Liver acetyl-coenzyme

M.A. Lunzer, J.a. Manning, and R. K. OcKNER, Inhibition of rat liver acetyl coenzyme A carboxylase by long chain acyl coenzyme A and fatty acid. Modulation by fatty acid-binding protein, J. Biol. Chem., 1977, 252, 5483-5487. 

WiELAND, 0., and L. Weiss Increase in liver acetyl-coenzyme A during ketosis. Biochem. biophys. Res. Commun. 10, 333 (1963a). 

FIGURE 9. Endogenous lipoprotein metabolism. In liver cells, cholesterol and triglycerides are packaged into VLDL particles and exported into blood where VLDL is converted to IDL. Intermediate-density lipoprotein can be either cleared by hepatic LDL receptors or further metabolized to LDL. LDL can be cleared by hepatic LDL receptors or can enter the arterial wall, contributing to atherosclerosis. Acetyl CoA, acetyl coenzyme A Apo, apolipoprotein C, cholesterol CE, cholesterol ester FA, fatty acid HL, hepatic lipase HMG CoA, 3-hydroxy-3-methyglutaryl coenzyme A IDL, intermediate-density lipoprotein LCAT, lecithin-cholesterol acyltransferase LDL, low-density lipoprotein LPL, lipoprotein lipase VLDL, very low-density lipoprotein. 

The oxidation of aciy lic acid can be rationalized in terms of the endogenous catabolism of propionic acid, in which acrylyl coenzyme A is an intermediate. This pathway is analogous with fatty acid 3-oxidation, common to all species and, unlike the corresponding pathway in plants, does not involve vitamin 8,2. 3-Hydroxypropionic acid has been found as an intennediate in the metabolism of acrylic acid in vitro in rat liver and mitochondria (Finch Frederick, 1992). The CO2 excreted derives from the carboxyl carbon, while carbon atoms 2 and 3 are converted to acetyl coenzyme A, which participates in a variety of reactions. The oxidation of acrylic acid is catalysed by enzymes in a variety of tissues (Black Finch, 1995). In mice, the greatest activity was found in kidney, which was five times more active than liver and 50 times more active than skin (Black et al., 1993). 

In the early 1940s, before the discovery of 14C and when acetyl-coenzyme A was unknown, two research groups used the stable isotope 13C and mass spectrometers to study carbon flow in the TCA cycle. Pyruvate and 13C02 were added to pigeon liver preparations to form carboxy-labeled oxaloacetate. Malonate was added to stop the TCA cycle at succinate. The expected result was that half of the 13C would be found in succinate and the other half in C02 (fig. 13.10). 

Ponce-Castaneda, M.V., Lopez-Casillas, F., Kim, K-H. 1991. Acetyl-coenzyme A carboxylase messenger ribonucleic acid metabolism in liver, adipose tissues, and mammary glands during pregnancy and lactation. J. Dairy Sci. 74, 4013 4021. 

The liver meets the larger part (60%) of its requirement for cholesterol by synthesis de novo from acetyl-coenzyme A. Synthesis rate is regulated at the step leading from hydroxymethylglutaryl-CoA (HMG-CoA) to mevalonic acid (p.l61A), with HMG-CoA reductase as the rate-limiting enzyme. 

New (de novo) fatty acids are synthesized from two-carbon acetyl units produced during metabolism. Two enzyme complexes, acetyl-coenzyme A carboxylase and fatty acid synthetase, work in concert to build up fatty acid chains, two carbons at a time, until released by the complex. The primer in plants and animals is essentially a two-carbon acetyl group and the fatty acid chains have even numbers of carbons. If the primer is a three-carbon propionate group, odd-number carbon chains result. Odd-number fatty acids are common in microbial lipids and also are synthesized de novo from propionic VFA by rumen bacteria and deposited in adipose tissue. The length of the fatty acid synthesized depends on the tissue. Palmitic acid is produced in the liver and adipose tissue, and shorter-chain fatty acids are also produced in the mammary glands (49). 

Another pharmaceutical administered as a racemic mixture to treat liver diseases is a-Iipoic acid (Thioctacid). Practically nothing is known about the activity of the individual enantiomers, although naturally occur-ring (+)-a-lipoic acid has an R-configuration. The first enantiomer separation of a-lipoic acid methyl ester was demonstrated on colunms with Lipodex D (Fig. 12,46). a-Lipoic acid is involved in the oxidative decarboxylation of pyruvic add to activated acetaldehyde, which is transferred to coenz3une A to form acetyl coenzyme A. 

