Question

Histidine is an important catalytic residue found at the active sites of many enzymes. In many cases, histidine appears to remove protons or to transfer protons from one location to another.

(a) Show which nitrogen atom of the histidine heterocycle is basic and which is not.

(b) Use resonance forms to show why the protonated form of histidine is a particularly stable cation.

(c) Show the structure that results when histidine accepts a proton on the basic nitrogen of the heterocycle and then is deprotonated on the other heterocyclic nitrogen. Explain how histidine might function as a pipeline to transfer protons between sites within an enzyme and its substrate.

Short answer

(a)

(b)

Resonance forms of protonated imidazole

(c)

Histidine serves the function of moving proton toward or away from particular site by using its different nitrogens as proton acceptor and proton donor.

Step-by-step solution

Step-1. Explanation of part (a):

Histidine has two type of nitrogen atoms; one is basic and other one is not basic. The nitrogen which is basic in nature do not have its lone pairs involved in the delocalisation whereas nitrogen atom which is not basic in nature has its lone pairs involved in the delocalisation process. As, basicity is the tendency of an atom to donate its lone pairs, thus, based on lone pair donation we can characterise two types of nitrogen in histidine.

Histidine

Step-2. Explanation of part (b):

In the protonated imidazole ring of histidine, the two nitrogen are similar in structure and both the N-H groups are acidic due to presence of positive charge on nitrogen atom, thus nitrogen will try to stabilise the positive charge on itself and attached hydrogen will become very acidic.

Resonance forms of protonated imidazole

Step-3. Explanation of part (c):

Conformational changes in the protein will move atoms closer or farther. Histidine serves the purpose of moving the proton toward or away from a particular site by using its different nitrogens as proton acceptor or proton donor. In enzyme active site, there is no solvent, so by the mechanism of proton acceptor or proton donor histidine serves as useful function of transferring protons between sites within an enzyme and its substrate.

Protonation and deprotonation in imidazole of histidine