Acetyl sulfanilamide, synthesis

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 ... 

In the presence of suitable enzymes, which can be prepared from animal tissues or bacteria, acetate becomes reactive, provided that coenzyme A and ATP are present. With these two cofactors and the appropriate enzymes acetate can acetylate sulfanilamide, undergo esterification with choline, or combinefwith oxalacetate to form citrate. Since acetyl coenzyme A is an intermediary in these reactions, one of the main problems concerning the enzymic mechanisms is that of the role of ATP in the synthesis of acetyl coenzyme A. Lynen and Reichert pointed out that it is very unlikely that ATP, acetate, and coenzyme A react together simultaneously, and that the most probable sequence is a primary phosphorylation of coenzyme A by ATP... 

All synthesis of amide bonds of biological significance are dependent upon energy, commonly in the form of ATP and of magnesium or manganese ions as cofactor. Some syntheses of amide bonds take place without the presence of any known coenzyme and others are dependent upon coenzyme A (CoA). The synthesis of acetyl sulfanilamide from acetate and sulfanilamide is an amide bond synthesis dependent upon CoA. This conjugation reaction has been studied by Chou and lipmann (1952) who showed that two enzymes took part in the reaction and that acetyl-l.S CoA was an intermediate product. 

In a few cases, A/ -heterocycHc sulfanilamides have been prepared by the condensation of an active heterocycHc haHde with the sulfonamide nitrogen of sulfanilamide or its A/-acetyl derivative in the presence of an acid-binding agent. Sulfapyridine, sulfadiazine, and sulfapyrazine have been made by this method (1), but the most important appHcation is probably for the synthesis of sulfachlorapyridazine (9) and sulfamethoxypyridazine (10) (45). 

Another observation on oxalate formation is that other a-keto acids, such as oxalosuccinic acid (74) and a-ketoglutaric acid (106) do not seem to yield oxalate directly but indirectly (123). This appears to be due to the fact that only oxaloacetic acid can function as an acetate donor. In this connection the intervention of Coenzyme A may be considered, since it is reported to function in the acetylation of sulfanilamide and choline (73) and recently was shown to take part in the enzymatic synthesis of citric acid. This concept may be illustrated as follows ... 

Several pantothenic acid analogs inhibit those reactions that require coenzyme A (acetylation of sulfanilamide and acetylcholine synthesis). Among these anti-... 

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. ... 

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