Histidine acid-base properties

The imidazole ring of histidine acid-base properties... 

Of the same importance is another component of the mechanism—the display of acid-base properties of His 552 fragment. According to X-ray patterns, among two probable mechanisms of distal histidine interaction with hydrogen bond formation ... 

The basicity of imidazole was thoroughly covered in CHEC(1984) and CHEC-II(1996). The ambivalent acid-base properties of imidazole play an important role in the biochemical activity of the histidine unit. 

Langella E, Improta R, Crescenzi O, Barone V (2006) Assessing the acid-base and conformational properties of histidine residues in human prion protein (125-228) by means of pKa calculations and molecular dynamics simulations. Proteins Struct Funct Bioinform 64 167... 

The imidazole ring, with a physiological pH value of 7.4, exists in the histidine building blocks of proteins as a free base and as a conjugate acid (pAT = 7.00, see p 166) because of a regulating acid-base equilibrium. Especially in enzymes, the ring can act as a Bronsted base or as a Bronsted acid as the occasion demands, i.e. it acts as a buffer. It is also able to form complexes with metal ions. Such properties are not found in any other proteinogenic amino acids [119]. 

Baltzer s group has recently described a fully-synthetic protein that is also capable of hydrolysing p-nitrophenyl esters the polypeptide, which contains 42 amino acids, was designed to fold into a hairpin helix-loop-helix motif that dimerises into a four-helix bundle. The dimer is predicted to present on its surface a shallow reactive site containing several histidine residues. The spectroscopic properties of the peptide are consistent with the predicted folded structure, and the molecule does indeed catalyse ester hydrolysis (and transesterification) more effectively than 4-methylimidazole does. However, there is little substrate selectivity, and not much turnover. The histidine array does not seem to act via general acid-base catalysis, but rather to bind and stabilise ester oxygens in the transition state. We return to this molecule below. 

A possible explanation for the preference of living systems for the L (levorotatory) over the D (dextrorotatory) optical isomer may be associated with the stereoselective properties of layered minerals. To test this hypothesis, the rates of L- and D-histidine intercalation into HT layered compound was investigated using the pressure-jump relaxation technique (21). The rate constants and interlayer spacing based on this investigation are summarized in Table V. As shown the slightly enhanced rate for L-histidine suggests that relative chemical reactivity may be associated with natural selection of the L-form of amino acids in nature. 

As with any metalloprotein, the chemical and physical properties of the metal ion in cytochromes are determined by the both the primary and secondary coordination spheres (58-60). The primary coordination sphere has two components, the heme macrocycle and the axial ligands, which directly affect the bound metal ion. The pyrrole nitrogen donors of the heme macrocycle that are influenced by the substitutents on the heme periphery establish the base heme properties. These properties are directly modulated by the number and type of axial ligands derived from the protein amino acids. Typical heme proteins utilize histidine, methionine, tyrosinate, and cysteinate ligands to affect five or six coordination at the metal center. 

Based on the properties of the side chains, the 20 amino acids can be put into six general classes. The first class contains amino acids whose side chains are aliphatic, and is usually considered to include glycine, alanine, valine, leucine, and isoleucine. The second class is composed of the amino acids with polar, nonionic side chains, and includes serine, threonine, cysteine, and methionine. The cyclic amino acid proline (actually, an imino acid) constitutes a third class by itself. The fourth class contains amino acids with aromatic side chains tyrosine, phenylalanine, and tryptophan. The fifth class has basic groups on the side chains and is made up of the three amino acids lysine, arginine, and histidine. The sixth class is composed of the acidic amino acids and their amides aspartate and asparagine, and glutamate and glutamine. 

Classically, the bell-shaped dependence of rate of the enzymic reaction on pH has been attributed to general acid and base catalysis by the two histidine residues in the active site, His-12 and His-119 (66). Support for this explanation based on the kinetic properties of a model system was first provided by an observation by Breslow and co-workers that 8-cyclodextrin functionalized with two imidazole groups will catalyze the 1,2-cyclic phosphate of 4-rert-butylcatechol (67). The dependence of hydrolysis rate on pH mimics that of RNase A, and this behavior demonstrates that the presence of two imidazole functional groups on a nonionizable framework is the simplest kinetic mimic of the enzyme. 

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