Acyl CoA synthetase

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. 

FIGURE 24.8 The mechanism of the acyl-CoA synthetase reaction involves fatty acid carboxylate attack on ATP to form an acyl-adenylate intermediate. The fatty acyl CoA thioester product is formed by CoA attack on this intermediate. 

Mammals can add additional double bonds to unsaturated fatty acids in their diets. Their ability to make arachidonic acid from linoleic acid is one example (Figure 25.15). This fatty acid is the precursor for prostaglandins and other biologically active derivatives such as leukotrienes. Synthesis involves formation of a linoleoyl ester of CoA from dietary linoleic acid, followed by introduction of a double bond at the 6-position. The triply unsaturated product is then elongated (by malonyl-CoA with a decarboxylation step) to yield a 20-carbon fatty acid with double bonds at the 8-, 11-, and 14-positions. A second desaturation reaction at the 5-position followed by an acyl-CoA synthetase reaction (Chapter 24) liberates the product, a 20-carbon fatty acid with double bonds at the 5-, 8-, IT, and ITpositions. 

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

Gene activated Lipoprotein lipase fatty acid transporter protein adipocyte fatty acid binding protein acyl-CoA synthetase malic enzyme GLUT-4 glucose transporter phosphoenolpyruvate carboxykinase... 

Fatty acid transport protein paralogues 1-6 FATP 1-6 Gene symbols SLC27A1-6 Solute carrier family 27A Very long-chain acyl-CoA synthetase VLCS... 

Acyl-CoA Synthetase Adaptive Immunity Adaptor Proteins Addiction Addison s Disease Additive Interaction Adenosine Adenosine Receptors Adenoviruses Adenylate Cyclase Adenylyl Cyclases ADH ADHD... 

Venus Flytrap Module Very Long-chain Acyl-CoA Synthetase Very Low-density Lipoprotein Vesicle... 

Mitochondria have an outer membrane that is permeable to most metabohtes, an inner membrane that is selectively permeable, and a matrix within (Figure 12-1). The outer membrane is characterized by the presence of various enzymes, including acyl-CoA synthetase and glycerolphosphate acyltransferase. Adenylyl kinase and creatine kinase are found in the intermembrane space. The phospholipid cardiolipin is concentrated in the inner membrane together with the enzymes of the respiratory chain. 

The free fatty acids formed by lipolysis can be reconverted in the tissue to acyl-CoA by acyl-CoA synthetase and reesterified with glycerol 3-phosphate to form triacylglycerol. Thus, there is a continuous cycle of lipolysis and reesterification within the tissue. However, when the rate of reesterification is not sufficient to match the rate of lipolysis, free fatty acids accumulate and diffuse into the plasma, where they bind to albumin and raise the concentration of plasma free fatty acids. 

The fatty acids, as produced by intracellular hydrolysis of triacylglycerides or supplied to the cell from the blood, must be brought into a state of activation. Their activation is effected in the cytoplasm with the participation of acyl-CoA synthetase according to the scheme ... 

A new pathway was recently engineered in vitro employing purified His6-tag-ged PhaCl and PhaC2 from P. aeruginosa plus a commercially available acyl-CoA synthetase allowing in vitro de novo PHA granules and in vitro synthesis of poly(3HD) from 3-hydroxydecanoate [74]. 

Herrmann, T., et al. Mouse fatty acid transport protein 4 (FATP4) characterization of the gene and functional assessment as a very long chain acyl-CoA synthetase. Gene 2001, 270,... 

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. 

Pantothenic acid CoA i Fatty acid synthase Fatty acyl CoA synthetase Pyruvate dehydrogenase ci-Ketoglutarate dehydrogenase Fatty acid metabolism PDH TCA cycle Rare... 

When fatty adds are used in metabolism, they are first activated by attaching coenzyme A (CoA) fatty acyl CoA synthetase catalyzes this activation step. The product is genetically referred to as a fatty acyl CoA or sometimes just acyl CoA. Specific examples would be acetyl CoA with a 2-carbon acyl group, or palmitoyl CoA with a 16-carbon acyl group. 

Long-chain fatty acids must be activated and transported into the mitochondria. Fatty acyl CoA synthetase, on the outer mitochondrial membrane, activates the fatty adds by attaching CoA. The fetty acyl portion is then transferred onto carnitine by carnitine aqdtransferase-I for transport into the mitochondria. The sequence of events is shown in Figure 1-16-2 and indudes the following steps ... 

There are three acyl-CoA synthetases, which are specific for fatty acids of different chain lengths ... 

Short-chain acyl-CoA synthetase activates short-chain fatty acids, acetic, butyric and propionic acid. The enzyme is present in both the cytosol and in the mitochondrial matrix of most tissues the activity is especially high in the liver and the colon. 

Medium-chain acyl-CoA synthetase, which is present within the mitochondrial matrix of the liver, activates fatty acids containing from four to ten carbon atoms. Medium-chain length fatty acids are obtained mainly from triacylglycerols in dairy products. However, unlike long-chain fatty acids, they are not esterified in the epithelial cells of the intestine but enter the hepatic portal vein as fatty acids to be transported to the liver. Within the liver, they enter the mitochondria directly, where they are converted to acyl-CoA, which can be fully oxidised and/or converted into ketone bodies. The latter are released and can be taken up and oxidised by tissues. 

Long-chain acyl-CoA synthetase activates fatty acids containing from 10 to 18 carbon atoms. 

A separate very long-chain-acyl-CoA synthetase is present in peroxisomes for the activation of very long-chain fatty acids, such as arachidonate (20 carbon atoms). These fatty acids are degraded exclusively in the peroxisomes. 

---