Inhibitor Ionization as a Determinant of Binding to 3-Dehydroquinate Synthase

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Abstract
Phosphinomethyl and carboxymethyl monoacids along with succinyl, malonyl ether, malonyl, and hydroxymalonyl diacids were substituted for phosphorylmethyl, phosphonoethyl, and phosphonomethyl groups in carbocyclic inhibitors of DHQ synthase. All but one of the carbocyclic inhibitors were synthesized via intermediacy of a 2,3-butane bisacetal-protected 3-dehydroquinic acid. Carbaphosphinate (Ki = 20 × 10-6 M) was a modest competitive inhibitor of DHQ synthase, while carbaacetate was a linear mixed-type inhibitor (Ki = 3 × 10-6 M, Ki‘ = 20 × 10-6 M). Carbasuccinate (Ki = 5 × 10-6 M), carbamalonate ether (Ki = 7 × 10-6 M), carbamalonate (Ki = 0.7 × 10-6 M), and carbahydroxymalonate (Ki = 0.3 × 10-6 M) were all competitive inhibitors. Carbaacetate was the only inhibitor that was not oxidized by DHQ synthase. On the basis of these data, carbocyclic inhibitors with malonyl and hydroxymalonyl groups are apparently bound by DHQ synthase as tightly as carbocyclic inhibitors possessing phosphorylmethyl and phosphonoethyl moieties.