Coenzyme A derivatives

Once formed cholesterol undergoes a number of biochemical transformations A very common one is acylation of its C 3 hydroxyl group by reaction with coenzyme A derivatives of fatty acids Other processes convert cholesterol to the biologically impor tant steroids described m the following sections... 

Two particularly interesting aspects of the pyruvate carboxylase reaction are (a) allosteric activation of the enzyme by acyl-coenzyme A derivatives and (b) compartmentation of the reaction in the mitochondrial matrix. The carboxy-lation of biotin requires the presence (at an allosteric site) of acetyl-coenzyme A or other acylated coenzyme A derivatives. The second half of the carboxylase reaction—the attack by pyruvate to form oxaloacetate—is not affected by CoA derivatives. 

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. 

This enzyme [EC 2.3.1.26], also known as sterol O-acyl-transferase, sterol-ester synthase, and cholesterol acyl-transferase, catalyzes the reaction of an acyl-coenzyme A derivative with cholesterol to produce coenzyme A and the cholesterol ester. The animal enzyme is highly specific for transfer of acyl groups having a single cis double bond at C9. 

A class of enzymes that catalyze the interconversion of one enantiomer with its mirror image. Care must be exercised in applying this term. For example, the enzyme that interconverts D-methyhnalonyl-CoA to L-meth-ylmalonyl-CoA is not a racemase, but is instead an epi-merase the two coenzyme A derivatives are diastereo-isomeric, and not enantiomeric, with respect to each other. 

The a-keto acids then undergo oxidative decarboxylation to their coenzyme A derivatives catalyzed by branched-chain a-keto acid dehydrogenase. 

CoA, the coenzyme A derivative of acetoacetate, reduces its reactivity as a substrate for /3-ketoacyl-CoA transferase (an enzyme of lipid metabolism) by a factor of 106. Although this requirement for adenosine has not been investigated in detail, it must involve the binding energy between enzyme and substrate (or cofactor) that is used both in catalysis and in stabilizing the initial enzyme-substrate complex (Chapter 6). In the case of /3-ketoacyl-CoA transferase, the nucleotide moiety of coenzyme A appears to be a binding handle that helps to pull the substrate (acetoacetyl-CoA) into the active site. Similar roles may be found for the nucleoside portion of other nucleotide cofactors. 

In peroxisomes, membrane-enclosed organelles of animal and plant cells, the intermediates for /3 oxidation of fatty acids are coenzyme A derivatives, and the process consists of four steps, as in mitochondrial /3 oxidation (Fig. 17-13) (1) dehydrogenation, (2) addition of water to the resulting double bond, (3) oxidation of the /3-hydroxyacyl-CoA to a ketone, and (4) thiolytic cleavage by coenzyme A (The identical reactions also occur in glyoxysomes, as discussed below.)... 

Compart mentation in fi Oxidation Free palmitate is activated to its coenzyme A derivative (palmitoyl-CoA) in the cytosol before it can be oxidized in the mitochondrion. If palmitate and [ CJcoenzyme A are added to a liver homogenate, palmitoyl-CoA isolated from the cytosolic fraction is radioactive, but that isolated from the mitochondrial fraction is not. Explain. 

Oxidative phosphorylation produces most of the ATP made in aerobic cells. Complete oxidation of a molecule of glucose to C02 yields 30 or 32 ATP (Table 19-5). By comparison, glycolysis under anaerobic conditions (lactate fermentation) yields only 2 ATP per glucose. Clearly, the evolution of oxidative phosphorylation provided a tremendous increase in the energy efficiency of catabolism. Complete oxidation to C02 of the coenzyme A derivative of palmitate (16 0), which also occurs in the mitochondrial matrix, yields 108 ATP per palmitoyl-... 

