Why is NAD+ regioselectively reduced at C-4 to form NADH?

[![NAD+ and NADH](https://i.stack.imgur.com/yx4rb.jpg)](https://i.stack.imgur.com/yx4rb.jpg)


We could draw a resonance form with the pi electrons shifting, placing a positive charge on C-4, to which a $\ce{H+}$ along with 2 electrons are added. Thus we get an NADH molecule as shown in the picture.


If this is how the reaction happens, then why doesn't the hydrogen get added to C-2 (or C-6 which is equivalent)? There's also a resonance form where C-2 has a positive charge and could accept a hydride ion. Why doesn't this happen?




Living organisms utilize protein based enzymes to catalyze otherwise unfavorable reactions under very mild conditions. They achieve this by bringing the substrates together in a very specific manner. [Dehydrogenases](https://en.wikipedia.org/wiki/Dehydrogenase) are a class of oxidoreductases that oxidize substrates using NAD$^+$. Here is the active site of [lactate dehydrogenase](https://en.wikipedia.org/wiki/Lactate_dehydrogenase):


[![lactate reductase](https://i.stack.imgur.com/AUXdy.png)](https://i.stack.imgur.com/AUXdy.png)


As you can see, carbon-4 of the nicotinamide ring is oriented towards the substrate. The orientation of the molecules is why carbon-4 is selectively reduced.


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