Cytosolic fatty acid synthase

Several additional reactions are required for the elongation of fatty-acid chains and the introduction of double bonds. When mammals produce fatty acids with longer chains than that of pahnitate, the reaction does not involve cytosolic fatty-acid synthase. There are two sites for the chain-lengthening reactions the endoplasmic reticulum (ER) and the mitochondrion. In the chain-lengthening reactions in the mitochondrion, the intermediates are of the acyl-GoA type rather than the acyl-AGP type. In other words, the chainlengthening reactions in the mitochondrion are the reverse of the catabolic reactions of fatty acids, with acetyl-GoA as the source of added carbon atoms this is a difference between the main pathway of fatty-acid biosynthesis and these modification reactions. In the ER, the source of additional carbon atoms... 

A9, 18 2A9,12 and 18 3A9,12,15. Several mutants in the fatty acid biosynthetic pathway exist. One such mutant is cd, which requires fatty acid supplementation for growth. 100 LIM 16 0 is sufficient to restore wild-type growth rates [1]. The defect in cel is in the cytosolic fatty acid synthase. The enzyme complex has only 2% of the wild-type level of phosphopantetheine [2]. The cd mutant was used to show that some fatty acids are synthesized in mitochondria [3]. 

The high level of polyunsaturates in may result from its increased ability to convert exogenous 16 0 to unsaturates, compared to wild type. When grown from the time of inoculation in the presence of [2H]16 0, on average more than 70% of its fatty acids are derived from the supplement. The remaining fatty acids are presumably synthesized by a combination of residual activity of cytosolic fatty acid synthase, and mitochondrial fatty acid synthase. 

The acetyl-CoA used as substrate for fatty acid synthases in the cytosol originates from the mitochondrion. This acetyl-CoA condenses with C02 to form malonyl-CoA, which eliminates (XL after an initial condensation reaction. After three more steps a two-carbon unit is added to a growing fatty acid chain. This cycle repeats itself many... 

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 major product of the fatty acid synthase is palmitate. In eukaryotes, longer fatty acids are formed by elongation reactions catalyzed by enzymes on the cytosolic face of the endoplasmic reticulum membrane. These reactions add two-carbon units sequentially to the carboxyl ends of both saturated and unsaturated fatty acyl CoA substrates. Malonyl CoA is the two-carbon donor in the elongation of fatty acyl CoAs. Again, condensation is driven by the decarboxylation of malonyl CoA. 

The de novo synthesis of fatty acids from acetyl CoA occurs in the cytosol on the fatty acid synthase complex. 

Fatty acid synthase is a multienzyme complex located in the cytosol that has two identical subunits with seven catalytic activities. 

C. Biotin is required for the acetyl CoA carboxylase reaction in which the substrate, acetyl CoA, is carboxylated by the addition of C02 to form malonyl CoA. This reaction occurs in the cytosol. Malonyl CoA provides the 2-carbon units that add to the growing fatty acid chain on the fatty acid synthase complex. As the growing chain is elongated, malonyl CoA is decarboxy-lated. 

B. The synthesis of fatty acids from glucose occurs in the cytosol, except for the mitochondrial reactions in which pyruvate is converted to citrate. Biotin is required for the conversion of pyruvate to oxaloacetate, which combines with acetyl CoA to form citrate. Biotin is also required by acetyl CoA carboxylase. Pantothenic acid is covalently bound to the fatty acid synthase complex as part of a phosphopantetheinyl residue. The growing fatty acid chain is attached to this residue during the sequence of reactions that produce palmitic acid. NADPH, produced by the malic enzyme as well as by the pentose phosphate pathway, provides reducing equivalents. Citrate, not isocitrate, is a key regulatory compound. 

Long-chain saturated fatty acids are synthesized from acetyl-CoA by a cytosolic complex of six enzyme activities plus acyl carrier protein (AGP). The fatty acid synthase... 