The average intake of pantothenic acid, as free pantothernc acid and as coenzyme A, acetyl-coenzyme A, and long-chain fatty acyl-coenzyme A, is 5 to 10 mg/day. An RDA for the vitamin has not been established because the vitamin is plentiful in a variety of foods. Pantothenic acid is present in all plant and animal foods. The richest sources of the vitamin are liver, yeast, egg yolk, and vegetables. In foods, the vitamin occurs mainly as coenz5rme A. 

The answer is d. (Murray, pp 190-198. Scriver, pp 1521-1552. Sack, pp 121-138. Wilson, pp 287-317.) Ketone bodies include acetoacetic acid and P-hydroxybutyrate, which are formed in the liver, and acetone, which is spontaneously formed from excess acetoacetate in the blood. Starvation results in glycogen depletion and deficiency of carbohydrates, causing increased use of lipids as energy sources. Increased oxidation of fatty acids produces acetyl coenzyme A (CoA) and acetoacetyl CoA, a precursor of ketone bodies. Although the liver synthesizes ketone bodies from excess... 

Thus, brain tissue is extremely sensitive to fluctuations in the blood glucose concentration, since no satisfactory endogenous substitute exists. Only in prolonged fasting are ketone bodies formed in liver (D-)3-hydroxybutyrate and acetoacetate), passively taken up by the brain from the bloodstream and utilized to produce acetyl-coenzyme A. 

Snoswell, A. Tubbs, P.K. (1978) Biochem. J. 171, 299-303. Deacylation of acetyl-coenzyme A and acetylcamitine by liver preparations. 

Ketoganesis the formation of ketone bodies. The primary product of K. is acetoacetate, which is synthesized in the liver from acetyl-coenzyme A via ace-toacetyl-CoA and p hydroxy-p-methylglutaryl-CoA. 

It was evident from early studies that in the presence of CoASH, ATP could in some way be used to activate acetate so that it will acetylate sulfanilamide (7) and choline (8). Chou and Lipmann (9) succeeded in partially purifying the enzyme(s) responsible for this activation from pigeon-liver extracts and they concluded that the phosphate bond energy of ATP is utilized to bring about the synthesis of acetyl coenzyme A (acetyl-SCoA) however, the mechanism of this activation remained obscure. The nature of the over-all process was further elucidated through the experiments of Lipmann et al. (10) who demonstrated that ATP, CoASH, and acetate react to form acetyl-SCoA, AMP, and inorganic pyrophosphate (P-P) in stoichiometric amounts [reaction (4)]. They also demonstrated that the reaction is freely reversible. More recently, the studies of Jones et al. (11) have indicated that the mechanism of this conversion is as follows ... 

The enzyme is specific for thiol esters of the type of S-acetyl and S-butyryl glutathione. Besides the three thiol esters already discussed, ethyl thiol-acetate, butyl thiolacetate, acetyl thioglycolic acid, acetyl mercapto propionic acid, S-acetyl-2 mercaptoethanol, acetyl thiomalic, acetyl coenzyme A, and butjryl coenzyme A were inactive with the purified enzyme. Crude extracts of liver attacked butyl thiolacetate and acetyl coenzyme A slowly. 

Pantothenic acid is required in the formation of acetyl coenzyme A which enjoys a key position in many metabolic pathways. Only the natural dextrorotatory form is active. This vitamin is to be found in most foods of plant and animal origin and good sources include liver, kidney, wheat germ, royal jelly, peanuts, spinach, cheese, and peas. There is no RDA, though most people consume at least 10 mg per day. 

The studies of Klein and Harris (1938) on different tissues of the rabbit indicated that acetylation was perhaps localized to the liver. Blon-dheim (1955) showed, however, that both red cells and white cells of peripheral blood had the capacity to convert sulfanilamide and p-amino-benzoic acid to their acetylated derivatives. With the development of more sensitive assay techniques making use initially of acetyl coenzyme A generating systems, and later of purified preparations of this cosubstrate, enzymic acetylating activity could be demonstrated in many other mammalian tissues. More recently, tissue distribution studies in animals and man have shown that both the pattern and type of arylamine drug-acety-lating activity varies from one tissue to another within an individual and also between individuals (Hearse and Weber, 1970), in support of pro-... 

Studies with the rabbit liver enzyme show that acetylthiocholine or N,S-diacetylcysteamine can be used as the acetyl donor in place of acetyl coenzyme A. The rate of acetylation with either of these compounds, however, is less than 10% of that observed with acetyl coenzyme A at concentrations which are 10-fold greater than acetyl coenzyme A (Weber and Cohen, 1967). 

---