Synthesis of 7,9-didecarboxymethoxatin (4,5-dihydro-4,5-dioxo-1H-pyrrolo[2,3-f]quinoline-2-carboxylic acid) and comparison of its chemical properties with those of methoxatin and analogous o-quinones. Model studies directed toward the action of PQQ requiring bacterial oxidoreductases and mammalian plasma amine oxidase

Abstract

The synthesis of 4,5-dihydro-4,5-dioxo-l/f-pyrrolo[2,3-/]quinoline-2-carboxylic acid (7,9-didecarboxymethoxatin, 70X) and its ester (60X) are described and their acid-base properties, electrochemistry, and chemical properties are compared to the cofactor Methoxatin, as well as to those of other o-quinones. The two-electron redox potentials of 60x and 70x are shown to be ca. 110 mV less than those of the penanthroline-5,6-quinones but to be comparable to those of methoxatin at all pH values. Replacement of the pyridine ring of 70X by a benzene ring reduces its oxidation potential by 100 mV. 70x forms a C-5 adduct with acetone and a cyclic bis(carbinolamine) adduct with urea. The rate constants for formation and dissociation of the urea adducts of methoxatin, 60X, and the most electrophilic phenanthrolinequinone (30x) are compared. The o-quinone

Mechanism of methanol oxidation by quinoprotein methanol dehydrogenase

“…Evidence Against Asp-297-CO 2 ؊ Being the General Base in the Oxidation of CH3OH 3 CH2O. In the 3-ns MD simulations (6,7,9) Ϫ becomes coordinated to Ca 2ϩ after Ϸ1.8 ns time (Fig.…”

“…This MD derived structure is not in accord with the following: (i) the suggestion that Asp-297-CO 2 Ϫ serves as the general-base catalyst (14)(15)(16)(17); and (ii) that the oxidation takes place, not by hydride transfer, but by an addition elimination reaction (18,19) (Scheme 1, in which the general base may be Glu-171-CO 2 Ϫ or Asp-297-CO 2 Ϫ ). The MD studies (6,7,9) showed that Asp-297-CO 2 Ϫ is not in position to act as a generalbase catalyst for the oxidation of MeOH by MDH.…”

“…After the departure of CH 2 (OH) 2 , rearrangement (Scheme 3) to provide the cofactor hydroquinone is exothermic by Ͼ4.1 kcal/mol at the SCCDFTB/MM level. Thus, the overall reaction, MeOH ϩ o-quinone ϩ Wat1 3 CH 2 (OH) 2 ϩ semiquinone, is favorable.…”

“…The crystal structure (PDB code 1G72; ref. 10) of the reduced PQQ bound to MDH presents Wat1 hydrogen bonding to the -CO 2 Ϫ group of Asp-297 (Asp-297-CO 2 Ϫ ) and ϪCO 2 Ϫ group of Glu-171 (Glu-171-CO 2 Ϫ ) associated with Ca 2ϩ . Attempts to crystallize MDH with MeOH substrate at the active site have not yet been successful (10,12,13).…”

“…During 3-ns molecular dynamics (MD) simulations (6,7,9) with MeOH at the active site, it was found that MeOH became hydrogen bonded to Glu-171-CO 2 Ϫ , with the C-H of MeOH adjacent to the quinone C5 of PQQ and Wat1 hydrogen bonded to Asp-297-CO 2 Ϫ . This MD derived structure is not in accord with the following: (i) the suggestion that Asp-297-CO 2 Ϫ serves as the general-base catalyst (14)(15)(16)(17); and (ii) that the oxidation takes place, not by hydride transfer, but by an addition elimination reaction (18,19) (Scheme 1, in which the general base may be Glu-171-CO 2 Ϫ or Asp-297-CO 2 Ϫ ).…”