The Fatty Acid Spiral

Fifty years were to pass before it became possible to define the individual enzyme steps in the 6-oxidative process outlined above. No intermediates in the pathway could be found in vivo nor was it possible to detect them in the isolated systems then in use, such as tissue slices. Simpler preparations were needed before the details of the enzymology could be established. 

In 1942, Lynen found acetate oxidation in starved yeast required the addition of energy which could be provided from the oxidation of 

The actual pathway by which fatty acid oxidation occurred was established by Lynen (1952-1953). Its unique and characteristic reaction was the thioclastic attack by coenzyme A on the B-ketoacyl CoA derivative, splitting off the 2C fragment, acetyl CoA. Free coenzyme A was very difficult to isolate and although it was synthesized in Todd s laboratory in Cambridge in the mid-1950s, much of the early work from Lynen s laboratory utilized A-acetyl cysteamine as a not very efficient (ca.1%) coenzyme A analogue. It carried the essential thiol group of the B-mercaptoethylamine end of CoA and could be used in most, but not all, of the steps in the spiral. 

Lynen had studied chemistry in Munich under Wieland his skill as a chemist led to the successful synthesis of a number of fatty acyl CoA derivatives which proved to be substrates in the catabolic pathway. Many of these C=0 or C=C compounds had characteristic UV absorption spectra so that enzyme reactions utilizing them could be followed spectrophotometrically. This technique was also used to identify and monitor the flavoprotein and pyridine nucleotide-dependent steps. Independent evidence for the pathway was provided by Barker, Stadtman and their colleagues using Clostridium kluyveri. Once the outline of the degradation had been proposed the individual steps of the reactions were analyzed very rapidly by Lynen, Green, and Ochoa s groups using in the main acetone-dried powders from mitochondria, which, when extracted with dilute salt solutions, contained all the enzymes of the fatty acid oxidation system. 

The mechanism of the initial, cytoplasmic, activation of the fatty acids was established in Lipmann s laboratory  

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The oxidation of fatty acids within the Knoop-Lynen cycle occurs in the matrix. The Knoop-Lynen cycle includes four enzymes that act successively on acetyl-CoA. These are acyl-CoA dehydrogenase (FAD-dependent enzyme), enoyl-CoA hydratase, 3-hydroxyacyl-CoA dehydrogenase (NAD-dependent enzyme), and acetyl-CoA acyltrans-ferase. Each turn, or revolution, of the fatty acid spiral produces... 

FATTY ACID SYNTHESIS The Reversibility of the Fatty Acid Spiral... 

Fatty acids have a basic structure, R-COOH, and the important fatty acids have long chains with an even number of carbon atoms (C12-C20), which may be described as saturated (e.g., stearic acid, C18 l), monounsaturated (e.g., oleic acid, C18 2), and polysaturated (e.g., linoleic, C18 2, and linolenic, C18 3, acids). These long chain fatty acids are used to provide energy by beta-oxidation, which shortens the fatty acid by two carbon atoms with the production of acetyl CoA (known as the fatty acid spiral). 

A number of detailed pathways such as glycolysis, the fatty acid spiral, and the urea cycle will be presented. Don t let the numerous reactions in these pathways intimidate you. Although each reaction could be looked at individually, we have tried to help you focus your attention by emphasizing the overall importance of each pathway by identifying its purpose, cellular location, starting material, products, energy requirements, and regulation. 

The new fatty acyl compound enters the p-oxidation process at Step 1, and the sequence is repeated until the fatty acyl CoA is completely degraded to acetyl CoA (Figure 14.5). The fatty acyl CoA molecule that starts each run through the P-oxidation process is two carbons shorter than the one going through the previous run. For this reason, the p-oxidation pathway for fatty acid degradation to acetyl CoA is often called the fatty acid spiral (rather than cycle). 

Figure 14.5 The fatty acid spiral P-oxidation of stearic add.

As a stearoyl CoA molecule (18 carbons) passes through the p-oxidation spiral, 9 acetyl CoA, 8 FADH2, and 8 NADH molecules are produced. Acetyl CoA produced in the fatty acid spiral can enter the citric acid cycle (followed by the electron transport chain), where each molecule of acetyl CoA results in the production of 10 ATP molecules. In addition, when the FADH2 and NADH molecnles enter the electron transport chain, each FADH2 yields 1.5 ATP molecules, and each NADH yields 2.5 molecules. The calculations are summarized in I Table 14.1, which shows a total of 120 molecules of ATP formed from the 18-carbon fatty acid. 

Every trip through the fatty acid spiral produces one NADH + H molecule and one FADH2 molecule. Thus,... 

Why is the oxidation of fatty acids referred to as the fatty acid spiral rather than the fatty acid cycle ... 

Complete the following equations for one turn of the fatty acid spiral ... 

Fig. 4.11. The conversion of fats to sucrose in germinating fatty seeds. The reactions of the fatty-acid spiral and glyoxylate cycle are shown to occur in the glyoxysome, the conversion of succinate to phosphoenolpyruvate in the mitochondrion and the remaining reactions at sites other than these.

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