Fatty acid metabolism citrate

Chenoweth believes that an explanation of the above results may lie in the reactions occurring before the entrance of fatty acid metabolites into the citric acid cycle. Activated acetate, i.e. acetyl coenzyme A (AcCoA) is the end-product of fatty acid metabolism prior to its condensation with oxalacetate to form citrate. Possibly fluoro-fatty acids behave like non-fluorinated fatty acids. The end-product before the oxalacetate condensation could be the same for all three fluorinated inhibitors, viz. fluoroacetyl coenzyme A (FAcCoA). Fluorocitrate could then be formed by the condensation of oxalacetate with FAcCoA, thereby blocking the citric acid cycle. The specificity of antagonisms must therefore occur before entrance of the metabolites into the citric acid cycle. 

S ATP -P acetate <1-18> (<8> acetate kinase/phosphotransacetylase, major role of this two-enzyme sequence is to provide acetyl coenzyme A which may participate in fatty acid synthesis, citrate formation and subsequent oxidation [1] <3> function in the metabolism of pyruvate or synthesis of acetyl-CoA coupling with phosphoacetyltransacetylase [15] <11> function in the initial activation of acetate for conversion to methane and CO2 [19] <10> key enzyme and responsible for dephosphorylation of acetyl phosphate with the concomitant production of acetate and ATP [30]) (Reversibility r <1-18> [1, 2, 5-21, 24-27, 29-33]) [1, 2, 5-21, 24-27, 29-33]... 

Although the effects of insulin on postprandial metabolism are profound, other factors (e.g., substrate supply and allosteric effectors) also affect the rate and degree to which these processes occur. For example, elevated levels of fatty acids in blood promote lipogenesis in adipose tissue. Regulation by several allosteric effectors further ensures that competing pathways do not occur simultaneously for example, in many cell types fatty acid synthesis is promoted by citrate (an activator of acetyl-CoA carboxylase), whereas fatty acid oxidation is depressed by malonyl-CoA (an inhibitor of carnitine acyltransferase I activity). The control of fatty acid metabolism is described in Section 12.1. 

Fatty-acid metabolism in the muscle can increase ATP and citrate, which can inhibit PFK raising G-6-P levels, which inhibits hexokinase and decreased use of glucose. 

Weinhouse S, Medes G, Floyd NF (1946) Fatty acid metabolism. V. The conversion of fatty acid intermediates to citrate studied with the aid of isotopic carbon. J Biol Chem 166 691-703... 

The citrate cycle is the final common pathway for the oxidation of acetyl-CoA derived from the metabolism of pyruvate, fatty acids, ketone bodies, and amino acids (Krebs, 1943 Greville, 1968). This is sometimes known as the Krebs or tricarboxylic acid cycle. Acetyl-CoA combines with oxaloacetate to form citrate which then undergoes a series of reactions involving the loss of two molecules of CO2 and four dehydrogenation steps. These reactions complete the cycle by regenerating oxaloacetate which can react with another molecule of acetyl-CoA (Figure 4). 

Fluoroacetate undergoes a "lethal synthesis"(18) to 2-fluorocitrate which may reversibly inhibit aconitase and which irreversibly binds to a membrane-associated citrate transport protein(19,20). Insecticidal and other biocidal uses of fluoroacetate (or its metabolic precursors) received considerable attention twenty-five years ago( ) but most uses have been abandoned due to high nonspecific vertebrate toxicity of these compounds. Vfe have reported the use of o)-fluoro fatty acids and their derivatives as delayed-action toxicants for targeted... 

While CoA was discovered as the "acetylation coenzyme," it has a far more general function. It is required, in the form of acetyl-CoA, to catalyze the synthesis of citrate in the citric acid cycle. It is essential to the P oxidation of fatty acids and carries propionyl and other acyl groups in a great variety of other metabolic reactions. About 4% of all known enzymes require CoA or one of its esters as a substrate.4... 

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. 

Glucagon affects hepatic lipid metabolism. A major effect is inhibition of fatty acid synthesis, which is mainly due to the phosphorylation and inhibition of acetyl-GoA carboxylase by cAMP-dependent protein kinase. ATP-citrate lyase is also phosphorylated, but it is unclear that this is involved in the inhibition of lipogene-sis. Glucagon also inhibits cholesterol synthesis apparently due to a decrease in the activity of hydroxymethylglutaryl-CoA reductase. This is thought to result from a decrease in the activity of protein phosphatase I due to the increased phosphorylation and activation of a heat stable inhibitor by cAMP-dependent protein kinase. This mechanism could also contribute to the effects of glucagon on other hepatic enzymes. 

The synthesis of palmitic acid occurs in the cytosol, from acetyl-CoA. When glucose is abundant and the amount of citrate in the mitochondrial matrix exceeds the demand by the citric acid cycle, the excess citrate is transported out of the mitochondria into the cytosol (Fig. 13-8). Citrate in the cytosol is the source of acetyl groups for fatty acid synthesis, and its metabolism there involves the following enzyme reactions ... 

Acetyl CoA. The major sources of this activated two-carbon unit are the oxidative decarboxylation of pyruvate and the P-oxidation of fatty acids (see Figure 30.11). Acetyl CoA is also derived from ketogenic amino acids. The fate of acetyl CoA, in contrast with that of many molecules in metabolism, is quite restricted. The acetyl unit can be completely oxidized to CO2 by the citric acid cycle. Alternatively, 3-hydroxy-3-methylglutaryl CoA can be formed from three molecules of acetyl CoA. This six-carbon unit is a precursor of cholesterol and of ketone bodies, which are transport forms of acetyl units released from the liver for use by some peripheral tissues. A third major fate of acetyl CoA is its export to the cytosol in the form of citrate for the synthesis of fatty acids. 

The second metabolic pathway which we have chosen to describe is the tricarboxylic acid cycle, often referred to as the Krebs cycle. This represents the biochemical hub of intermediary metabolism, not only in the oxidative catabolism of carbohydrates, lipids, and amino acids in aerobic eukaryotes and prokaryotes, but also as a source of numerous biosynthetic precursors. Pyruvate, formed in the cytosol by glycolysis, is transported into the matrix of the mitochondria where it is converted to acetyl CoA by the multi-enzyme complex, pyruvate dehydrogenase. Acetyl CoA is also produced by the mitochondrial S-oxidation of fatty acids and by the oxidative metabolism of a number of amino acids. The first reaction of the cycle (Figure 5.12) involves the condensation of acetyl Co and oxaloacetate to form citrate (1), a Claisen ester condensation. Citrate is then converted to the more easily oxidised secondary alcohol, isocitrate (2), by the iron-sulfur centre of the enzyme aconitase (described in Chapter 13). This reaction involves successive dehydration of citrate, producing enzyme-bound cis-aconitate, followed by rehydration, to give isocitrate. In this reaction, the enzyme distinguishes between the two external carboxyl groups... 

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