From fatty acid oxidation

Migratory Birds Travel Long Distances on Energy from Fatty Acid Oxidation... 

Even though acetate units, such as those obtained from fatty acid oxidation, cannot be used for net synthesis of carbohydrate in animals, labeled carbon from " C-labeled acetate can be found in newly synthesized glucose (for example, in liver glycogen) in animal tracer studies. Explain how this can be. Which carbons of glucose would you expect to be the first to be labeled by "Relabeled acetate ... 

FIGURE 25.1 The citrate-malate-pyruvate shuttle provides cytosolic acetate units and reducing equivalents (electrons) for fatty acid synthesis. The shuttle collects carbon substrates, primarily from glycolysis but also from fatty acid oxidation and amino acid catabolism. Most of the reducing equivalents are glycolytic in origin. Pathways that provide carbon for fatty acid synthesis are shown in blue pathways that supply electrons for fatty acid synthesis are shown in red. 

The role of fatty acids as oxidizable fuels for brain metabolism is negligible, but ketone bodies, derived from fatty acid oxidation, can be utilized, particularly in the neonatal period. Diseases of carbohydrate and fatty acid metabolism may affect the brain directly or indirectly [1,10]. 

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. 

In the second stage of fatty acid oxidation, the acetyl-CoA is oxidized to C02 in the citric acid cycle. A large fraction of the theoretical yield of free energy from fatty acid oxidation is recovered as ATP by oxidative phosphorylation, the final stage of the oxidative pathway. 

Energy yield from fatty acid oxidation The energy yield from ihe P-oxidation pathway is high. For example, the oxidation of a molecule of palmitoyl CoA to C02 and H20 yields 131 AIRs (Figure 16.19). A comparison of the processes of synthesis and degradation of saturated fatty acids with an even number of car bon atoms is provided in Figure 16.20. 

Liver mitochondria can convert acetyl CoA derived from fatty acid oxidation into the ketone bodies, acetoacetate and (3-hydroxybutyrate. (Acetone, a nonmetabolizable ketone body, is produced spontaneously from acetoacetate in the blood.) Peripheral tissues possessing mitochondria can oxidize 3-hydroxybutyrate to acetoacetate, which can be reconverted to acetyl CoA, thus producing energy for the cell. 

Acetyl-CoA from fatty acid oxidation enters the TCA cycle in the same way as does acetyl-CoA derived from glucose addition to oxaloacetate to make citrate. This can cause complications if an individual is metabolizing only fat, because the efficient metabolism of fat requires a supply of TCA-cycle intermediates, especially dicar-boxylic acids, which can t (usually) be made from fatty acids. These intermediates must be supplied by the metabolism of carbohydrates, or more often, amino acids derived from muscle tissue. 

Carbohydrates are introduced into the Krebs cycle at the point where pyruvate dehydrogenase catalyzes conversion of pyruvate to acetyl-Co A with the concomitant reduction of NAD. Citrate synthase catalyzes introduction of the 2-carbon unit of acetyl-CoA into the Krebs cycle. Pyruvate can arise from glucose, fructose, lactate, alanine, and glycerol. Acetyl-CcjAcan arise from pyruvate, as well as from fatty acids. Oxidation of fatty acids results in production of acetyl-Co A, which enters the Krebs cycle at the point catalyzed by citrate synthase. Breakdown of ketogenic amino adds also results in the production of acctyl-CoA, which enters the Krebs cycle at this point. Citrate and malate occur in high cor centrations in certain fruits and vegetables. These chemicals directly enter the Krebs cycle at the indicated points. 

An insulin infusion should be considered for severe cases of calcium channel blocker toxicity." Case reports suggest that an intravenous bolus of regular insulin (0.5-1 units/kg) with 50 mL dextrose 50% (0.25 mg/kg for children) followed with a continuous infusion of regular insulin (0.5-1 units/kg per hour) may improve myocardial contractility. The effect of insulin is presently unclear, but it may improve myocardial metabolism that is adversely affected by calcium channel blocker overdoses, such as decreased cellular uptake of glucose and free fatty acids and a shift from fatty acid oxidation to carbohydrate metabolism. This insulin regimen is titrated to improvement in systolic blood pressure over 100 mm Hg and heart rate... 

Though the reactions in fatty acid biosynthesis resemble the reversal of the analogous reactions in oxidation, fatty acid synthesis is distinct from fatty acid oxidation (Figure 18.23). For example, acyl groups are carried by acyl carrier protein in fatty acid synthesis, instead of coenzyme A. Furthermore, reducing equivalents come from NADPH and energy is provided by ATP. Overall, the biosynthesis of palmitate from 8 acetyl-CoAs requires 7 ATPs and 14 NADPHs. 

