Acetyl coenzyme reactions

The form in which acetate is used in most of its important biochemical reactions is acetyl coenzyme A (Figure 26 la) Acetyl coenzyme A is a thwester (Section 20 13) Its for matron from pyruvate involves several steps and is summarized m the overall equation... 

As we saw m Chapter 20 thioesters are more reactive than ordinary esters toward nucleophilic acyl substitution They also contain a greater proportion of enol at equilib rmm Both properties are apparent m the properties of acetyl coenzyme A In some reactions it is the carbonyl group of acetyl coenzyme A that reacts m others it is the a carbon atom... 

The four carbon atoms of the butanoyl group originate m two molecules of acetyl coenzyme A Carbon dioxide assists the reaction but is not incorporated into the prod uct The same carbon dioxide that is used to convert one molecule of acetyl coenzyme A to malonyl coenzyme A is regenerated m the decarboxylation step that accompanies carbon-carbon bond formation... 

The introduction to Section 26 8 pointed out that mevalonic acid is the biosynthetic pre cursor of isopentenyl pyrophosphate The early steps m the biosynthesis of mevalonate from three molecules of acetic acid are analogous to those m fatty acid biosynthesis (Sec tion 26 3) except that they do not involve acyl earner protein Thus the reaction of acetyl coenzyme A with malonyl coenzyme A yields a molecule of acetoacetyl coenzyme A... 

Acetylcholine is the product of the reaction between choline and acetyl coenzyme A in the presence of choline acetylase (41). 

Two particularly interesting aspects of the pyruvate carboxylase reaction are (a) allosteric activation of the enzyme by acyl-coenzyme A derivatives and (b) compartmentation of the reaction in the mitochondrial matrix. The carboxy-lation of biotin requires the presence (at an allosteric site) of acetyl-coenzyme A or other acylated coenzyme A derivatives. The second half of the carboxylase reaction—the attack by pyruvate to form oxaloacetate—is not affected by CoA derivatives. 

Histone Acetylation. Figure 1 Histone acetylation is a posttranslational modification of lysine residues of histones. This modification is catalyzed by histone actyl transferases (HATs), which transfer an acetyl group (yellow) from acetyl-Coenzyme A onto the E-amino group of the lysine residue. Histone deacetylation is catalyzed by histone deacetylases (HDACs), which hydrolyze the lysine bound acetyl group. HDAC inhibitors like Trichostatin A (TSA) are known to inhibit the deacetylation reaction in vivo and in vitro. 

The degradation of vinyl chloride and ethene has been examined in Mycobacterium sp. strain JS 60 (Coleman and Spain 2003) and in Nocardioides sp. strain JS614 (Mattes et al. 2005). For both substrates, the initially formed epoxides underwent reaction with reduced coenzyme M and, after dehydrogenation and formation of the coenzyme A esters, reductive loss of coenzyme M acetate resulted in the production of 5-acetyl-coenzyme A. The reductive fission is formally analogous to that in the glutathione-mediated reaction. 

Mononuclear Ni complexes have been investigated as functional models for individual steps of the reactions mediated by the CODH/acetyl coenzyme A synthase.2018-2020 These are mentioned in the respective sections on mononuclear Ni complexes. The dinuclear type (770) complexes are... 

N-Hydroxy arylamines are also converted to N-acetoxy arylamines (V), but apparently by an acetyl coenzyme A-dependent enzymatic O-esterification (7, 8). Similarly, N-sulfonyloxy arylamines (VI) are thought to arise by a PAPS-dependent enzymatic O-sulfonylation of N-hydroxy arylamines (9,10) while 0-seryl or 0-prolyl esters (VII) are formed by their corresponding aminoacyl tRNA synthetases in a ATP-dependent reaction (11,12). 

The role of N-acetoxy arylamides as metabolically formed ultimate carcinogens jji vivo also appears to be limited. Their enzymatic formation via peroxidation of N-hydroxy arylamides can be excluded since tissues containing high levels of peroxidases such as the rat mammary gland (83) and the dog urinary bladder (84) do not form acetylated carcinogen-DNA adducts in vivo (63). Their non-enzymatic formation by reaction of acetyl coenzyme A with N-hydroxy arylamides (6 ) cannot be excluded however, even if formed, their direct reaction with cellular DNA appears unlikely as treatment of cultured cells with synthetic N-acetoxy AAF (85,86) results primarily in deacetylated arylamine-DNA adducts, apparently due to rapid N-deacetylation to form the reactive N-acetoxy arylamine (V). 

