Acetoacetate from fatty acids

As applied to the washed liver homo nate system where tim formation of acetoacetate from fatty acids is quantitative (Crandall e< al. >) ... 

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. 

From fatty acid to ketone body. Write a balanced equation for the conversion of stearate into acetoacetate. 

P-Methylglutaconyl CoA is then hydrated to form 3-hydroxy-3-methylglutaryl CoA, which is cleaved into acetyl CoA and acetoacetate. This reaction has already been discussed in regard to the formation of ketone bodies from fatty acids (Section 22.3.5). 

Ketone body production and utilization. Ketone bodies are produced in the liver from fatty acids derived from adipocyte lipolysis. They are released and used as fuel in peripheral tissues. The initial step in acetoacetate metabolism is activation to acetoacetyl-CoA by succinyl-CoA. HMG-CoA, /S-hydroxy-y3-methylglutaryl-CoA HB, /i-hydroxybutyrate. 

Under some conditions, fatty acid degradation occurs more rapidly than glycolysis. As a result, a large amount of acetyl CoA is produced from fatty acids, but little oxaloac-etate is generated from pyruvate. When oxaloacetate levels are too low, the excess acetyl CoA is converted to the ketone bodies acetone, acetoacetate, and (3-hydroxybutyrate. 

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. 

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... 

Liver tissue carries out the synthesis of ketone bodies from fatty acids. Suppose a liver cell converts palmitic acid to acetoacetate and then exports it to the circulation. How many molecules of ATP per molecule of palmitate converted to acetoacetate are available to the liver cell ... 

Apart from the symptoms we have already discussed, type 1 diabetics tend to present with another characteristic readily picked up by an alert clinician. Since sugar is not being properly handled, the tissues have to obtain more of their energy from fatty acid oxidation, but the capacity of the Krebs cycle tends also to be impaired, so that in uncontrolled type 1 diabetes there is a pile-up of ketone bodies made by the Uver. This is discussed in more detail in Topic 21. Acetoacetic acid, one of the two major ketone bodies, spontaneously breaks down to acetone, which, being very volatile, is easily lost into the air the patient breathes out. The smell of acetone on the breath is unmistakeable. This should not of course be detectable if the diabetes is well managed. 

Ketone body Acetoacetate or /9-hydroxybutyrate, soluble and easily transported metabolites produced from fatty acids and some amino acids. 

II) Similarly, protons are formed during the production of acetoacetate and 3-hydroxybutyrate from fatty acids (Chapter 33)... 

In the post-absorptive state stored fat is presented to the tissues in four forms free fatty acids derived directly from adipose tissue triglycerides formed in the liver from fatty acids and acetoacetate and hydroxybutyrate formed by the partial oxidation of free fatty acids. Free fatty acids and ketone bodies are readily oxidizable. It may be that more than one form is necessary because free fatty acids alone, owing to their low solubility and their relative toxicity, cannot be transported in sufficient quantities to meet the fuel requirements of some tissues, such as heart muscle. The other possibility for the existence of multiple forms of this substrate is that it allows direction of particular fuels to specific organs. 

Krebs Cycle and Fatty Acid Oxidation. A possible role of Krebs cycle intermediates in supporting fatty acid oxidation is now apparent. Complete oxidation to CO2 requires oxalacetate to introduce acetyl CoA into the citric acid cycle. But even the formation of acetoacetate requires the continued generation of ATP to support the activation of fatty acids. The transfer of electrons from fatty acid to oxygen is coupled with phosphate esterification, so that fatty acid oxidation has the theoretical capacity to be self-supporting. In the crude systems that contain all of the essential factors for fatty acid oxidation, fatty acid activation must compete with other reactions for the available ATP, and maximum rates of oxidation occur only when additional ATP is generated through operation of the Krebs cycle. 

Coenzyme A was discovered by Lipmann in 1945 as necessary for the acetylation of sulfanilamide by pigeon liver extracts. Shortly thereafter this same coenzyme was identified as the activator of choline acetylation earlier observed by Nachmansohn and Berman, as well as Feldberg and Mann. Subsequently, work from Lipmann s laboratory, as well as from other laboratories, extended the role of CoA to a large variety of transacetylation reactions, i.e., acetylation of aromatic amines, synthesis of acetylcholine, of citrate, of acetoacetate, of fatty acids, of sterols, and of phospholipids. ... 

Ketone bodies Acetoacetate and 3-hydroxybutyrate (not chemically a ketone) formed in the liver from fatty acids in the fasting state and released into the circulation as metabolic fuels for use by other tissues. Acetone is also formed non-enzymically from acetoacetate. 

A group of compounds which include acetoacetic acid, acetone and >3-hydroxybutyrate. They result from fatty acid oxidation... 

The particulars of the condensation mechanism will be disregarded for the moment. The essential point here is that 2-carbon fragments are formed from fatty acids which may then condense to yield acetoacetate. The fact that little or no isotope is found in the a- and y-carbons of acetoacetate from carboxyl-labeled fatty acids in liver - - or from carboxyl-labeled acetate in kidney slices provides evidence that the orientation of the carbons of the 2-carbon fragment is not altered. 

The oxidation of acetate, acetoacetate, and fatty acids by a nonmito-chondrial system from pig heart has been described. The heart system consists of three parts (1) a particulate nonmitochondrial fraction (2) a group of soluble enzymes and (3) a coenzyme concentrate, incompletely characterized, but which is known to contain di- and triphospho-pyridine nucleotides, coenzyme A, and ATP. The system reflects many of the properties of intact mitochondria and lends itself to a study of the reaction sequences in the activation and oxidation of fatty acids. 

Although nearly all of the studies of acetoacetate formation from isotopic fatty acids have been carried out in vitro, there is no doubt that the formation of the ketone body from 2-carbon fragments occurs in the intact animal. Hexanoate-l-C, when injected intravenously into the goat, forms acetoacetate with isotope in the acetone moiety (presumably only in the carbonyl carbon) and in the carboxyl carbon. This provides direct evidence for the formation of 2-carbon fragments from fatty acids by the intact animal. 

Acetoacetate and /3-hydroxybutyrate are transported through the blood from liver to target organs and tissues, where they are converted to acetyl-CoA (Figure 24.29). Ketone bodies are easily transportable forms of fatty acids that move through the circulatory system without the need for eomplexation with serum albumin and other fatty acid—binding proteins. 

Between 1906 and 1908 the breakdown of fatty acids to acetone was detected by Embden in perfused livers. Only fatty acids with even numbers of carbon atoms produced this effect. The acetone was postulated to have originated from acetoacetate. For the next 30 years the 6-oxidative route of fatty acid oxidation was generally unchallenged. By 1935-1936 however much more accurate determinations of the yields of acetoacetate per mole of fatty acid consumed (Deuel et al., Jowett and Quastel) indicated convincingly that more than one mole of acetoacetate might be obtained from 6C or 8C fatty acids. (Octanoic acid was often used as a model fatty acid as it is the longest fatty acid which is sufficiently soluble in water at pH 7.0 for experimental purposes.) The possibility had therefore to be entertained that 2C fragments could recondense (MacKay et al. 1942). 

Although sequential B-oxidation from the carboxyl end of fatty acids was believed to be the mechanism for their breakdown, other schemes had been proposed, notably by Hurtley in 1915, who suggested multiple alternate oxidation—this idea was not widely accepted because the probable intermediates, polyketonic or polyunsaturated fatty acids, had never been detected. The abnormally high levels of acetoacetate produced by various liver preparations, however, caused multiple... 

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