Cyanide as a copper and quinone-directed inhibitor of amine oxidases from pea seedlings (Pisum sativum) and Arthrobacter globiformis: evidence for both copper coordination and cyanohydrin derivatization of the quinone cofactor

Abstract

The interactions of cyanide with two copper-containing amine oxidases (CuAOs) from pea seedlings (PSAO) and the soil bacterium Arthrobacter globiformis (AGAO) have been investigated by spectroscopic and kinetic techniques. Previously, we rationalized the effects of azide and cyanide for several CuAOs in terms of copper coordination by these exogenous ligands and their effects on the internal redox equilibrium TPQ(amr)-Cu(II) right harpoon over left harpoon TPQ(sq)-Cu(I). The mechanism of cyanide inhibition was proposed to occur through complexation to Cu(I), thereby directly competing with O(2) for reoxidation of TPQ. Although cyanide readily and reversibly reacts with quinones, no direct spectroscopic evidence for cyanohydrin derivatization of TPQ has been previously documented for CuAOs. This work describes the first direct spectroscopic evidence, using both model and enzyme systems, for cyanohydrin derivatization of TPQ. K(d) values for Cu(II)-CN(-) and Cu(I)-CN(-), as well as the K(i) for cyanide inhibition versus substrate amine, are reported for PSAO and AGAO. In spite of cyanohydrin derivatization of the TPQ cofactor in these enzymes, the uncompetitive inhibition of amine oxidation is determined to arise almost exclusively through CN(-) complexation of Cu(I).

Probing the Catalytic Mechanism of Copper Amine Oxidase from Arthrobacter globiformis with Halide Ions

“…For AGAO, cyanide is an uncompetitive inhibitor with respect to the amine substrate, and azide is a noncompetitive inhibitor with respect to both amine and dioxygen (57,61). Although the inhibition patterns of halide ions (uncompetitive and noncompetitive with respect to amine substrate and dioxygen, respectively) (Fig.…”

“…Monovalent anions, such as cyanide and azide, were reported to be inhibitors of various CAOs, showing competitive, noncompetitive, uncompetitive, or mixed type inhibition with respect to the amine substrate and dioxygen (57,61,62). For AGAO, cyanide is an uncompetitive inhibitor with respect to the amine substrate, and azide is a noncompetitive inhibitor with respect to both amine and dioxygen (57,61).…”

“…7F and 8 (D and E) and Table 3). These are the first x-ray crystal structures of CAO with an anionic inhibitor (57,61,62) bound to the active site copper center. In contrast, the axial position in AGAO NaBr was occupied by a water molecule rather than Br Ϫ (Fig.…”

Part III. keyword-based, boolean-logic driven data-mining discloses correlations between additional idiopathic conditions, occlusive vascular diseases such as tropical endomyocardial fibrosis with unexplained eosinophilia, and ‘histamine dysmetabolism’

“…5. Cyanide is a potent (uncompetitive) inhibitor of copper-containing amine oxidases [5], (7771783); such amine oxidases are instrumental to histamine degradation (see citation no. 1 in [3]).…”

Quinoid systems in chemistry and pharmacology

“…20). Furthermore, the cyanide can add to the quinone nucleus, generating inactive derivatives (Shepard et al, 2004).…”