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

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 (K(i) = 20 x 10(-)(6) M) was a modest competitive inhibitor of DHQ synthase, while carbaacetate was a linear mixed-type inhibitor (K(i) = 3 x 10(-)(6) M, K(i)' = 20 x 10(-)(6) M). Carbasuccinate (K(i) = 5 x 10(-)(6) M), carbamalonate ether (K(i) = 7 x 10(-)(6) M), carbamalonate (K(i) = 0.7 x 10(-)(6) M), and carbahydroxymalonate (K(i) = 0.3 x 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.

Borane complexes of the H3PO2 P(III) tautomer: useful phosphinate equivalents

“…However, the possibility to extend this chemistry to chiral borane complexes could provide an approach to asymmetric P-C bond-forming reactions. It is also important to note that the radical reactions of the Ciba-Geigy reagents 1 and 2 , are either inefficient, or require specialized initiators 15. Thus, the new synthons described herein provide added flexibility in terms of the range of available reactions.…”

Identification of Novel Polyphenolic Inhibitors of Shikimate Dehydrogenase (AroE)

“…1 The pathway has received considerable attention due in large part to the identification of one of its enzymes, 5-enolpyruvylshikimate-3-phosphate (EPSP) synthase, as the cellular target of the herbicide, glyphosate (N-(phosphonomethyl) glycine). 2 While a number of studies have sought to identify inhibitors of other enzymes in the pathway, [3][4][5][6][7][8][9] a relatively small number of compounds have been identified that block the pathway's fourth reaction, the NADPH-dependent conversion of 3-dehydroshikimate to shikimate. [10][11][12] This reaction is catalyzed by shikimate dehydrogenase (AroE).…”

Synthesis and in vitro evaluation of aspartate transcarbamoylase inhibitors

“…Phosphorus-free carboxylate compounds 38 , 40 , and 42 were synthesized because similar carboxylate-containing compounds significantly inhibited the enzyme 3-dehydroquinate synthase (DHQS),26 and replacing a phosphonate with carboxylate(s) has significant implications for the design of prodrugs 27. DHQS was established as an example of an enzyme which exploits a phosphate residue in its substrate to achieve catalytic efficiency 28.…”

“…In the inhibition of DHQS, some dicarboxylates were very potent (nanomolar-level) inhibitors and therefore good mimics of the phosphate moiety 26. Even the simplest monocarboxylate analog displayed an inhibition constant comparable to the Michaelis constant (K m ) of the substrate (DAHP).…”