Fatty acid synthesis location

The first formation of a carbon-carbon bond occnrs between malonyl and acetyl units bonnd to fatty acid synthase. After redaction, dehydration, and farther redaction, the acyl enzyme is condensed with more malonyl-CoA and the cycle is repeated nntil the acyl chain grows to Cie- When the growing fatty acid reaches a chain length of 16 carbons, the acyl group is hydrolyzed to give the free fatty acid. 

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Fatty Acid Synthesis Function Fatty Acid Synthesis Location Fatty Acid Synthesis Connections Fatty Acid Synthesis Regulation Fatty Acid Synthesis ATP Costs (for C16)... 

In eukaryotes, the cytoplasm, representing slightly more than 50% of the cell volume, is the most important cellular compartment. It is the central reaction space of the cell. This is where many important pathways of the intermediary metabolism take place—e.g., glycolysis, the pentose phosphate pathway, the majority of gluconeogenesis, and fatty acid synthesis. Protein biosynthesis (translation see p. 250) also takes place in the cytoplasm. By contrast, fatty acid degradation, the tricarboxylic acid cycle, and oxidative phosphorylation are located in the mitochondria (see p. 210). 

In non-ruminants, the malonyl CoA is combined with an acyl carrier protein (ACP) which is part of a six-enzyme complex (molecular weight c. 500 kDa) located in the cytoplasm. All subsequent steps in fatty acid synthesis occur attached to this complex through a series of steps and repeated cycles, the fatty acid is elongated by two carbon units per cycle (Figure 3.8, see also Lehninger, Nelson and Cox, 1993). 

Before discussing the specific aspects of regulation of fatty acid metabolism, let us review the main steps in fatty acid synthesis and degradation. Figure 18.18 illustrates these processes in a way that emphasizes the parallels and differences. In both cases, two-carbon units are involved. However, different enzymes and coenzymes are utilized in the biosynthetic and degradative processes. Moreover, the processes take place in different compartments of the cell. The differences in the location of the two processes and in the... 

The rate limiting step in fatty acid synthesis is catalyzed by acetyl-CoA carboxylase to produce malonyl-CoA at the expense of one ATP.31 Malonate and acetate are transferred from CoA to acyl carrier protein in the cytosolic fatty acid synthetase complex, where chain extension leads to the production of palmitate. Palmitate can then be transferred back to CoA, and the chain can be extended two carbons at a time through the action of a fatty acid elongase system located in the endoplasmic reticulum. The >-hydroxylation that produces the >-hydroxyacids of the acylceramides is thought to be mediated by a cytochrome p450 just when the fatty acid is long enough to span the endoplasmic reticular membrane. 

The main goal of this chapter is to leam how to determine the body s overall style of energy metabolism, via respiratory quotient (RQ) measure-ntents, and to derive the daily energy requirement. A view of the stoichiometries of the glycolytic pathway, Krebs cycle, and pathways of fatty acid synthesis and oxidation will allow RQ calculations for each individual pathway. Glycolysis and the Krebs cycle were presented in Chapter 4, Fatt> add synthesis and oxidation are detailed here. The locations, at points along various metabolic pathways, whereCO2 is produced (in the Krebs cycle) and Oj is consumed (in the respiratory chain), are points of focus in this chapter... 

We already mentioned that the enzymes involved in the P-oxidation of fatty acids are located in the mitochondria. The source of two-carbon fragments for the biosynthesis of both fatty acids and isoprenoids like cholesterol is acetyl CoA, which is generated by oxidative metabolism in the mitochondria. Acetyl CoA cannot escape from the mitochondria, but it can be exported to the cyosol as citrate, where it is reconverted to oxaloacete and acetyl CoA. Fatty acid (and cholesterol) biosynthesis takes place in the cyosol, and requires bicarbonate, which is incorporated into acetyl CoA to form malonyl CoA by acetyl CoA carboxylase. The biosynthesis of fatty acids, mostly the Cie palmitate (Chapter 4), requires one molecule of acetyl CoA and seven molecules of malonyl CoA. In animals, the seven enzymatic reactions which are required for fatty acid synthesis are present in a single multifunctional protein complex, known as fatty acid synthase. The synthase also contains an acyl-carrier protein... 

This transport is accomplished by carnitine (L-jS-hydroxy-y-trimethylammonium butyrate), which is required in catalytic amounts for the oxidation of fatty acids (Figure 18-1). Carnitine also participates in the transport of acetyl-CoA for cytosolic fatty acid synthesis. Two carnitine acyl-transferases are involved in acyl-CoA transport carnitine palmitoyltransferase I (CPTI), located on the outer surface of the inner mitochondrial membrane, and carnitine palmitoyltransferase II (CPTII), located on the inner surface. 

Figure 22.28 PATHWAY INTEGRATION Fatty acid synthesis. Fatty add synthesis requires the cooperation of various metabolic pathways located in different cellular compartments.

The answer is a. (Murray, pp 258-297. Scriver, pp 2705-2716. Sack, pp 121—138. Wilson, pp 362—367.) Under conditions of active synthesis of fatty acids in the cytosol of hepatocytes, levels of malonyl CoA are high. Malonyl CoA is the activated source of two carbon units for fatty acid synthesis. Malonyl CoA inhibits carnitine acyltransferase 1, which is located on the cytosolic face of the inner mitochondrial membrane. Thus, long-chain fatty acyl CoA units cannot be transported into mitochondria where p oxidation occurs, and translocation from cytosol to mitochondrial matrix is prevented. In this situation compartmentalization of membranes as well as inhibition of enzymes comes into play. 

