Aldehyde Dehydrogenase - Mechanism

Mechanism

The overall reaction catalysed by the aldehyde dehydrogenases is:

  • RCHO + NAD+ + H2O → RCOOH + NADH + H+

In this NAD(P)+-dependent reaction, the aldehyde enters the active site through a channel located on the outside of the enzyme. The active site contains a Rossman fold, and interactions between the cofactor and the fold allow for the isomerization of the enzyme while keeping the active site functional.

A sulfur from a cysteine in the active site makes a nucleophilic attack on the carbonyl carbon of the aldehyde. The hydrogen is kicked off as a hydride and attacks NAD(P)+ to make NAD(P)H. The enzyme's active site then goes through an isomorphic change whereby the NAD(P)H is moved, creating room for a water molecule to access the substrate. The water is primed by a glutamate in the active site, and the water makes a nucleophilic attack on the carbonyl carbon, kicking off the sulfur as a leaving group.

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