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Monday 7 April 2014

A mechanism model for NHase using a cyclic and a disulfide intermediate.


There is a very interesting paper proposing a new mechanism for the hydration reaction of iron-centred NHases published in Inorganic Chemistry by Kathrin Hopmann. The paper, entitled "Full Reaction Mechanism of Nitrile Hydratase: A Cyclic Intermediate and an Unexpected Disulfide Switch" sides with the opinion that the nitrile ligates to the iron centre. Hopmann suggests that the oxygen of the cysteine post-translationally modified to a sulfenic acid then acts as the nucleophile attached the C-N bond.

 


This oxygen is the one that becomes the oxygen in the nascent amide carbonyl, with the two cysteine sulfurs combining to form a disulfide link.



After loss of the amide from the iron centre, the cysteine is oxidized again using an oxygen from water. My suspicion with all these mechanistic investigation is that it may be that a lot of different mechanisms may operate with the dominant one being very tied to the specific sequence/space properties of each enzyme. I have been a fan of nitrile-bound mechanisms solely on the basis that they seem much more likely to render chiral selectivity which we know is a possibility for some enzymes and some substrates.

I also wonder how the numbers from the calculations reported in this paper change for cobalt centre NHases.

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