Enzymes enol inhibition

In recent years, agribusiness firms have developed pf empirically several compounds that inhibit essential steps in the biosynthesis of amino acids found in plants but missing in animals. One of these compounds, glyphosate, is a highly specific inhibitor of 5-enol pyruvyl-shikimate-3-phosphate synthase (an enzyme needed for aromatic amino acid biosynthesis). Glyphosate is the active ingredient in the widely used herbicide Roundup. 

Nonselective COX inhibitors derive from salicylic acid. The majority are carbonic acids, such as ibuprofen, naproxene, diclofenac, indometacin, and many more or enolic acids, such as azapropazone and meloxicam. All these drugs inhibit both COX enzymes. 

The substrate arachidonic aeid, whieh often leads to formation of inflammatory prostaglandins, is stored in tissues as one of a number of phospholipids these compounds, as the name indicates, comprise complex phosphate-containing esters. The antiinflammatory corticosteroids inhibit the action of the enzyme, phospholipase A2, that frees arachidonic acid. The many undesired effects of those steroids has led to the search for non-steroidal inhibitors of that enzyme. A highly substituted indole derivative has shown good activity as a phospholipase A2 inhibitor. Alkylation of the anion from treatment of indole (32) with benzyl chloride affords the corresponding A-benzylated derivative (33). The methyl ether at the 4 position is then cleaved by means of boron tribromide to yield 34. Alkylation of the enolate from reaction of the phenol with sodium hydride with tert-butylbromoacetate affords the corresponding... 

An alternate approach, which also uses enzyme-catalyzed ring-opening of a lactone to generate a mechanism-activated inhibitor, was developed by Katzenellenbogen and his co-workers [183], who found enol lactones, exemplified by (13-8) and (13-9), to be potent, selective inhibitors of HLE. The haloenol lactone (13-9) was an irreversible inactivator of HLE and chymotrypsin, and after exposure to (13-9), active enzyme could not be regenerated even upon treatment with hydrazine. Enol lactone (13-8), on the other hand, was an alternate-substrate inhibitor, which produced only transient inhibition of HLE and chymotrypsin. These results have been interpreted to mean that, with the halo-substituted compounds, ring opening results in formation of an acyl-enzyme that contains a reactive halomethyl ketone, which then alkylates His-57. That these compounds... 

Bromopyruvic acid inhibits S-deoxy-D-erj t ro-hexulosonate 6-phosphate aldolase " and 3-deoxy-D-ar-a6mo-heptulosonate 7-phosphate synthetase " in a similar way. The enzymes are protected from inhibition by pyruvate and phospho-enol pyruvate respectively. Since aldolases must possess a nucleophilic group to initiate the reaction, this type of inhibition should be a general property of aldolases. 

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