Microsomal fatty acid synthase

One of the sex pheromone components of the housefly, Musca domestica, is Z9-21 H that is found on the cuticular surface of the fly. This compound is formed by the elongation of Z9-18 CoA using malonyl-CoA and NADPH to Z15-24 CoA which is decarboxylated to form Z9-21 Hc (Fig. 3) [78-80]. Other pheromone components include an epoxide and ketone that are produced from Z9-21 Hc by a cytochrome P450 [81,82] and methyl-branched alkanes that are produced by the substitution of methylmalonyl-CoA in place of malonyl-CoA at specific points during chain elongation [83,84]. A novel microsomal fatty acid synthase is involved in production of methyl-branched alkanes in most insects [85-87]. This fatty acid synthase is different from the ubiquitous soluble fatty acid synthase that produces saturated straight chain fatty acids in that it is found in the microsomes and prefers methylmalonyl-CoA. The amino acids valine and isoleucine can provide the carbon skeletons for methylmalonyl-CoA as well as propionate [83]. 

The soluble and a unique microsomal fatty acid synthase (FAS) which are involved in producing the 18-carbon fatty acyl precursors to hydrocarbons have been purified to homogeneity and characterized (Gu et al., 1997). It appears that the soluble FAS synthesizes the straight chain fatty acids involved in n-alkane and alkene formation, whereas the microsomal FAS produces the precursors for the methyl-branched hydrocarbons (Blomquist et al. 1995). 

B. S. Kaphalia, R. R. Fritz, G. A. S. Ansari, Purification and Characterization of Rat Liver Microsomal Fatty Acid Ethyl and 2-Chloroethyl Ester Synthase and Their Relationship with Carboxylesterase (p/ 6.1) , Chem. Res. Toxicol. 1997, 10, 211 -218. 

Elongation microsomal process (ER), requires malonylCoA and two NADPH, process is similar to that occurring with fatty acid synthase. 

Synthesis of prostaglandins and thromboxanes begins with the oxidative cyclization of free arachidonic acid to yield PGH2 by prostaglandin endoperoxide synthase—a microsomal protein that has two catalytic activities fatty acid cyclooxygenase (COX) and peroxidase. There are two isozymes of the synthase COX-1 and COX-2. Leukotrienes are produced by the 5-lipoxygenase pathway. 

The biosynthetic reactions involve a series of condensation processes and are distributed between cytosol and microsomes. All of the carbons of cholesterol are derived from acetyl-CoA, 15 from the methyl and 12 from the carboxyl carbon atoms. Acetyl-CoA is derived from mitochondrial oxidation of metabolic fuels (e.g., fatty acids) and transported to cytosol as citrate (Chapter 18) or by activation of acetate (e.g., derived from ethanol oxidation) by cytosolic acetyl-CoA synthase (Chapter 18). All of the reducing equivalents are provided by NADPH. 

A 1996 report by Treolar et al. provided additional information on the cytosolic and microsomal forms of EAEE synthase (Treloar, 1996). The cytosolic EAEE synthase activity, which uses ethanol and free fatty acid as substrates for EAEE synthesis, was designated as EAEE synthase, and the microsomal FAEE synthase activity, which uses... 

CJ-13,981 (45) and CJ-13,982 (46) were isolated from the fermentation broth of CL 15036, an unidentified fungus, as new squalene synthase inhibitors. They inhibited human liver microsomal squalene synthase with IC50 values of 2.8 and 1.1 pM, respectively. Based on the spectroscopic analyses, the structures of CJ-13,981 and CJ-13,982 were elucidated to be highly carboxylated fatty acids, 3-hydroxy-3,4-dicarboxy-15-hexadecenoic acid (45) and 3-hydroxy-3,4-dicarboxyhexa-decanoic acid (46), respectively [70]. 

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