Keenan, T.W. 1994. Cytosolic lipoprotein particles from milk-secreting cells contain fatty acid synthase and interact with endoplasmic reticulum. Biochim. Biophys. Acta 1215, 327-336. 

The enolic thiofuranone derivatives 35 (e.g. R = n-propyl and R = n-decyl) and 36 are also inhibitors of fatty acid synthase and have served as drug leads against Plasmodium falciparum (malaria) and Trypanosoma (sleeping sickness) . Several tetronic acid derivatives exhibit significant inhibition toward bacterial peptidoglycan synthesis (K = 0.19 p.M for the derivative R = 2-naphthalene and (R, R ) = vinyl-1-naphthalene in equation 8 analogous to 39) . ... 

Polyketide synthases, fatty acid synthases, and non-ribosomal peptide synthetases are a structurally and mechanistically related class of enzymes that catalyze the synthesis of biopolymers in the absence of a nucleic acid or other template. These enzymes utilize the common mechanistic feature of activating monomers for condensation via covalently-bound thioesters of phosphopantetheine prosthetic groups. The information for the sequence and length of the resulting polymer appears to be encoded entirely within the responsible proteins. 

Fig. 2a-d. The major architectural paridigms of fatty acid and polyketide synthases. Relationships between genes encoding a bacterial aromatic polyketide synthases, b eukaryotic fatty acid synthases and fungal polyketide synthases, c modular polyketide synthases, and d plant polyketide synthases... 

Organisms of all biological kingdoms convert 64 into the cys-teamine derivative phosphopantetheine (65) using L-cysteine as substrate. 65 is converted to coenzyme A (66) by attachment of an adenosine moiety via a pyrophosphate linker and phosphorylation of the ribose moiety. Phosphopantetheine can be attached covalently to serine residues of acyl carrier proteins that are parts of fatty acid synthases and polyketide synthases. 

Watanabe CMH, Townsend CA. Initial characterisation of a type 1 fatty acid synthase and polyketide synthase multienzyme complex NorS in the biosynthesis of aflatoxin Bi. Chem. Biol. 2002 9 981-988. 

Acyl carrier protein, found in fatty acid synthases and polyketide synthases, functions to carry the elongating fatty acyl chain... 

H.S. Sul and D. Wang, Nutritional and hormonal regulation of enzymes in fat synthesis Studies on fatty acid synthase and mitochondrial glycerol-3-phosphate acyltransferase gene transcription, Annu. Rev. Nutr., 1998, 18, 331-351. 

Clarke SD, Romsos DR, Leveille GA. Differential effects of dietary methyl esters of long chain saturated and polyunsaturated fatty acids on rat liver and adipose tissue lipogenesis. J Nutr 1977 107 1170-1180. Clarke SD, Armstrong MK, Jump DB. Nutritional control of rat liver fatty acid synthase and S14 mRNA... 

Kuhajda, F. P. 2000. Fatty acid synthase and human cancer New perspectives on its role in tumor biology. Nutrition 16 202-8. 

Ren, B., Thelen, A. P., Peters, J. M., Gonzalez, F. J., and Jump, D. B. Polyunsaturated fatty acid suppression of hepatic fatty acid synthase and S14 gene expression does not require peroxisome proliferator-activated receptor alpha. J Biol Chem 272 (1997) 26827-26832. 

Egner, R., Thumm, M., Straub, M., Simeon, A., Schuller, H. J. and Wolf, D. H., Tracing intracellular proteolytic pathways. Proteolysis of fatty acid synthase and other cytoplasmic proteins in the yeast Saccharomyces cerevisiae, J Biol Chem 268 (1993) 27269-27276. 

Kuhajda, F. P., Fatty acid synthase and cancer new application of an old pathway, Cancer Res 66 (2006) 5977-5980. 

Paulauskis, J. D. and Sul, H. S., Cloning and expression of mouse fatty acid synthase and other specific mRNAs. Developmental and hormonal regulation in 3T3-L1 cells, J Biol Chem 263 (1988) 7049-7054. 

Rashid, A., Pizer, E. S., Moga, M., Milgraum, L. Z., Zahurak, M., Pasternack, G. R., Kuhajda, F. P. and Hamilton, S. R., Elevated expression of fatty acid synthase and fatty acid synthetic activity in colorectal neoplasia. Am J Pathol 150 (1997) 201-208. 

Jenni, S., Leibundgut, M., Boehringer, D., Frick, C., Mikolasek, B., Ban, N. 2007. Structure of fungal fatty acid synthase and implications for iterative substrate shuttling. Science 316 254-261. 

Jenni, S., M. Leibundgut, D. Boehringer, C. Frick, B. Mikolasek, B., and N. Ban. Structure of Fungal Fatty Acid Synthase and Implications for Iterative Substrate Shuttling. Science 316, 254—261 (2007). [An in-depth look at the reaction sites for a multiple-subunit enzyme]. 

These fatty acids are formed by desaturation of saturated fatty acids. The process occurs after the release of the saturated fatty acid from fatty acid synthase, and it requires a special enzyme, fatty-acid desaturase, which uses FAD as a cofactor. The enzyme only creates —C=C— double bonds between carbon atoms less than nine away from the carboxyl end. Thus many nutritionally important unsaturated fatty acids that contain double bonds at higher positions along their carbon chain, such as linolenic acid, which is unsaturated at the C9, C12, and Cl5, must be derived from the diet. Such fatty acids are called essential, as is the case for those amino acids for which there is an obligatory requirement in the diet. 

Morris, SM, Jr., Nilson, JH, Jenik, RA, Winberry, LK, McDevitt, MA, and Goodridge, AG, Molecular cloning of gene sequences for avian fatty acid synthase and evidence for nutritional regulation of fatty acid synthase mrna concentration, J Biol Chem, 1982. 257(6) 3225-3229. 

---