Fig. 8. Pathways involved in the conversion of glucose to fatty acid. Reaction (1) is catalyzed by cytosolic malate dehydrogenase. Reaction (2) is catalyzed by mitochondrial malate dehydrogenase. (T) designates tricarboxylate anion transporter. Reactions catalyzed by glucose-6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase in the pentose phosphate pathway produce NADPH. CS, citrate synthase ACL, ATP citrate lyase PDH, pyruvate dehydrogenase complex ACC, acetyl-CoA carboxylase FAS, fatty acid synthase.

Most mammalian cells have the capacity to synthesize fatty acids from glucose de novo in a pathway that uses products from glycolysis and two key cytosolic enzymes, acetyl-CoA carboxylase and fatty acid synthase (Chapter 6). This pathway generates long-chain SFA, mainly palmitate (16 0). The de novo synthesized palmitate and the palmitate derived from dietary sources are transported to the ER membranes. In the membranes, two major fatty acid enzymatic modifications of chain elongation and desaturation occur to yield longer chain SFA and unsaturated fatty acids of the n - 9 series. The n - 3 and n - 6 series of PUFA can be synthesized only from dietary fats, as animal cells do not have the... 

Adipocytes readily convert the products of glycolysis into fatty acids via the de novo biosynthetic pathway (Chapter 6). Briefly, surplus citrate is transported from the mitochondrion and cleaved to produce cytosolic acetyl-CoA. This acetyl-CoA is acted upon by acetyl-CoA carboxylase producing malonyl-CoA. The next steps of the fatty acid biosynthetic pathway are carried out by the multifunctional fatty acid synthase that utilizes NADPH to catalyze multiple condensations of malonyl-CoA with acetyl-CoA or the elongating lipid, eventually generating palmitate. 

Fatty acids are synthesized mainly in the liver in humans, with dietary glucose serving as the major source of carbon. Glucose is converted through glycolysis to pyruvate, which enters the mitochondrion and forms both acetyl CoA and oxaloacetate (Fig. 33.1). These two compounds condense, forming citrate. Citrate is transported to the cytosol, where it is cleaved to form acetyl CoA, the source of carbon for the reactions that occur on the fatty acid synthase complex. The key regulatory enzyme for the process, acetyl CoA carboxylase, produces malonyl CoA from acetyl CoA. 

The growing fatty acid chain, attached to the fatty acid synthase complex in the cytosol, is elongated by the sequential addition of 2-carbon units provided by malonyl CoA. NADPH, produced by the pentose phosphate pathway and the malic enzyme, provides reducing equivalents When the growing fatty acid chain is 16 carbons in length, it is released as palmitate After activation to a CoA derivative, palmitate can be elongated and desaturated to produce a series of fatty acids. 

When an excess of dietary carbohydrate is consumed, glucose is converted to acetyl CoA, which provides the 2-carbon units that condense in a series of reactions on the fatty acid synthase complex, producing palmitate (see Fig. 33.1). Palmitate is then converted to other fatty acids. The fatty acid synthase complex is located in the cytosol, and, therefore, it uses cytosolic acetyl CoA. 

Cytosolic acetyl CoA is converted to malonyl CoA, which serves as the immediate donor of the 2-carbon units that are added to the growing fatty acid chain on the fatty acid synthase complex. To synthesize malonyl CoA, acetyl CoA carboxylase adds a carboxyl group to acetyl CoA in a reaction requiring biotin and adenosine triphosphate (ATP) (Fig. 33.10). 

Fatty-acid biosynthesis occurs in the cytosol, catalyzed by an ordered multienzyme complex called fatty-acid synthase. 

Because malonyl CoA is a substrate for fatty acid synthase, competition from methyl-malonyl CoA could cause a decrease in the rate of palmitoyl CoA synthesis in the cytosol, which could in turn lead to an increase in the concentration of acetyl CoA because palmitoyl CoA inhibits acetyl CoA carboxylase. In addition, high levels of methylmalonyl CoA could interfere with transport of long-chain fatty acyl chains into mitochondria by inhibiting carnitine acyltransferase, as does malonyl CoA. Thus, both the synthesis and the oxidation of fatty acids could be inhibited by methylmalonyl CoA. 

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