NAD-Dependent Oxidation of Ethanol

The oxidation of an alcohol to a carbonyl group is a common metabohc reaction. The reverse reaction, reduction of a carbonyl compound to an alcohol, is also common. In fact, the two related reactions often occur by the same mechanism, with the direction of the reaction controlled by needs of the cell. The two reactions transfer a hydride ion either to or from carbon atoms bonded to the oxygen atom in the substrate to a carbon atom of a coenzyme. 

In human liver cells, the enzyme alcohol dehydrogenase (LADH) catalyzes the oxidation of ethanol to yield acetaldehyde. In this reaction, the coenzyme nicotinamide adenine dinucleotide, NAD, is converted to its reduced form, NADH. 

The stereochemistry of the oxidation of ethanol and the reduction of acetaldehyde has been determined using deuterium-labeled reactants. Reaction of 1-deutero-ethanol with NAD occurs to give NADH-4- l with the R configuration at the C-4 ring atom. Therefore, the hydride ion was transferred to the re face. 

In the reverse reaction, the reduction acetaldehyde by (/ )-NADH-4-zif. Only the deuterium is transferred yielding (J )-l-pH]-ethanol even though cleaving a C—D bond requires more energy than cleaving a C—H bond. We conclude that the arrangement of the reactants within the reactive site of the enzyme places the deuterium in a position to be transferred to the carbonyl carbon atom. The plane of NAD and the plane of acetaldehyde are arranged so that the two re faces are next to each other. As a consequence, the deuterium is stereospecifically transferred. 

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