Mechanisms of ammonia activation and ammonium ion inhibition of quinoprotein methanol dehydrogenase: A computational approach
Authors: Reddy Swarnalatha Y. , Bruice Thomas C. 
Published: November 2004

The mechanism of methanol oxidation by quinoprotein methanol dehydrogenase (MDH·PQQ) in combination with methanol (MDH·PQQ·methanol) involves Glu-171

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\begin{equation*}{\mathrm{CO}}_{2}^{-}\end{equation*}\end{document}

general base removal of the hydroxyl proton of methanol in concert with hydride equivalent transfer to the

quinone carbon of pyrroloquinoline quinone (PQQ) and rearrangement to hydroquinone (PQQH
2
) with release of formaldehyde. Molecular dynamics (MD) studies of the structures of MDH·PQQ·methanol in the presence of activator NH
3
and inhibitor

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have been carried out. In the MD structure of MDH·PQQ·methanol·NH
3
, the hydrated NH
3
resides at a distance of ≈24 Å away from methanol and the
ortho
-quinone portion of PQQ. As such, influence of NH
3
on the oxidation reaction is not probable. We find that

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competes with the substrate by hydrogen-bonding to Glu-171

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such that the

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\begin{equation*}{\mathrm{MDH}}{\cdot}{\mathrm{PQQ}}{\cdot}{\mathrm{methanol}}{\cdot}{\mathrm{NH}}_{4}^{+}\end{equation*}\end{document}

complex is not reactive. Ammonia readily forms imines with quinone. Imines are present in solution as neutral (

) and protonated (

) species. MD simulations establish that the

derivative of

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\begin{equation*}{\mathrm{MDH}}{\cdot}{\mathrm{PQQ}}({\mathrm{NH}}_{2}^{+}){\cdot}{\mathrm{methanol}}\end{equation*}\end{document}

structure is unreactive because of the nonproductive means of methanol binding. The structure obtained by the MD simulations with the neutral

imine of MDH·PQQ(NH)·methanol structure is similar to the reactive MDH·PQQ·methanol complex. This active site geometry allows for catalysis of hydride equivalent transfer to the

of PQQ(NH) by concerted Glu-171

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general-base removal of the H

OCH
3
proton and Arg-324

H
+
general-acid proton transfer to the imine nitrogen. Enzyme-bound

derivative of PQQ [PQQ(NH)] and CH
2
O product are formed.