Fatty acids, oxidation synthetase

Fatty acid utilized by muscle may arise from storage triglycerides from either adipose tissue depot or from lipid stores within the muscle itself. Lipolysis of adipose triglyceride in response to hormonal stimulation liberates free fatty acids (see Section 9.6.2) which are transported through the bloodstream to the muscle bound to albumin. Because the enzymes of fatty acid oxidation are located within subcellular organelles (peroxisomes and mitochondria), there is also need for transport of the fatty acid within the muscle cell this is achieved by fatty acid binding proteins (FABPs). Finally, the fatty acid molecules must be translocated across the mitochondrial membranes into the matrix where their catabolism occurs. To achieve this transfer, the fatty acids must first be activated by formation of a coenzyme A derivative, fatty acyl CoA, in a reaction catalysed by acyl CoA synthetase. 

Other changes noted were the loss of certain enzymes and other proteins as well as ATP synthetase already mentioned, including a number involved with (3-oxidation and glycolysis (e.g., thiolase and GAPDH). These changes would tend to reduce ATP generation from fatty acid oxidation and glycolysis. 

Fatty acid oxidation is a multistep process requiring orchestration of reactions in the cytoplasm and mitochondria (Fig. 9-1). Free fatty acids enter the cell and are activated to their coenzyme A (CoA) thioesters in the reaction catalyzed by fatty acyl-CoA synthetase ... 

In mammals, acetyl CoA from fatty acid oxidation cannot be used for the net synthesis of pyruvate or oxaloacetate, which in turn means that net glucose synthesis from acetyl CoA is impossible. However, glucose can be radioactively labeled when C-labeled acetate is introduced into human tissue culture cells and converted to acetyl CoA by acetyl CoA synthetase. Radioactive fatty acids can also be used to label glucose. Why If the methyl carbon of acetate is labeled, where will glucose be labeled ... 

The short chain activating enzyme, acetyl-CoA synthetase, showed a similar developmental increment. Palmitylcarnitine transferase activity of developing rat liver and heart homogenates increased from negligible levels at the time of birth to adult levels by thirty days of age (Fig. 4). These changes were associated with a large increase in the overall rate of fatty acid oxidation in the rat (Fig. 5). Thus, both fatty acid activation and acylcarnitine transferase activity appear to be of considerable importance for the development of fatty acid oxidation in the rat. Augenfeldt... 

In conclusion, it is very likely that pantethine stimulated fatty acid oxidation through activation of fatty acyl CoA synthetase after conversion to phosphopantetheine and through stimulation of the mitochondrial membrane transport system of acyl CoA which is the key step of fatty acid oxidation [ 12 ]. Further studies are now in progress along this line. 

FIGURE 24.7 The acyl-CoA synthetase reaction activates fatty acids for /3-oxidation. The reaction is driven by hydrolysis of ATP to AMP and pyrophosphate and by the subsequent hydrolysis of pyrophosphate. 

Acyl-CoA synthetases are enzymes (i.e., ligases) that convert fatty acid molecules into acyl-Coenzyme A molecules for their subsequent oxidation. 

After a LCFA enters a cell, it is converted to the CoA derivative by long-chain fatty acyl CoA synthetase (thiokinase) in the cytosol (see p. 174). Because 0-oxidation occurs in the mitochondrial matrix, the fatty acid must be transported across the mitochon drial inner membrane. Therefore, a specialized carrier transports the long-chain acyl group from the cytosol into the mitochondrial matrix. This carrier is carnitine, and the transport process is called the carnitine shuttle (Figure 16.16). 

In the ruminant mammary tissue, it appears that acetate and /3-hydroxybutyrate contribute almost equally as primers for fatty acid synthesis (Palmquist et al. 1969 Smith and McCarthy 1969 Luick and Kameoka 1966). In nonruminant mammary tissue there is a preference for butyryl-CoA over acetyl-CoA as a primer. This preference increases with the length of the fatty acid being synthesized (Lin and Kumar 1972 Smith and Abraham 1971). The primary source of carbons for elongation is malonyl-CoA synthesized from acetate. The acetate is derived from blood acetate or from catabolism of glucose and is activated to acetyl-CoA by the action of acetyl-CoA synthetase and then converted to malonyl-CoA via the action of acetyl-CoA carboxylase (Moore and Christie, 1978). Acetyl-CoA carboxylase requires biotin to function. While this pathway is the primary source of carbons for synthesis of fatty acids, there also appears to be a nonbiotin pathway for synthesis of fatty acids C4, C6, and C8 in ruminant mammary-tissue (Kumar et al. 1965 McCarthy and Smith 1972). This nonmalonyl pathway for short chain fatty acid synthesis may be a reversal of the /3-oxidation pathway (Lin and Kumar 1972). 

Fatty acids are utilized as fuels by most tissues, although the brain, red and white blood cells, the retina, and adrenal medulla are important exceptions. Catabolism of fatty acids requires extramitochondrial activation, transport into mitochondria, and then oxidation via the /3-oxidative pathway. The initial step is catalyzed by fatty acyl-CoA synthetase (also called thiokinase and fatty acyl-CoA ligase), as shown in Equation (19.5). The product, fatty acyl-CoA, then exchanges the CoA for carnitine, as shown in Equation (19.6) ... 

Fatty acid synthetase has all the activities that would be necessary to reverse the /8-oxidation pathway. Thus, a cis double bond is generated from /3-hydroxy fatty acyl-CoA residues by a dehydration process. 

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