The Imidazole Group of Histidine

FIGURE 6.10 The side chain of histidine is readily acylated (A) by activated residues. The imidazolide produced is an activated species similar to the intermediate generated by reaction (B) of a carboxylic acid with coupling reagent carbonyldiimidazole. (Staab, 1956). Imida-zolides acylate amino and hydroxyl groups. Isomerization of histidyl during activation results from abstraction (C) of the a-proton by the 7t-nitrogen. 

T Brown, JH Jones, JD Richards. Further studies on the protection of histidine side chains in peptide synthesis the use of the 7i-benzyloxylmethyl group. J Chem Soc Perkin Trans 1 1553, 1982. 

P Sieber, B Riniker. Protection of histidine in peptide synthesis a reassessment of the trityl group. Tetrahedron Lett 48, 6031, 1987. 

SJ Harding, I Heslop, JH Jones, ME Wood. The racemization of histidine in peptide synthesis. Further studies, in HLS Maia, ed. Peptides 1994. Proceedings of the 23rd European Peptide Symposium, Escom, Leiden, 1995, pp 189-190. 

Y Okada, J Wang, T Yamamoto, Y Mu, T Yokoi. Amino acids and peptides. Part 45. Development of a new N-protecting group of histidine, NK-( -adamantyloxymethyl)-histidine, and its evaluation for peptide synthesis. J Chem Soc Perkin Trans 1 2139. 1996. 

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Figure 3.2 Examples of amino adds with electron-donating or electron-withdrawing groups. An electron is represented by e. Note that the imidazole group of histidine can either donate or withdraw electrons.

Now let us see how the imidazole grouping of histidine can be involved in the general acid-catalysed and general base-catalysed hydrolysis of esters by enzymes. In essence, the chemical and enzymic reactions are very similar. This is to be... 

Buffers are often added to maintain a constant pH in biochemical research6 and naturally occurring buffer systems within body fluids and cells are very important (Box 6-A). Among the most important natural buffers are the proteins themselves, with the imidazole groups of histidine side chains providing much of the buffering capacity of cells around pH 7 (Figs. 3-1 and 3-2). Table 3-1 lists some useful biochemical buffers and their pKa values. Here are a few... 

Imidazole Groups. The imidazole group of histidine side chains is modified by alkylations of the nitrogens or by nucleophilic attack of the... 

The mechanism of the inhibitory reaction is uncertain, although two proposals have gained some currency (115-118). One of these invokes activation of histidine, which is then subject to an unexpectedly selective nucleophilic attack by AT (or some related compounds) (115, 116). The other demands compulsory two-electron equivalent oxidation of AT (117, 118), giving an electrophilic intermediate which, prior to its solvation, reacts with the imidazole group of histidine. Although AT is an... 

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.

As P or a approach zero basic or acidic catalysis is indetectable. Thus, general base or general acid catalysis is most significant when P or a is in the neighborhood of 0.5. Under these circumstances it is easy to see how a moderately weak basic group, such as the imidazole group of histidine, can be an unusually effective catalyst at pH 7. 

With the involvement of the imidazole group of histidine as a general base, as we deduced in the first part of the question, we can fill in more details r)f this outline mechanism. If the ester and the... 

Figure 37.2 depicts the action of chymolrypsin, with the imidazole group of histidine-57 playing the same role of general base as that just described—and with protonated imidazole necessarily acting as general acid. There is general acid-base catalysis of both reactions involved first, in the formation of the acyl enzyme, and then in its hydrolysis. 

The imidazole group of histidine is the most important buffer group in the physiological pH range... 

Plasma Protein Buffer System and Plasma Base Excess The buffer value (p) of the nonbicarbonate buffers of plasma is about 7.7 mmol/L at pH 7.40 and a normal plasma protein concentration of 72 g/L. Proteins, especially albumin, account for the greatest portion (95%) of the nonbicarbonate buffer value of the plasma. The most important buffer groups of proteins in the physiological pH range are the imidazole groups of histidines (pimolecule contains 16 histidines. 

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