Lynen cycle

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... 

At high concentrations of acetyl-CoA in the liver mitochondria, two molecules condense to form acetoacetyl CoA [1]. The transfer of another acetyl group [2] gives rise to 3-hydroxy-3-methylglutaryl-CoA (HMC CoA), which after release of acetyl CoA [3] yields free acetoacetate (Lynen cycle). Acetoacetate can be converted to 3-hydroxybutyrate by reduction [4], or can pass into acetone by nonenzymatic decarboxylation [5]. These three compounds are together referred to as "ketone bodies," although in fact 3-hydroxy-butyrate is not actually a ketone. As reaction [3] releases an ion, metabolic acidosis can occur as a result of increased ketone body synthesis (see p. 288). 

Lynen, and Virtanen and Sundman have reported that in yeast, acetate is metabolized by way of the tricarboxylic cycle. Wieland and Rosenthal have also shown that kidney contains an enzyme system which can convert acetate or acetoacetate to citrate. Upon addition of oxalacetate along with either of these acids, the yield of citrate is significantly increased. In these experiments barium ions were added to inhibit further breakdown of the resulting citrate. These authors have proposed that oxalacetate and acetoacetate condense to form either acetyl citrate or citroyl acetate which are subsequently hydrolyzed to citrate and acetate. 

Many aroma compounds in fruits and plant materials are derived from lipid metabolism. Fatty acid biosynthesis and degradation and their connections with glycolysis, gluconeogenesis, TCA cycle, glyoxylate cycle and terpene metabolism have been described by Lynen (2) and Stumpf ( ). During fatty acid biosynthesis in the cytoplasm acetyl-CoA is transformed into malonyl-CoA. The de novo synthesis of palmitic acid by palmitoyl-ACP synthetase involves the sequential addition of C2-units by a series of reactions which have been well characterized. Palmitoyl-ACP is transformed into stearoyl-ACP and oleoyl-CoA in chloroplasts and plastides. During B-oxi-dation in mitochondria and microsomes the fatty acids are bound to CoASH. The B-oxidation pathway shows a similar reaction sequence compared to that of de novo synthesis. B-Oxidation and de novo synthesis possess differences in activation, coenzymes, enzymes and the intermediates (SM+)-3-hydroxyacyl-S-CoA (B-oxidation) and (R)-(-)-3-hydroxyacyl-ACP (de novo synthesis). The key enzyme for de novo synthesis (acetyl-CoA carboxylase) is inhibited by palmitoyl-S-CoA and plays an important role in fatty acid metabolism. 

Lynen, F. 1952-1953. Acetyl coenzyme A and the fatty acid cycle. Harvey Lect. Sen 48 210-244. 

Data which were not available at the time this report was prepared indicate that coenzyme A plays as crucial a role in the metabolism of fatty acids as that of phosphate in carbohydrate metabolism. Lynen (1952, 1953) has described a fatty acid cycle of reversible reactions which can result either in the breakdown of fatty acids to acetyl-CoA or in the synthesis of fatty acids from acetyl-CoA. The reactions can be summarized as follows ... 

Martius, C., Lynen, F. Probleme des Citronensaurecyklus (Problems of citric acid cycle). Advanc. Enzymol. 10, 167-222 (1950)... 

Fio. 42 (after Lynen)—The enzymatic cycle for the fatty acids. (This process can also be considered as a spiral of fatty acids, a Ca fragment being lost or gained at each turn in the form of CHjCO—S—CoA. In Fig. 42, the change from one turn of the spiral to the next, with addition or subtraction of a Ca fragment, is indicated by the dotted arrow.)... 

Using the crystalline enzyme and a precious sample of acetyl-CoA sent by Lynen, Ochoa was able to show in 1951 that the condensing enzyme required only this compound and oxaloacetic acid to produce citric acid. The key reaction of the Krebs cycle was thus formulated ... 

In 1948 Ochoa demonstrated the existence of an enzyme, isocitric dehydrogenase, which catalyzed the oxidation of isocitric acid and required NADP. He was, however, unable to demonstrate the formation of the expected product oxalosuccinic acid (Fig. 1). The existence of this acid as an intermediate in the Krebs cycle had been postulated by Carl Martius. Ochoa was able to prepare the compound by chemical synthesis and showed that cell extracts catalyzed the decarboxylation of this very unstable /S-keto acid to a-ketoglutaric acid. Similar results were simultaneously obtained by Lynen in Germany. 

Lynen, F. (1953) Functional group of coenzyme A and its metabolic relations, especially in the fatty acid cycle. Ferf. Proc. 12, 683-691. 

The newer development began in 1942 when Lynen - reported experiments which in his view supported the occurrence of the tricarboxylic acid cycle in yeast cells, but the evidence was not generally accepted as conclusive because it fell short in satisfying the quantitative requirements. Since 1949, however, new observations, especially those based on the use of isotopic tracers, have lent support to the view that the cycle represents the main terminal pathway of oxidation in some microorganisms. Microorganisms, however, show a greater variety of metabolic properties than do animals, and there is much evidence indicating the occurrence of other intermediary pathways. 

It is generally accepted that only NADPH would be able to supply the hydrogen necessary for lipogenesis in the condensation system (Lynen, 1961 Ball, 1966). Lowenstein, therefore, has suggested another pathway for the formation of NADPH in the cytoplasm (Lowenstein, 1961b). It is dependent on the capacity of the cytoplasm to accomplish the first reactions of the tricarboxylic cycle, i.e., the reactions that yield a-ketoglutaric acid. A cytoplasmic NADP-isocitrate dehydrogenase, in contrast to the mitochondrial enzyme, the coen-... 

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