Fatty acids shorter than twelve carbons can cross the inner mita chondrial membrane without the aid of carnitine or the CPTsystem Once inside the mitochondria, they are activated to their coenzyme A derivatives by matrix enzymes, and are oxidized. [Note MCfAs are plentiful in human milk. Because their oxidation is not depen dent on CPT-I, it is not subject to inhibition by malonyl CoA.]... 

Figure 21-3 Major pathways of synthesis of fatty acids and glycerolipids in the green plant Arabidopsis. The major site of fatty acid synthesis is chloroplasts. Most is exported to the cytosol as oleic acid (18 1). After conversion to its coenzyme A derivative it is converted to phosphatidic acid (PA), diacylglycerol (DAG), and the phospholipids phosphatidylcholine (PC), phosphatidylinositol (PI), phosphatidylglycerol (PG), and phosphatidylethanolamine (PE). Desaturation also occurs, and some linoleic and linolenic acids are returned to the chloroplasts. See text also. From Sommerville and Browse.106 See also Figs. 21-4 and 21-5. Other abbreviations monogalactosyldiacylglycerol (MGD), digalactosyldiacylglycerol (DGD), sulfolipid (SL), glycerol 3-phosphate (G3P), lysophosphatidic acid (LPA), acyl carrier protein (ACP), cytidine diphosphate-DAG (CDP-DAG).

The researchers incubated the coenzyme A derivative of each acid with rat liver mitochondria for 5 minutes, then separated the remaining CoA derivatives in each mixture by HPLC (high-performance liquid chromatography). The results are shown below, with separate panels for the three experiments. 

The initial step in the metabolism of short-chain fatty acids, whether in cells of the gut lining or in the liver, is conversion to the coenzyme A derivative. For example, acetate is converted to acetyl coenz)mie A (acetyl CoA). The acetyl CoA formed in the cytoplasm can be used for the synthesis of fatty acids, whereas that formed in the mitochondria can be used for immediate oxidation. Propionyl CoA can be metabolized as shown in Figure 8.7 in Chapter 8. Butyric acid can enter the mitochondria for conversion to but5rryl CoA and oxidation in the pathway of fatty acid oxidation. 

The concentration of free pantothenic acid in the liver is about 15 xM that in the heart is about tenfold greater (Robishaw and Neely, 1985). The concentration of the cofactor form of the vitamin, coenzyme A, is higher in the mitochondrion than in the cytosol. In the Ever, cytosolic coenzyme A is about 0.06 mM, and mitochondrial coenzjmie A, about 2.6 mM. In the liver, about 70% of coenzyme A is mitochondrial, whereas in the heart about 95% is mitochondrial (Tahiliani and Neely, 1987). These values might be compared with that for carnitine, another molecule used in the handling of fatty acids. Please consult the Carnitine section in Chapter Four. About half of the coenzjrme A in liver occurs as the long-chain fatty acyl-coenzyme A derivative. The concentration of fatty acid s)mthase in the cytoplasm is quite low, about 0.01 pM. Hence, the concentration of the 4 -phospho-pantetheine cofactor is much lower than that of coenzyme A. The pantothenic acid boimd to this enzyme does not make a significant contribution to our dietary vitamin. 

Other cofactors involved in deriving energy from food include coenzyme A (derived from the vitamin pantothenate), thiamine pyrophosphate, and Upoic acid. 

The (3-oxidation cycle activates A" VPA to its Coenzyme A derivative and, through sequential steps of (3-oxidation, yields the Coenzyme A ester of 3-oxo-2-propyl-4-pentenoic acid. This hnal metabolite is believed to be a... 

Electrons from succinate are transferred to FAD in complex n and several Fe-S centers and then to UQ. Electrons from cytoplasmic NADH are transferred to UQ via a pathway involving glycerol-3-phosphate and the flavoprotein glycerol-3-phosphate dehydrogenase (see p. 316). Fatty acids are oxidized as coenzyme A derivatives. Acyl-CoA dehydrogenase, one of several enzymes in fatty acid oxidation, transfers 2 electrons to FAD. They are then donated to UQ. 

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