Palmitate synthesis from acetyl-CoA

The overall reaction for palmitate synthesis from acetyl-CoA is... 

See also Acetyl-CoA, Fats, Albumin, Fatty Acid Activation, Oxidation of Saturated Fatty Acids, Oxidation of Unsaturated Fatty Acids, Fatty Acid Biosynthesis Strategy, Palmitate Synthesis from Acetyl-CoA, Fatty Acid Desaturation, Essential Fatty Acids, Control of Fatty Acid Synthesis, Molecular Structures and Properties of Lipids (from Chapter 10)... 

See also Fatty Acids, Table 10.1, Synthesis of Long Chain Fatty Acids, Fatty Acid Desaturation, Fatty Acid Synthase, Palmitate Synthesis from Acetyl-CoA... 

See also Fatty Acid Biosynthesis Strategy, Palmitate Synthesis from Acetyl-CoA... 

FIGURE 21.15 The pathway of palmitate synthesis from acetyl-CoA and malonyl-CoA. 

What are the metabolic sources of NADPH used in fatty acid biosynthesis How many moles of NADPH are required for the synthesis of 1 mole of palmitic acid from acetyl-CoA ... 

Although fatty acid synthesis occurs within the cytoplasm of most animal cells, liver is the major site for this process. (Recall, for example, that liver produces VLDL. See p. 349.) Fatty acids are synthesized when the diet is low in fat and/or high in carbohydrate or protein. Most fatty acids are synthesized from dietary glucose. As discussed, glucose is converted to pyruvate in the cytoplasm. After entering the mitochondrion, pyruvate is converted to acetyl-CoA, which condenses with oxaloacetate, a citric acid cycle intermediate, to form citrate. When mitochondrial citrate levels are sufficiently high (i.e., cellular energy requirements are low), citrate enters the cytoplasm, where it is cleaved to form acetyl-CoA and oxaloacetate. The net reaction for the synthesis of palmitic acid from acetyl-CoA is as follows ... 

The summary equation for the synthesis of palmitic acid from acetyl CoA demonstrates that a great deal of energy, 7 ATP + 14 NADPH (a phosphate derivative of NADH), is required ... 

In prokaryotic cells fatty acid synthesis occurs in the cytosolic compartment. However, it has been observed that ACP in E. coli appears to be somewhat loosely associated with the inner face of the plasma membrane of the cell (van den Bosch et al., 1970). Nevertheless, all the activities associated with the synthesis of palmitic acid from acetyl-CoA can be readily separated and assigned to individual proteins which have been purified and their molecular and kinetic characteristics examined in considerable detail (Vagelos, 1974). In yeast and animal cells, the fatty acid synthetase responsible for the formation of palmitic acid is always associated with the cytosolic compartment as a dimer of a polyfunctional polypeptide (ibid.). 

Fatty acids are synthesized by an extramitochondrial system, which is responsible for the complete synthesis of palmitate from acetyl-CoA in the cytosol. In the rat, the pathway is well represented in adipose tissue and liver, whereas in humans adipose tissue may not be an important site, and liver has only low activity. In birds, lipogenesis is confined to the liver, where it is particularly important in providing lipids for egg formation. In most mammals, glucose is the primary substrate for lipogenesis, but in ruminants it is acetate, the main fuel molecule produced by the diet. Critical diseases of the pathway have not been reported in humans. However, inhibition of lipogenesis occurs in type 1 (insulin-de-pendent) diabetes mellitus, and variations in its activity may affect the nature and extent of obesity. 

We can consider the overall reaction for the synthesis of palmitate from acetyl-CoA in two parts. First, the formation of seven malonyl-CoA molecules ... 

The synthesis of palmitic acid occurs in the cytosol, from acetyl-CoA. When glucose is abundant and the amount of citrate in the mitochondrial matrix exceeds the demand by the citric acid cycle, the excess citrate is transported out of the mitochondria into the cytosol (Fig. 13-8). Citrate in the cytosol is the source of acetyl groups for fatty acid synthesis, and its metabolism there involves the following enzyme reactions ... 

Fatty acid synthesis is also carried out by a multienzyme complex and leads from acetyl-CoA, malonyl-CoA, and NADPH to palmitic acid. The overall process is as follows ... 

The first step in de novo fatty acid synthesis is the production of malonyl-CoA from acetyl-CoA and bicarbonate. This committed step is catalyzed by acetyl-CoA carboxylase present in the cytoplasm of liver cells and adipocytes. After replacement of the CoA residue in acetyl-CoA by ACP (acyl carrier protein), malonyl-ACP is used to convert acetyl-ACP to butyryl-ACP by the fatty acid synthase complex. In this multistep reaction, NADPH is used as donor of hydrogen atoms and CO2 is produced. Butyryl-ACP is subsequently elongated to hexanoyl-ACP by a similar process in which malonyl-ACP serves as donor of two carbon atoms required for lengthening of the growing acyl chain. This process is repeated until palmitic acid... 

Saturated fatty acids containing up to 16 carbon atoms (palmitate) are assembled in cytoplasm from acetyl-CoA. Depending on cellular conditions, the product of this process (palmitoyl-CoA) can be used directly in the synthesis of several types of lipid (e.g., triacylglycerol or phospholipids), or it can enter the mito-... 

Most of the enzymatic activities required for the synthesis of palmitate from acetyl-CoA are found on a multienzyme complex called fatty acid synthase that is composed of two polypeptide chains. 

The first step in the synthesis of palmitate is the synthesis of malonyl-CoA from acetyl-CoA and HC03-(Figure 18.24), This reaction requires ATP and is catalyzed by acetyl-CoA carboxylase. It is the point of regulation of the pathway. The active form of acetyl-CoA carboxylase is a long filamentous array of monomer units. The individual monomers are generally inactive. The malonyl-CoA produced in this reaction, along with acetyl-CoA, provide substrates for the fatty acid synthase complex. The various enzymatic activities of the fatty acid synthase complex are summarized as follows (Figure 18.27). 

As shown in Figure 22.22 on page 619 of the text, acetyl-ACP and malonyl-ACP condense to form acetoacetyl-ACP. Carbons 4 and 3 of acetoacetyl-ACP are not labeled, because they are derived from acetyl CoA. These two carbons vdll become carbons 15 and 16 of palmitate. Only C-2 of acetoacetyl-ACP will be labeled because it is derived from the methylene carbon of malonyl-ACP. When the second round of synthesis begins, butyryl-ACP condenses with a second molecule of methylene-labeled malonyl-ACP, which contributes C-1 and C-2 of the newly formed six-carbon ACP derivative. In this compound, C-2 and C-4 will be labeled. Chain elongation continues until palmitoyl-ACP is formed. Each even-numbered carbon atom, except for carbon 16 (at the co end), will be labeled. 

Wakil et al. (1958a) described a system of enzyme fractions from pigeon liver that catalyzed the synthesis of palmitate from acetyl CoA in the presence of Mn++, ATP, TPNH, and HCOs . Subsequently Wakil (1958b) demonstrated that malonyl CoA (HOOC—CHsf—C(0)—SCoA) was an intermediate in the synthesis of palmitate by this system. He suggested that the first step in fatty acid synthesis was the carboxylation of acetyl CoA to a malonyl derivative catalyzed by a biotin-containing enzyme fraction in the presence of ATP and Mn++. In the system isolated by Martin et al. (1961) it appears that the initial step involves the condensation of... 

---