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. 

ATP and magnesium were required for the activation of acetate. Acetylations were inhibited by mercuric chloride suggesting an SH group was involved in the reaction either on the enzyme or, like lipoic acid, as a cofactor. Experiments from Lipmann s laboratory then demonstrated that a relatively heat-stable coenzyme was needed—a coenzyme for acetylation—coenzyme A (1945). The thiol-dependence appeared to be associated with the coenzyme. There was also a strong correlation between active coenzyme preparations and the presence in them of pantothenic acid—a widely distributed molecule which was a growth factor for some microorganisms and which, by 1942-1943, had been shown to be required for the oxidation of pyruvate. 

Figure 6.1 Pathways involved in glucose oxidation by plant cells (a) glycolysis, (b) Krebs cycle, (c) mitochondrial cytochrome chain. Under anoxic conditions. Reactions 1, 2 and 3 of glycolysis are catalysed by lactate dehydrogenase, pyruvate decarboxylase and alcohol dehydrogenase, respectively. ATP and ADP, adenosine tri- and diphosphate NAD and NADHa, oxidized and reduced forms of nicotinamide adenine dinucleotide PGA, phosphoglyceraldehyde PEP, phosphoenolpyruvate Acetyl-CoA, acetyl coenzyme A FP, flavoprotein cyt, cytochrome e, electron. (Modified from Fitter and Hay, 2002). Reprinted with permission from Elsevier...

In nature, the biologically active form of acetic acid is acetyl-coenzyme A (acetyl-CoA) (see Box 7.18). Two molecules of acetyl-CoA may combine in a Claisen-type reaction to produce acetoacetyl-CoA, the biochemical equivalent of ethyl acetoacetate. This reaction features as the start of the sequence to mevalonic acid (MVA), the precursor in animals of the sterol cholesterol. Later, we shall see another variant of this reaction that employs malonyl-CoA as the nucleophile (see Box 10.17). 

This enzyme [EC 2.3.1.5], also known as acetyl-CoA arylamine A-acetyltransferase and arylamine acetylase, catalyzes the reaction of acetyl-CoA with an arylamine to produce coenzyme A and an A-acetylarylamine. This enzyme exhibits a low specificity with respect to the aromatic amine substrate. In fact, even serotonin can serve as a substrate. The enzyme has also been reported to catalyze acetyl-transfer reactions between arylamines without the use of coenzyme A. 

UV/Vis-spectroscopy is the classical method of analysis of enzyme activity. The principle is the change in absorption behavior of a substrate during the reaction process, for example by modification or Hberation of a chromophoric function. A number of enzymes from different classes can be assayed spectrophoto-metrically using their natural substrates or cofactors. In this way, activity of acetyltransferases can be estimated by measurement of absorption of acetyl coenzyme A at 232 nm [33]. Oxidoreductases which require a cofactor, e.g., NAD/NADH, to carry out the transfer of hydrogen can be characterized by measuring the absorption of this cofactor depending on its oxidation stage [33]. 

As their name implies, the A-acetyltransferase (NAT) enzymes catalyze to a drug molecule the conjugation of an acetyl moiety derived from acetyl coenzyme A. Examples of this type of reaction are depicted in Figure 4.1. The net result of this conjugation is an increase in water solubility and increased elimination of the compound. The NATs identified to date and involved in human drug metabolism include NAT-1 and NAT-2. Little overlap in substrate specificities of the two isoforms appears to exist. NAT-2 is a polymorphic enzyme, a... 

It is synthesized within the cholinergic neurons by the transfer of an acetyl group from acetyl coenzyme A to the organic base choline. The specific enzyme choline acetylase is essential for this reaction. Coenzyme A is widely distributed in the body and choline acetylase is synthesized in the cell bodies of the cholinergic neurons. 

Problem 16.47 In living cells, alcohols are converted to acetate esters (acetylated) by the thiol ester CH,COS—(CoA), acetyl coenzyme A. CoA is an abbreviation for a very complex piece. Illustrate this reaction using glycerol-1-phosphate. 4... 

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