Imidazole/imidazolium groups histidine

Imidazolium groups of histidine are essential for the transfer of a hydrogen ion to the displaced fructosyl moiety [12], The reprotonation of the imidazole takes place by abstracting a proton from the C6 hydroxyl moiety and facilitating the formation of the glycosidic linkage. 

Figure 4 The enzyme ribonuclease A cleaves RNA using the imidazole group of histidine 12 as a base and the imidazolium group of histidine 119 as an acid in a simultaneous two-proton transfer process. Studies discussed in this article indicate that the process is not as simple as shown.

Buffer function of the imidazole/imidazolium functional groups of histidine residues in protein. 

The mechanism of hydrolysis of cysteine peptidases, in particular cysteine endopeptidases (EC 3.4.22), shows similarities and differences with that of serine peptidases [2] [3a] [55 - 59]. Cysteine peptidases also form a covalent, ac-ylated intermediate, but here the attacking nucleophile is the SH group of a cysteine residue, or, rather, the deprotonated thiolate group. Like in serine hydrolases, the imidazole ring of a histidine residue activates the nucleophile, but there is a major difference, since here proton abstraction does not appear to be concerted with nucleophilic substitution but with formation of the stable thiolate-imidazolium ion pair. Presumably as a result of this specific activation of the nucleophile, a H-bond acceptor group like Glu or Asp as found in serine hydrolases is seldom present to complete a catalytic triad. For this reason, cysteine endopeptidases are considered to possess a catalytic dyad (i.e., Cys-S plus H-His+). The active site also contains an oxyanion hole where the terminal NH2 group of a glutamine residue plays a major role. 

A typical role for the histidine imidazole ring is shown below, in the enzyme mechanism for a general base-catalysed hydrolysis of an ester. The imidazole nitrogen acts as a base to remove a proton from water, generating hydroxide that attacks the carbonyl. Subsequently, the alkoxide leaving group is reprotonated by the imidazolium... 

The imidazolium ion is much more reactive (k = 4x 10 M-1 sec-1) (Braams, 1966) than the base. This may be explained by the strong inductive effect of the ammonium group on the C=N— reactive centre. Histidine shows good agreement with the behaviour of imidazole k = 3-9 x 10 M-1 sec-1 for the acid form and 1-2 x 107 m-1 sec-1 for the basic form (Braams, 1966). 

Resonance and tautomerism are closely related. Thus the acidity of carbon-bound hydrogen in ketones, which allows formation of enol tautomers, is a direct result of the fact that the enolate anion produced by dissociation of one of these hydrogen atoms is stabilized by resonance. Similarly, tautomerism in the imidazole group of histidines is related to resonance in the imidazolium cations. 

We have now to consider the covalent iron- obin linkage. In accordance with arguments presented in earlier sections, we assume that this is with one of the nitrogen atoms of the imidazole group of histidine. In free histidine in acid solution this group exists in the form of the imidazolium ion ... 

Of these B, which is the only one with significant acid properties, is almost wholly suppressed, and this accountsfor thefact that the free imidazolium ion is a monobasic acid. Bonding with the iron occurs only with the dissociated form and in acid solution leads to the displacement of a proton. We may therefore represent the covalent linkage of the ferrous iron and imidazole group of histidine by means of the three resonating structures ... 

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