Histidine, imidazole side chain

A second example illustrates how hydrogen bonding interactions may stabilize the more oxidized form of a redox cofactor. The porphyrin iron in heme proteins is often liganded by a histidine imidazole side chain. The imidazole is frequently... 

The imidazole side-chain of histidine has a value of 6.0, making it a weaker base than the unsubstituted imidazole. This reflects the electron-withdrawing inductive effect of the amino group, or, more correctly the ammonium ion, since amino acids at pH values around neutrality exist as doubly charged zwitterionic forms (see Box 4.7). Using the Henderson-Hasselbalch equation, this translates to approximately 9% ionization of the heterocyclic side-chain of histidine at pH 7 (see Box 4.7). In proteins, plCa values for histidine side-chains are estimated to be in range 6-7, so that the level of ionization will, therefore, be somewhere between 9 and 50%, depending upon the protein. 

In general, there are several chemical ambiguities regarding the imidazole side chain of histidine as it is observed in protein structures. For example, the protonation state of histidine cannot be ascertained from X-ray crystallographic experiments, and this is of particular concern because the near-physiological first pK of the imidazole side chain is about 6.0—6.5. The second pXa of histidine is about 14.0—14.5, and this value may be lowered 2 units by imidazole coordination to a metal ion (Tainer eprotein structures as the protonated imidazolium or as the neutral imidazole, and even sometimes as the deprotonated imidazolate. 

Why is it advantageous to regulate pH in a temperature-dependent fashion, as shown in figure 7.16 The hypothesis of Austin et al. (1927) provides a partial answer to this question, an answer that has been elaborated in detail by Reeves, Rahn, Howell, and their colleagues (Rahn et al., 1975 Reeves, 1977). In essence, the temperature-dependent variation in pH and pHB conserves the ionization states of proteins in all cellular compartments. The component of the protein that is pivotal in this relationship is the imidazole side-chain of histidine. 

Protonated and deprotonated states of the imidazole side-chain of histidine... 

Buffering capacity of blood. Albumin provides a significant buffering capacity of blood, due mainly to the presence of histidine and the buffering potential of the imidazole side chain. 

Amino acid side chains with pK, values below 7, such as aspartic acid or glutamic acid, will be deprotonated at pH 7 and, therefore, wiU be used normally in general base catalysis. Amino acid side chains with pK, values above 7, such as lysine or tyrosine, will be protonated at pH 7 and, therefore, will be used normally in general acid catalysis. The imidazole side chain of histidine has a pKa value of 6-8 and, therefore, might... 

The synthesis of histidine-containing peptides without protection of the imidazole side chains is feasible, but it can be inconvenient and unsatisfactory because of the basic, nucleophilic and hydrophihc character of such side chains. /w-Nitrogens can react with electrophilic reagents such as Ar,AT -dicyclohexylcarbodiimide,W catalyze undesirable acyl-transfer reactions,Pl and cause loss of chiral integrity at the histidine a-carbon.t l Side-chain protection has therefore generally been employed. 

Figure 2-6. Titration curves for glycine (A) and histidine (6). The molecular species of glycine present at various pHs are indicated by the molecules above the curve. For histidine, pKa is the dissociation constant of the imidazole (side chain) group.

Yan, S. and Bu, Y. (2005) Coupling properties of imidazole dimer radical cation assisted by embedded water molecule toward understanding of interaction character of hydrogen-bonded histidine residue side-chains, J. Chem. Phys. 122, 184324. 

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