Histidine in proteins

Wilchek, M., Ben-Hur, H., and Bayer, E.A. (1986) p-Diazobenzoyl biocytin—A new biotinylating reagent for the labeling of tyrosines and histidines in proteins. Biochem. Biophys. Res. Comm. 138, 872-879. 

Histidine is often dassified as a basic amino acid because it has a version of an amino group in the imidazole ring of its R group. However, its pK of 6,5-7 is close to neutral. Nevertheless, at physiologic pH, a (variable) percentage of the histidine in proteins will carry a positive charge and so it best fits that classification. 

Huebner, V.D. Matthews, H.R. Phosphorylation of histidine in proteins by a nuclear extract of Physarum polycephalum plasmodia. J. Biol. Chem., 260, 16106-16113 (1985)... 

Kundig, W., Ghosh, S. and Roseman, S. 1964. Phosphate bound to histidine in protein as an intermediate in a novel phosphotransferase system. Proc. Natl. Acad Sci. USA 52, 1067-1074. 

Protein ( histidine ) Methyltransferase. An enzyme which methylates histidine in proteins to give primarily 3-methylhistidine residues has been observed in myofibrillar protein and in the sarcoplasmic fraction of muscle homogenates (218). S-Adenosyl-L-methionine serves as the methyl donor for the enzyme. The enzyme has not been solubilized and purified. Very little is known about the substrate specificity of protein-(histidine) methyltransferase. Actins from a wide variety of species consistently contain one 3-N-methylhistidine residue per molecule (191, 219). It appears that myosin from white muscle contains two residues of 3-N-methylhistidine (one residue per heavy chain), whereas myosin from red muscle contains no 3-N-methylhistidine (220). The amino acid sequence around the methylated residue of rabbit skeletal muscle is (221) ... 

As expected for a biosynthetic pathway [7], the activity of the first enzyme (PR-ATP synthetase ) is controlled by the end product of the pathway [8]. At the pH used in the standard assay, pH 8.5, feedback inhibition by histidine is noncompetitive with respect to both substrates (PRPP and ATP), having a Ki of 100 fiM. When the pH is reduced to one more likely representative of that in the cell, pH 7.5, the strength of the inhibition is about doubled [8]. Feedback-resistant mutants of the PR-ATP s)mthetase have been obtained by selecting for resistance to the histidine analog 2-thiazolealanine (for structure, see Fig. 2). This analog does not substitute for histidine in proteins, but inhibits the PR-ATP synthetase [8,11,12], and thereby produces bacteriostasis in the sensitive cell by cutting off its histidine supply. Feedback-resistant mutants excrete Itistidine into the medium, whereas... 

The and nmr spectra of [Co(NH3)5(ImH)] and the nmr spectra of d5-a-[Co(trien)(ImH)2] and cis-a [Co(trien)(ImH)2] have been recorded (ImH = imidazole). The values of coordinated imidazole determined from the dependence of the chemical shift on pH are 10.0,9.6, and 10.1, respectively. The C-2 proton is not exchanged with solvent deuterium under acidic or basic conditions, in marked contrast to the rapid exchange observed in free imidazole and 1-methyl imidazole. Lack of C-2 exchange should be useful for the identification of metal-coordinated histidines in proteins. 

Moreover, OH-Cbl binding to plasma proteins can be prevented by N-ethyl-maleimide, p-hydroxomercuribenzoate, or iodoacetamide, which are aU SH-directed agents. In addition, Cd ions not only bind to histidine in proteins, but can also block SH groups (77). This observation has been confirmed in our laboratory in 1% acetic acid and hot ethanol extracts of human plasma using protein-SH group detection with 5,5 -dithio-bis-(2-nitrobenzoic acid, DTNB) according to Sedlak and Lindsay (78). 

Ovadi J, Libor S and Elodi P (1967) Spectophotometric determination of histidine in proteins with diethylpyrocarbonate, Acta Biochim. Biophys. 

Figure 1.9 Examples of functionally important intrinsic metal atoms in proteins, (a) The di-iron center of the enzyme ribonucleotide reductase. Two iron atoms form a redox center that produces a free radical in a nearby tyrosine side chain. The iron atoms are bridged by a glutamic acid residue and a negatively charged oxygen atom called a p-oxo bridge. The coordination of the iron atoms is completed by histidine, aspartic acid, and glutamic acid side chains as well as water molecules, (b) The catalytically active zinc atom in the enzyme alcohol dehydrogenase. The zinc atom is coordinated to the protein by one histidine and two cysteine side chains. During catalysis zinc binds an alcohol molecule in a suitable position for hydride transfer to the coenzyme moiety, a nicotinamide, [(a) Adapted from P. Nordlund et al., Nature 345 593-598, 1990.)...

Histidine is one of the 20 naturally occurring amino acids commonly found in proteins (see Chapter 4). It possesses as part of its structure an imidazole group, a five-membered heterocyclic ring possessing two nitrogen atoms. The pAl for dissociation of the imidazole hydrogen of histidine is 6.04. 

Certain amino acids and their derivatives, although not found in proteins, nonetheless are biochemically important. A few of the more notable examples are shown in Figure 4.5. y-Aminobutyric acid, or GABA, is produced by the decarboxylation of glutamic acid and is a potent neurotransmitter. Histamine, which is synthesized by decarboxylation of histidine, and serotonin, which is derived from tryptophan, similarly function as neurotransmitters and regulators. /3-Alanine is found in nature in the peptides carnosine and anserine and is a component of pantothenic acid (a vitamin), which is a part of coenzyme A. Epinephrine (also known as adrenaline), derived from tyrosine, is an important hormone. Penicillamine is a constituent of the penicillin antibiotics. Ornithine, betaine, homocysteine, and homoserine are important metabolic intermediates. Citrulline is the immediate precursor of arginine. 

Special attention has been given to the study of tautomeric equilibria in solutions of histidine 22 because the key functional role of such equilibria in proteins is recognized. In aqueous solutions the tautomers of histidine rapidly interconvert and only a single averaged signal is observed for each ring nitrogen (Scheme 10). 

Pyrimidine and imidazole rings are particularly important in biological chemistry. Pyrimidine, for instance, is the parent ring system in cytosine, thymine, and uracil, three of the five heterocyclic amine bases found in nucleic acids An aromatic imidazole ring is present in histidine, one of the twenty amino acids found in proteins. 

In general, the resonance Raman spectra reveal strong structural similarity of the Fe " site in Rieske proteins and in proteins containing a 4-cysteine coordinated [2Fe-2S] cluster, while additional modes are observed for vibrations involving the Fe" site and the histidine ligands. 

In contrast to the lability of certain dN adducts formed by the BHT metabolite above, amino acid and protein adducts formed by this metabolite were relatively stable.28,29 The thiol of cysteine reacted most rapidly in accord with its nucleophilic strength and was followed in reactivity by the a-amine common to all amino acids. This type of amine even reacted preferentially over the e-amine of lysine.28 In proteins, however, the e-amine of lysine and thiol of cysteine dominate reaction since the vast majority of a-amino groups are involved in peptide bonds. Other nucleophilic side chains such as the carboxylate of aspartate and glutamate and the imidazole of histidine may react as well, but their adducts are likely to be too labile to detect as suggested by the relative stability of QMs and the leaving group ability of the carboxylate and imidazole groups (see Section 9.2.3). 

Lee K, Fitch CA, Lecomte JT, Garcfa-Moreno EB (2002) Electrostatic effects in highly charged proteins Salt sensitivity of pKa values of histidines in staphylococcal nuclease. Biochemistry 41 5656-5667. 

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