Biochemistry: The Chemical Reactions of Living Cells, Volume 2 - D. Metzler 1980

Enzymes: Protein Catalysts of the Cell
Enzyme Inhibition and Activation
Agonists and Antagonists

Enzyme Inhibition forms The basis of action for Antibiotics and other chemotherapeutic agents (see, for example, Box 6-A). However, many drugs interact with Cell-surface receptors that are not Enzymes in the traditional sense of the word. According to the receptor theory developed around 1937, structurally similar drugs often produce analogous effects because they bind to the same receptor. Under normal conditions, a receptor may bind a hormone, a neurotransmitter, or a metabolite that is structurally similar to the drug. The binding of drugs belonging to a single Class—referred to in pharmacological literature as agonists—triggers the same cellular response as the binding of the hormone. At the same time, compounds with a related Structure can also act as antagonists: their binding to the receptor fails to elicit the proper response. The relationship between an agonist and an antagonist is frequently competitive in nature, much like competitive enzyme inhibition.

Box 6-A

Sulfonamides as Antimetabolites

The impetus for the synthesis of sulfonamide derivatives^a-c came from P. Ehrlich's research on staining parasitic unicellular organisms with synthetic Dyes. In 1932, it was discovered that the red dye 2,4-diaminoazobenzene-4'-sulfonamide (prontosil)

is an effective Treatment against Infections caused by Gram-positive Bacteria. Further studies showed that bacteria convert the azo dye into sulfanilamide—a compound exhibiting pronounced bacteriostatic activity (i.e., it inhibits bacterial growth without causing cell death). Although sulfanilamide had been used in large quantities since 1908 as an intermediate in dye synthesis, its antibacterial properties remained unknown.

In 1935, D. Woods discovered that the bacteriostatic effect of sulfanilamide is reversed by Yeast extract. From this source, in 1940, he isolated p-aminobenzoic acid^d and demonstrated that the inhibitory effect caused by 3∙10^-4 M sulfanilamide is abolished in the presence of 6∙10^-8 M p-aminobenzoate. The relationship between the two compounds is strictly competitive: doubling the sulfanilamide concentration requires a twofold increase in the p-aminobenzoate concentration to overcome the inhibition. Based on these findings, Woods and Fildes^d,e formulated the antimetabolite theory. They hypothesized that bacteria require p-aminobenzoate and that sulfanilamide blocks the p-aminobenzoate binding site. As is now known, this hypothesis proved correct: the enzyme contested by the two substances catalyzes the synthesis of dihydropteroic acid (Fig. 14-34), a precursor of Folic acid.

Because sulfanilamide itself proved to be toxic, numerous less toxic related compounds were synthesized. Over 10,000 such drugs have been tested for antibacterial activity.

^a Gale Е. F., Cundliffe Е., Reynolds Р. Е., Richmond М. Н., Waring М. J. (1972). The Molecular Basis of antibiotic action, Wiley, New York.

^б Bardos T. J. (1974). Top Curr. Chem., 52.

^в Shepherd R. G. (1970). In: Medicinal Chemistry, 3rd ed. (A. Burger, ed.), pp 255—304. Wiley (Intersciencc), New York

^г Woods D D. (1940). Brit J Exp. Pathol, 21, 74—90.

^д Fildes P. (1940) Lancet, 1, 955—957.