Mechanism of the Inhibition of Enzymatic Halogenation by Antithyroid Agents

Abstract

Abstract Antithyroid agents of the thiourea type (thiourea, thiouracil, and 5-vinyl-2-oxazolidinethione) inhibit the enzymatic halogenation reactions catalyzed by chloroperoxidase. These compounds are competitive with the halogen acceptor molecule and serve as substrates for chloroperoxidase. These antithyroid agents are oxidized by chloroperoxidase in the presence of hydrogen peroxide and a suitable halogen anion (chloride, bromide, or iodide). The first isolable oxidation product of thiourea and thiouracil is the corresponding disulfide. It is proposed that a sulfenyl halide is a precursor of the disulfide. Spectral evidence indicates the formation of an intermediate in the oxidation of 5-vinyl-2-oxazolidinethione. This intermediate is postulated to be a disulfide by analogy to the thiourea and thiouracil oxidations. The goitrogen 1,1,3-tricyano-2-amino-1-propene serves as a halogen acceptor in the chloroperoxidase reaction. Chloroperoxidase catalyzes the hydrogen peroxide-dependent oxidation of thiocyanate. Thiocyanate oxidation does not require the presence of a halogen anion. Cyanide ion is one of the oxidation products. Thiocyanate ion inhibits the enzymatic halogenation reactions catalyzed by chloroperoxidase in a manner which is noncompetitive with respect to other chloroperoxidase substrates. It is proposed that antithyroid agents containing the thiourylene group or related structures inhibit enzymatic halogenation reactions by virtue of being extremely active nucleophiles and thus capable of reacting with an enzyme-bound halogenium ion.