The transport of hydrogen ions out of the cell is also important for maintenance of a constant intracellular pH. Metabolism produces a number of other acids in addition to CO2. For example, the metabolic acids acetoacetic acid and (3-hydroxybutyric acid are produced from fatty acid oxidation to ketone bodies in the liver, and lactic acid is produced by glycolysis in muscle and other tissues. The pKa for most metabolic carboxylic acids is below 5, so these acids are completely dissociated at the pH of blood and cellular fluid. Metabolic anions are transported out of the cell together with H (see Fig. 4.9, circle 8). If the cell becomes too acidic, more H is transported out in exchange for Na ions by a different transporter. If the cell becomes too alkaline, more bicarbonate is transported out in exchange for Cl ions. 

PDC stimulates its phosphorylation to the inactive form. The substrates of the enzyme, CoASH and NAD, antagonize this product inhibition. Thus, when an ample supply of acetyl CoA for the TCA cycle is already available from fatty acid oxidation, acetyl CoA and NADH build up and dramatically decrease their own further synthesis by PDC. 

In addition to NADH dehydrogenase, succinic dehydrogenase and other flavopro-teins in the inner mitochondrial membrane also pass electrons to CoQ (see Fig. 21.5). Succinate dehydrogenase is part of the TCA cycle. ETF-CoQ oxidore-ductase accepts electrons from ETF (electron transferring flavoprotein), which acquires them from fatty acid oxidation and other pathways. Both of these flavo-proteins have Fe-S centers. a-Glycerophosphate dehydrogenase is a flavoprotein that is part of a shuttle for reoxidizing cytosolic NADH. 

In the liver, much of the acetyl CoA generated from fatty acid oxidation is converted to the ketone bodies, acetoacetate and p-hydroxybutyrate, which enter the blood (see Fig. 23.1). In other tissues, these ketone bodies are converted to acetyl... 

Between meals, a decreased insulin level and increased levels of insulin counter-regulatory hormones (e.g., glucagon) activate hpolysis, and free fatty acids are transported to tissues bound to serum albumin. Within tissnes, energy is derived from oxidation of fatty acids to acetyl CoA in the pathway of -oxidation. Most of the enzymes involved in fatty acid oxidation are present as 2-3 isoenzymes, which have different but overlapping specificities for the chain length of the fatty acid. Metabolism of unsaturated fatty acids, odd-chain-length fatty acids, and medium-chain-length fatty acids requires variations of this basic pattern. The acetyl CoA produced from fatty acid oxidation is principally oxidized in the TCA cycle or converted to ketone bodies in the liver. 

In the liver, ketone bodies are synthesized in the mitochondrial matrix from acetyl CoA generated from fatty acid oxidation (Fig. 23.18). The thiolase reaction of fatty acid oxidation, which converts acetoacetyl CoA to two molecules of acetyl CoA, is a reversible reaction, although formation of acetoacetyl-CoA is not the favored direction. It can, thus, when acetyl-CoA levels are high, generate acetoacetyl CoA... 

Al Martini s admitting physician suspected an alcohol-induced ketoacidosis superimposed on a starvation ketoacidosis. Tests showed that his plasma free fatty acid level was elevated, and his plasma (3-hydroxybutyrate level was 40 times the upper limit of normal. The increased NADH/NAD ratio from ethanol consumption inhibited the TCA cycle and shifted acetyl CoA from fatty acid oxidation into the pathway of ketone body synthesis. 

Fig. 31.5. Conversion of pyruvate to phosphoenolpyruvate (PEP). Follow the shaded circled numbers on the diagram, starting with the precursors alanine and lactate. The first step is the conversion of alanine and lactate to pyruvate. Pyruvate then enters the mitochondria and is converted to OAA (circle 2) by pyruvate carboxylase. Pyruvate dehydrogenase has been inactivated by both the NADH and acetyl-CoA generated from fatty acid oxidation, which allows oxaloacetate production for gluconeogenesis. The oxaloacetate formed in the mitochondria is converted to either malate or aspartate to enter the cytoplasm via the malate/aspartate shuttle. Once in the cytoplasm the malate or aspartate is converted back into oxaloacetate (circle 3), and phosphoenolpyruvate carboxykinase will convert it to PEP (circle 4). The white circled numbers are alternate routes for exit of carbon from the mitochondrion using the malate/aspartate shuttle. OAA = oxaloacetate FA = fatty acid TG = triacylglycerol.

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