Beta oxidation
From Proteopedia
In biochemistry and metabolism, beta-oxidation is the catabolic process by which fatty acid molecules are broken down. See also [1]. Activation and membrane transport 1) Long-chain-fatty-acid-CoA ligase catalyzes the reaction between a fatty acid with ATP to give a fatty acyl adenylate, plus inorganic pyrophosphate, which then reacts with free coenzyme A to give a fatty acyl-CoA ester and AMP. 2) If the fatty acyl-CoA has a long chain, then the shuttle must be utilized: a) Acyl-CoA is transferred to the hydroxyl group of carnitine by carnitine palmitoyltransferase I (see Carnitine palmitoyltransferase), located on the cytosolic faces of the outer and inner mitochondrial membranes. b) Acyl-carnitine is shuttled inside by a carnitine-acylcarnitine translocase, as a carnitine is shuttled outside. c) Acyl-carnitine is converted back to acyl-CoA by carnitine palmitoyltransferase II (see Carnitine palmitoyltransferase), located on the interior face of the inner mitochondrial membrane. The liberated carnitine is shuttled back to the cytosol, as an acyl-carnitine is shuttled into the matrix. 3) If the fatty acyl-CoA contains a short chain, these short-chain fatty acids can simply diffuse through the inner mitochondrial membrane. General mechanism Even-numbered saturated fatty acids Once the fatty acid is inside the mitochondrial matrix, beta-oxidation occurs by cleaving two carbons every cycle to form . The process consists of 4 steps. 1) A long-chain fatty acid is dehydrogenated to create a trans double bond between C2 and C3. This is catalyzed by acyl-CoA dehydrogenase to produce trans-delta 2-enoyl CoA. It uses FAD as an electron acceptor and it is reduced to FADH2. 2) Trans-delta2-enoyl CoA is hydrated at the double bond to produce L-3-hydroxyacyl CoA by enoyl-CoA hydratase. 3) L-3-hydroxyacyl CoA is dehydrogenated again to create 3-ketoacyl CoA by 3-hydroxyacyl CoA dehydrogenase. This enzyme uses NAD as an electron acceptor. 4) Thiolysis occurs between C2 and C3 (alpha and beta carbons) of 3-ketoacyl CoA. Thiolase enzyme catalyzes the reaction when a new molecule of coenzyme A breaks the bond by nucleophilic attack on C3. This releases the first two carbon units, as acetyl CoA, and a fatty acyl CoA minus two carbons. The process continues until all of the carbons in the fatty acid are turned into acetyl CoA. Odd-numbered saturated fatty acids Chains with an odd-number of carbons are oxidized in the same manner as even-numbered chains, but the final products are and . Propionyl-CoA is first carboxylated using a bicarbonate ion into D-stereoisomer of methylmalonyl-CoA, in a reaction that involves a biotin co-factor, ATP, and the enzyme propionyl-CoA carboxylase. The bicarbonate ion's carbon is added to the middle carbon of propionyl-CoA, forming a D-methylmalonyl-CoA. However, the D conformation is enzymatically converted into the L conformation by methylmalonyl-CoA epimerase, then it undergoes intramolecular rearrangement, which is catalyzed by methylmalonyl-CoA mutase (requiring B12 as a coenzyme) to form . The succinyl-CoA formed can then enter the Citric Acid Cycle. However, whereas acetyl-CoA enters the citric acid cycle by condensing with an existing molecule of oxaloacetate, succinyl-CoA enters the cycle as a principal in its own right. Thus the succinate just adds to the population of circulating molecules in the cycle and undergoes no net metabolization while in it. When this infusion of citric acid cycle intermediates exceeds cataplerotic demand (such as for aspartate or glutamate synthesis), some of them can be extracted to the gluconeogenesis pathway, in the liver and kidneys, through phosphoenolpyruvate carboxykinase, and converted to free glucose. Unsaturated fatty acids β-Oxidation of unsaturated fatty acids poses a problem since the location of a cis bond can prevent the formation of a trans-Δ2 bond. These situations are handled by an additional two enzymes, Enoyl CoA isomerase or 2,4 Dienoyl CoA reductase. Peroxisomal beta-oxidation Fatty acid oxidation also occurs in peroxisomes when the fatty acid chains are too long to be handled by the mitochondria. The same enzymes are used in peroxisomes as in the mitochondrial matrix, and acetyl-CoA is generated. It is believed that very long chain (greater than C-22) fatty acids, branched fatty acids, some prostaglandins and leukotrienes undergo initial oxidation in peroxisomes until is formed, at which point it undergoes mitochondrial oxidation.
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