Ketone bodies, origin

There is adequate proof that ketone bodies originate in the liver81 1H 192-199 and that the muscles can utilize the ketone bodies in fasting or diabetic ketosis200-202 as well as normally.208-208 Shaw206 has... 

Thujyl alcohol, Cj Hj OH, occurs in the oils of wormwood and thuja leaves, etc., and also results from the reduction of its ketone, thujone, by means of sodium. It is identical with the body originally described by Semmler under the name tanacetyl alcohol. 

S. R. Benedict17 suggested that since the theory postulated that the simultaneous oxidation of carbohydrate caused the breakdown of the ketone bodies formed in normal metabolism, the term ketolytic should be used in place of antiketogenic. Thus, these two terms have come to have entirely different connotations from those originally intended. 

On the other hand, there are a number of experiments which indicate that a relationship must exist between the oxidation of the ketone bodies and sugar these cannot be explained on the antiketogenesis theory. The strongest in vitro proof was originally demonstrated by Shaffer178 and has since been extended by West.179 180... 

Acetyl-CoA is oxidized to C02 by the Krebs cycle, also called the tricarboxylic acid cycle or citric acid cycle. The origin of the acetyl-CoA may be pyruvate, fatty acids, amino acids, or the ketone bodies. The Krebs cycle may be considered the terminal oxidative pathway for all foodstuffs. It operates in the mitochondria, its enzymes being located in their matrices. Succinate dehydrogenase is located on the inner mitochondrial membrane and is part of the oxidative phosphorylation enzyme system as well (Chapter 17). The chemical reactions involved are summarized in Figure 18.7. The overall reaction from pyruvate can be represented by Equation (18.5) ... 

We shall not discuss here either the classic increase in the blood and urine levels of ketone bodies during diabetic acidosis or the metabolic origin of such an increase data about these subjects have been treated in recent reviews (F2). 

Concentrations of various carboxylic acids in human body fluids reflect some of the major metabolic processes of the body. These metabolites apparently originate from lipid and amino acid metabolism the major metabolic defects are frequently associated with unbalanced concentrations of these acidic substances. One of the most widely occurring conditions of this kind is ketoacidosis in diabetic disease high concentrations of the so-called ketone bodies (3-hydroxybutyric acids, acetoacetic acid and others) are the traditional hallmarks of ketoacidosis. Many additional acidurias were discovered (particularly during the last 15 years) in major part due to the availability of GC and GC/MS techniques. Acidurias are among the serious medical conditions that are usually a result of genetic aberration (enzyme deficiencies), but environmental factors or nutritional deficiency could occasionally be involved. These conditions are characterized by either (a) drastically enhanced excretion of normal metabolic intermediates, or (b) excretion of unusual metabolites that are produced from the accumulated intermediates via alternate biochemical pathways. Many acidemic conditions have now been documented in the literature, and the role of GC in such medical discoveries has been adequately stressed in the recent reviews of Jellum [15] and Tanaka and Hine [373]. 

The liver is the main origin of ketones in laboratory animals, where the long chain fatty acids are released from plasma albumin and bound to fatty acid-binding proteins in the hepatocytes. The long chain fatty acids react with CoA and then can be used to synthesize triacylglycerol or undergo beta-oxidation to acetyl CoA. When the levels of plasma fatty acids are elevated, acetyl CoA can be metabolized to form acetoacetate and 3-hydroxybutyrate or enter the tricarboxylic acid cycle. In ketosis, the levels of acetone, acetoacetate, and 3-hydroxybutyrate (also known as beta-hydroxybutyrate) are increased in both plasma and urine these three compounds historically were collectively called ketone bodies. Urine test strips can be used to test for ketonuria, and there are several enzymatic assays for 3-hydroxybutyrate and acetoacetate. 

Fig. 20.14. Origin of the acetyl group from various fuels. Acetyl CoA is derived from the oxidation of fuels. The portions of fatty acids, ketone bodies, glucose, pyruvate, the amino acid alanine, and ethanol that are converted to the acetyl group of acetyl CoA are shown in blue.

As is well known, the dietary carbohydrates are normally catabolized to give the neutral end products carbon dioxide and water. The intermediately formed organic acids such as lactic acid or tri- and dicarbonic acids of the Krebs cycle solely influence the acid-base balance if they are excreted in their ionic form, leaving behind the protons that would normally be oxidized together with the acidic anion to the neutral end products mentioned above. The same is true for the fatty acids, originating from the dietary fats. Under special circumstances, the fatty acid, degradation leads to the accumulation of ketone bodies. The excretion of acetoacetic and of jS-hydroxybutyric acid in their ionic form results in acidosis, as observed in diabetes. Under normal conditions, however, there is no influence of dietary fat on the acid-base balance. 

The cycle was originally proposed as a mechanism for the terminal oxidation of carbohydrate. It was always obvious that it must also apply to parts of the protein molecule because several amino acids yield members of the cycle directly—glutamic acid, aspartic acid, and alanine—or indirectly—histidine, proline, arginine, and others. Work carried out during the last decade with the help of specially prepared tissue extracts and of isotopes has produced conclusive evidence in support of the conception that the tricarboxylic acid cycle is also the terminal mechanism of the oxidation of fatty acids and ketone bodies. These substances all form the same derivative of acetic acid—acetyl coenzyme A— which can condense with oxalacetate to form citrate. The pathway leading from various... 

All these samples were free from sulphur and neutral to litmus. No ketones or aldehydes were detected in the oil. A prolonged series of fractionations at 60 mm. pressure yielded the following fractions (1) 89 to 91 (2) 145 to 150 (3) 163 to 168 (4) 168 to 173 . The first and fourth were the main fractions, the second and third being very small. Fraction No. 1 was a colourless oil, practically unacted upon by sodium. When distilled from this metal, it boiled at 86 to 89 at the same pressure. Under ordinary pressure it boiled at 166 to 171 almost entirely, but towards the end, the temperature went to 250 , due to polymerisation of the original substance. The specif gravity at 20 was found to be -799 and the rotation - 0-56. It is clear that this body is not a normal terpene, and Chapman s experiments lead him to consider it as a mixture of tetrahydrocymene, and one of the so. called olefenic -terpenes, bodies as yet but Uttle understood. Frac. 

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