Cytoplasm fatty acid synthesis

ER fatty acid chain elongation, which uses two-carbon units provided by mal-onyl-CoA, is a cycle of condensation, reduction, dehydration, and reduction reactions similar to those observed in cytoplasmic fatty acid synthesis. In contrast to the cytoplasmic process, the intermediates in the ER elongation process are CoA esters. These reactions can lengthen both saturated and unsaturated fatty acids. Reducing equivalents are provided by NADPH. 

The hydrogen of NAD H is probably used for die cytoplasmic fatty acid synthesis after previous transformations into NADH P. 

Citrate may leave the mitochondria (citrate shuttle) to deliver acetyl CoA into the cytoplasm for fatty acid synthesis. 

Citrate carries acetyl CoA into cytoplasm for fatty acid synthesis. 

In the weU-fed, absorptive state (insulin), accumulating acetyl CoA is shuttled into the cytoplasm for fatty acid synthesis. OAA is necessary for this transport, and acetyl CoA can stimulate its formation from pyruvate (see Chapter 15, Figure 1-15-1). 

The citrate shuttle transports acetyl CoA groups from the mitochondria to the cytoplasm for fatty acid synthesis. Acetyl CoA combines with oxaloacetate in the mitochondria to form citrate, but rather than continuing in the citric add cycle, citrate is transported into the cytoplasm. Factors that indirectly promote this process indude insuKn and high-energy status. 

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). 

Malonyl CoA, an indicator that fatty acid synthesis is active in the cytoplasm, is an inhibitor of CPT-I. 

In all species, the principal precursor for fatty acid synthesis is acetyl CoA, derived in non-ruminants from glucose and in ruminants from acetate or oxidation of /1-hydroxybutyrate. Acetyl CoA is first converted, in the cytoplasm, to malonyl CoA ... 

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). 

Fatty acid synthesis occurs in the cytoplasm, whereas fatty acid oxidation occurs in mitochondria. As mentioned previously, physicians are not so much interested in the intracellular localization of reactions as they are in the distribution of the reactions in the various organ systems. Lipids are such important components of cell membranes that the processes of lipid biosynthesis and degradation are near universal. Lipid" storage as triglycerides, however, is mainly a function of fat cells. 

The pathway is cytoplasmic and results in the production of CO2, but no cfatty acid synthesis. Hence, an increase in activity of the PPP would be expected to result in an increase in the value of the RQ. The two enzymes of the FPF directly involved in NADP reduction are glucose-6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase, as shown under Thianrdrt in Chapter 9. 

The malic enzyme/citrate lyase pathway is shown in Figure 5.10. The 2-carbon units acetyl groups) for fatty acid synthesis are supplied by the activity of citrate lyase, which may be considered an enzyme of fatty acid biosynthesis. The reduced NADP is Supplied at the point of malic enzyme. Figure 5.10 reveals no net production or utilization of NAD in the cytoplasm. The NADPH + H generated in the cytoplasm is used for fatly acid synthesis, which regenerates NADP. One molecule of CO is produced in the cytoplasm. The diagram reveals no net production or utilization of CO in the mitochondrion. One molecule of NAD is... 

The site of fatty acid synthesis is the cytoplasm. The first step of this procedure is the formation of the malonyl-CoA Fig. (3). This reaction is catalyzed by acetyl-CoA carboxylase (ACC), which is the enzyme that regulates the formation rate of fatty acids. 

Regulation is also accomplished by compartmentaliza-tion of enzyme systems involved in anabolic and catabolic pathways into different cell organelles. For example, fatty acid synthesis occurs in the soluble fraction of the cytoplasm, whereas fatty acid oxidation takes place in mitochondria. Heme synthesis begins and is completed in mitochondria, but some of the intermediate reactions take place in the cytosol. Heme catabolism is initiated in the smooth endoplasmic reticulum. Transport of key metabolites across an organelle membrane system is also a form of regulation. 

Citrate provides the precursors (acetyl-CoA, NADPH) for fatty acid synthesis and is a positive allosteric modulator of acetyl-CoA carboxylase, which is involved in the initiation of long-chain fatty acid synthesis (Chapter 18). It regulates glycolysis by negative modulation of 6-phosphofructokinase activity (see above). All of the above reactions occur in the cytoplasm, and citrate exits from mitochondria via the tricarboxylate carrier. 

Controlling the Accessibility of Substrates. In eukaryotes, metabolic regulation and flexibility are enhanced by compartmentalization. For example, fatty acid oxidation takes place in mitochondria, whereas fatty acid synthesis takes place in the cytoplasm. Compartmentalization segregates opposed... 

Fatty Acid Synthesis and Degradation. Fatty acids are synthesized in the cytoplasm by the addition of two-carbon units to a growing chain on an acyl carrier protein. Malonyl GoA, the activated intermediate, is formed by the carboxylation of acetyl CoA. Acetyl groups are carried from mitochondria to the cytoplasm as citrate by the citrate-malate shuttle. In the cytoplasm, citrate is cleaved to yield acetyl CoA. In addition to transporting acetyl CoA, citrate in the cytoplasm stimulates acetyl CoA carboxylase, the enzym... 

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... 

When citrate, a citric acid cycle intermediate, moves from the mitochondrial matrix into the cytoplasm, it is cleaved to form acetyl-CoA and oxaloacetate by citrate lyase. The citrate lyase reaction is driven by ATP hydrolysis. Most of the oxaloacetate is reduced to malate by malate dehydrogenase. Malate may then be oxidized to pyruvate and CO, by malic enzyme. The NADPH produced in this reaction is used in cytoplasmic biosynthetic processes, such as fatty acid synthesis. Pyruvate enters the mitochondria, where it may be converted to oxaloacetate or acetyl-CoA. Malate may also reenter the mitochondria, where it is reoxidized to form oxaloacetate. 

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 ... 

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

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). 

The synthesis of fatty acids and sterols in the liver cytosol depends upon a common pool of acetyl-CoA. This was demonstrated by Decker and Barth in a series of experiments utilizing perfused rat liver [10]. Lipid synthesis was measured by incorporation of tritium from [ H]H20. They used (- )-hydroxycitrate to inhibit ATP-dependent citrate lyase and measured radioisotope incorporation into fatty acids and sterols as a function of the concentration of this inhibitor. A parallel decrease in incorporation into these two products was found as the concentration of (- )-hydroxycitrate in the perfusate was increased. Contrastingly, if radioisotopic acetate was used as the substrate in the perfusing medium, this inhibitor had relatively little effect on the rate of sterologenesis, a result that would be expected if the natural source of acetate was from the action of the cytoplasmic citrate lyase. Their experiments also demonstrated that the ratio of fatty acid synthesis to sterol synthesis in the liver of fed rats is about 10 1. 

Fatty acid biosynthesis occurs by the sequential addition of acetyl groups and, on first inspection, appears to be a simple reversal of the (3-oxidation pathway. Although the biochemical reactions are similar, fatty acid synthesis differs from (3-oxidation in the following ways It occurs in the cytoplasm, utilizes acyl carrier protein and NADPH, and is carried out by a multienzyme complex, fatty acid synthase. 

The major site for fatty acid synthesis is the cytosol. However, acetyl-CoA, the substrate for fatty acid synthesis, is formed from pyruvate in the mitochondria and, since the inner membrane is impermeable to acetyl-CoA, is translocated to the cytoplasm indirectly as citrate (Fig. 8). When the rate of production of acetyl-CoA from pyruvate is high, the rate of formation of citrate, catalyzed by citrate synthase in the citric acid cycle, is also elevated, and citrate accumulates in mitochondria. Citrate is then translocated into the... 

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