Location. Fatty acid synthesis occurs predominantly in the cytoplasm. (Recall that /3-oxidation occurs within mitochondria and peroxisomes.)... 

Location. Plant fatty acid synthesis appears to be limited to chloroplasts. A chloroplast isozyme of pyruvate dehyrogenase catalyzes the conversion of pyruvate to acetyl-CoA. Pyruvate is also derived from glycerate-3-phosphate, an intermediate in the Calvin cycle, a biosynthetic pathway in which plants incorporate COz into sugar molecules. (The Calvin cycle is discussed in Chapter 13.)... 

Fatty acid synthesis in plants differs from that in animals in the following ways location (plant fatty acid synthesis occurs mainly in the chloroplasts, whereas in animals fatty acid biosynthesis occurs in the cytoplasm), metabolic control (in animals the rate-limiting step is catalyzed by acetyl-CoA carboxylase, whereas in plants, this does not appear to be the case), enzyme structure (the structures of plant acetyl-CoA carboxylase and fatty acid synthetase are more closely related to similar enzymes in E. coli than to those in animals). 

In muscle, most of the fatty acids undergoing beta oxidation are completely oxidized to C02 and water. In liver, however, there is another major fate for fatty acids this is the formation of ketone bodies, namely acetoacetate and b-hydroxybutyrate. The fatty acids must be transported into the mitochondrion for normal beta oxidation. This may be a limiting factor for beta oxidation in many tissues and ketone-body formation in the liver. The extramitochondrial fatty-acyl portion of fatty-acyl CoA can be transferred across the outer mitochondrial membrane to carnitine by carnitine palmitoyltransferase I (CPTI). This enzyme is located on the inner side of the outer mitochondrial membrane. The acylcarnitine is now located in mitochondrial intermembrane space. The fatty-acid portion of acylcarnitine is then transported across the inner mitochondrial membrane to coenzyme A to form fatty-acyl CoA in the mitochondrial matrix. This translocation is catalyzed by carnitine palmitoyltransferase II (CPTII Fig. 14.1), located on the inner side of the inner membrane. This later translocation is also facilitated by camitine-acylcamitine translocase, located in the inner mitochondrial membrane. The CPTI is inhibited by malonyl CoA, an intermediate of fatty-acid synthesis (see Chapter 15). This inhibition occurs in all tissues that oxidize fatty acids. The level of malonyl CoA varies among tissues and with various nutritional and hormonal conditions. The sensitivity of CPTI to malonyl CoA also varies among tissues and with nutritional and hormonal conditions, even within a given tissue. Thus, fatty-acid oxidation may be controlled by the activity and relative inhibition of CPTI. 

High levels of citrate signal that glucose utilization is no longer necessary and that adequate carbon atoms are available for synthesis of palmitoyl CoA. Citrate inhibits phos-phofructokinase 1 activity, decelerating the rate of glycolysis. On the other hand, citrate stimulates the activity of acetyl CoA carboxylase, so that increased production of mal-onyl CoA leads to stimulation of fatty acid synthesis. The transport of citrate from the mitochondrial matrix to the cytosol is important because both phosphofructokinase f and acetyl CoA carboxylase are located in the cytosol. 

As is trne in the opposing processes of glycolysis and glnconeogenesis, the pathways for the opposing processes of fatty acid degradation and fatty acid synthesis are not simply the reverse of each other. The processes are separate from each other, utilize different enzyme systems, and are even located in different cellnlar compartments. Degradation by the (3-oxidation pathway takes place in cellular mitochondria, whereas biosynthesis of fatty acids occnrs in the cytoplasm. 

Acetyl-CoA carboxylase (ACCase) catalyses the ATP-dependant carboxylation of acetyl-CoA to form malonyl-CoA, thus providing the essential substrate for fatty acid biosynthesis. Dicotyledonous plants contain two forms of ACCase a multifunctional enzyme (typel) wich is presumed to be cytosolic, and a multi-subunit complex (typell) located in the plastid wich is responsible for de novo fatty acid synthesis. In prokaryotes, the ACCase is a type II enzyme comprising biotin carboxylase (BC), biotin carboxyl carrier protein (BCCP) and a carboxyl transferase with two subunits (CTa and CTp). The cDNA encoding the B.napus CXp and BCCP have already been cloned (Elborough et a/.,1995) as have the cDNAs encoding the BC and BCCP from tobacco and Arabidopsis respectively (Shorrosh et al, 1995 Choi et al.y 1995). 

In mammals the introduction of new double bonds into mono- and polyunsaturated fatty acids exclusively occurs in the carboxyl end and is never directed toward the terminal methyl-group. Therefore no transition of fatty acids belonging to the linoleic acid family into those of the linolenic acid type has been observed. This has been shown by means of terminally labeled synthetic polyunsaturated fatty acids (Stoffel 1961, Klenk 1964). The complete enzyme system for polyunsaturated fatty acid synthesis is arranged on the cytoplasmic membranes. In view of the importance of polyunsaturated fatty acids for the structure of glycero-phospholipids, it is interesting to mention the acyl-transferases catalyzing the acylation of the j8-position of lysolecithin, lysophosphatidic acid and L-a-glycero-phosphate. These and other enzymes of phospholipid biosynthesis are located in the cytoplasmic reticulum, which therefore appears to be the main site of lipid synthesis of the cell. 

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